Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[Cl:21][CH2:22][C:23](Cl)=[O:24]>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:23](=[O:24])[CH2:22][Cl:21])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)CCl)c3C2=O)C(=O)N1

Procedure:
To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.37 g, 5.00 mmol) in THF (30 ml) was added chloroacetyl chloride-(0.62 g, 5.5 mmol). The mixture was heated to reflux for 30 minutes. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 1.67 g (96-%) of product as an off-white solid: 1H NMR (DMSO-d6) δ 11.18 (s, 1H), 10.31 (s, 1H), 8.54 (d, J=8.4 Hz, 1H), 7.88 (t, J=7.7 Hz, 1H), 7.68 (d, J=7.3 Hz, 1H), 5.17 (dd, J=5.2 and 12.7 Hz, 1H), 4.54 (s, 2H), 2.90-2.85 (m, 1H), 2.65-2.51 (m, 2H), 2.10-2.06 (m, 1H).
Reaction SMILES: [NH2:1][C:2]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][N:4]1[C:11](=[O:29])[C:12]([OH:28])=[C:13]([C:15]3[NH:16][CH:17]=[C:18]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[N:19]=3)[N:14]=[C:3]21.[CH3:30][N:31]([CH3:37])[C:32](=[O:36])[C:33](O)=[O:34].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:18]2[N:19]=[C:15]([C:13]3[N:14]=[C:3]4[C:2]5([NH:1][C:33](=[O:34])[C:32]([N:31]([CH3:37])[CH3:30])=[O:36])[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]5)[CH2:5][N:4]4[C:11](=[O:29])[C:12]=3[OH:28])[NH:16][CH:17]=2)=[CH:22][CH:23]=1
Reactant: CN(C)C(=O)C(=O)O
Reactant: NC12CCC(CC1)Cn1c2nc(-c2nc(Cc3ccc(F)cc3)c[nH]2)c(O)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(=O)NC12CCC(CC1)Cn1c2nc(-c2nc(Cc3ccc(F)cc3)c[nH]2)c(O)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 8 %

Procedure:
To a stirred solution of 10-amino-2-(4-(4-fluorobenzyl)-1H-imidazol-2-yl)-3-hydroxy-7,8,9,10-tetrahydro-7,10-ethanopyrimido[1,2-a]azepin-4(6H)-one, Example 1 (27 mg, 0.068 mmol) and 2-(dimethylamino)-2-oxoacetic acid (11.99 mg, 0.102 mmol) in DMF (3 mL) was added N,N-diisopropylethylamine (0.061 mL, 0.35 mmol), DMAP (1.668 mg, 0.014 mmol) and HATU (38.9 mg, 0.102 mmol) and the resulting mixture stirred at room temp for 3 h. The mixture was then concentrated and purified by preparative HPLC to afford the title compound (6 mg, 8% yield) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ ppm 1.63-1.77 (m, 2H), 1.93-1.98 (m, 2H), 2.29-2.38 (m, 4H), 2.50 (br. s., 1H), 3.00 (s, 3H), 3.17 (s, 3H), 4.03 (s, 2H), 4.14 (s, 2H), 6.82 (br. s., 1H), 7.00 (t, J=8.39 Hz, 1H), 7.21-7.27 (m, 3H), 7.70 (s, 1H). LCMS (M+H)=495.20.
Reaction SMILES: C(I)(I)(I)I.[C:6]([C:16]([F:19])([F:18])[F:17])([C:12]([F:15])([F:14])[F:13])([C:8]([F:11])([F:10])[F:9])I>>[F:9][C:8]([F:11])([F:10])[C:6]([C:8]([F:11])([F:10])[F:9])([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13]
Reactant: FC(F)(F)C(I)(C(F)(F)F)C(F)(F)F
Agent: IC(I)(I)I
Product: FC(F)(F)C(C(F)(F)F)(C(F)(F)F)C(F)(F)F

Procedure:
Perfluoroneopentane is prepared from CI4 employing the apparatus described above. Five grams of carbon tetraiodide were placed in the Vycorcontainer and the reactor was evacuated to 0.1 mm pressure. The Vycor container is located as in the position shown in the FIGURE. Hexafluoroethane was admitted to the reactor at a flow rate of 15 cc/min to maintain a 0.5 to 1 mm pressure during constant pumping. The discharge was initiated at 10 megahertz and 20 watts using a radio frequency generator. After eight hours the products were removed along with fluorocarbons from a -196° C trap downstream from the reactor. The products were separated from fluorocarbons by trap to trap distillation and purified using liquid nitrogen-cooled columns of a gas chromatograph. A 55% yield of the white solid CI(CF3)3 was obtained, which had a F19N.M.R. singlet -13.3 ppm from external trifluoroacetic acid. The mass spectrum contained a parent at 346 and a P-19 peak at 327. The infrared spectrum contained peaks at (1270) (960) and (725) cm-1. The elemental analysis was in agreement with the calculated values. The perfluoroneopentane C(CF3)4 was obtained in 25% yield and is a white solid melting at 72.5° to 73° C.The mass spectrum of the compound contains a P-19 at 269 while the F19N.M.R. consists of a singlet at -13.92 ppm from external trifluoroacetic acid. The infrared spectrum contains peaks at (9.80) (720) and 1190 cm-1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=O)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:19]1[C:20](=[O:29])[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:30][CH2:31][C:32]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)=[O:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O-]S([O-])(=O)=O.[Mg+2].[H-]>ClC(Cl)C.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][N:37]3[CH2:38][CH2:39][N:34]([C:32](=[O:33])[CH2:31][OH:30])[CH2:35][CH2:36]3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:19]1[C:20](=[O:29])[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CO)N1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3[nH]c2=O)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3[nH]c2=O)cc2cc(CN3CCN(C(=O)CO)CC3)ccc21
Reaction time: 3 h
Yield: 56.8 %

Procedure:
To a stirred solution of the aldehyde (5-8, 2.01 g, 5.15 mmol, 1 equiv) and N-(2-hydroxyacetyl)piperazine (2.97 g, 20.60 mmol, 4 equiv) in dichloroethane (400 mL) was added at ambient temperature acetic acid (1.2 mL). The reaction mixture was treated with sodium triacetoxyborohydride and stirred for 3 h. The reaction stopped at 76% of conversion and treated with MgSO4 and additional 1 g of the hydride. After further stirring for 1 h the reaction was complete. The reaction mixture was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was once again washed with saturated aqueous NaHCO3, and then with brine, separated, dried with (Na2SO4) and concentrated in vacuo. The crude solid was dissolved in N,N-dimethylformamide and treated with the activated carbon. The filtrate solution (celite) was concentrated to syrup which was quickly triturated with methanol (100 mL). The resulting solid was collected by filtration, redissolved in N,N-dimethylformamide, concentrated to syrup, triturated with methanol (100 mL), collected by filtration and vacuum-dried to give 5-[4-(2-hydroxy-ethanoyl)-piperazin-1-ylmethyl]-2-(2-oxo-1,2-dihydro-quinolin-3-yl)-indole-1-carboxylic acid tert-butyl ester (5-9, 1.51 g, 57%) as a white powder; 1H NMR (500 MHz, DMSO-d6) δ 12.24 (br s, 1H), 8.21 (d, 1H, J=8.7 Hz), 7.91 (s, 1H), 7.61 (d, 1H, J=6.9 Hz), 7.52 (s, 1H), 7.49 (m, 1H), 7.36 (d, 1H, J=8.1 Hz), 7.33 (dd, 1H, J=8.4, 1.5 Hz), 7.24 (m, 1H), 6.67 (s, 1H), 4.15 (s, 2H), 3.69 (m, 2H), 3.65 (s, 2H), 3.28 (m, 2H), 2.49 (m, 4H), 1.40 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[NH:6][C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:25]=2[C:26]([NH:28][CH2:29][CH3:30])=[O:27])[C:20]([Cl:36])=[CH:19][N:18]=1>>[Cl:36][C:20]1[C:21]([NH:23][C:24]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:25]=2[C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[N:22][C:17]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[NH:6][C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)=[N:18][CH:19]=1
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Reactant: CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl

Procedure:
2-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-ethyl-3-fluoro-benzamide was prepared from 7-amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-ethyl-3-fluoro-benzamide in an analogous manner to Example 308c. Product isolated as a yellow foam (213 mg, 51%). LCMS (m/e) 497 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.73 (s, 1H), 8.10 (s, 1H), 7.56 (d, 1H, J=8.5 Hz), 7.40-7.35 (m, 1H), 7.34-7.25 (m, 2H), 7.21 (s, 1H), 7.10 (s, 1H), 6.96 (s, 1H), 6.72 (d, 1H, J=8.5 Hz), 6.15-6.06 (m, 1H), 3.48-3.38 (m, 2H), 2.36 (t, 2H, J=6.8 Hz), 2.08 (t, 2H, J=6.8 Hz), 1.35 (s, 6H), 1.17 (t, 3H, J=7.3 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[F:9].[CH2:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1)[CH2:11][CH3:12].Cl>C(NCC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:20]#[C:19][C:16]2[CH:17]=[CH:18][C:13]([CH2:10][CH2:11][CH3:12])=[CH:14][CH:15]=2)=[CH:4][C:3]=1[F:9]
Reactant: C#Cc1ccc(CCC)cc1
Reactant: Fc1cc(I)ccc1Br
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: Cl
Solvent: CCNCC
Product: CCCc1ccc(C#Cc2ccc(Br)c(F)c2)cc1
Temperature: 5 °C
Yield: 69.6 %

Procedure:
1-Bromo-2-fluoro-4-iodobenzene (15 g) was dissolved in diethylamine (17 ml) under nitrogen atmosphere, and then bis(triphenylphosphine) palladium(II) chloride (0.12 g) and copper(I) iodide (0.12 g) were added thereto, followed by stirring. The flask was cooled to 5° C. or lower, and then 4-propylphenylacetylene (8 g) was added dropwise thereto. After stirring at room temperature for 5 hours, the reaction solution was poured into a mixture of concentrated hydrochloric acid (10 ml) and ice (50 g). After extraction with chloroform, the resultant was washed with water twice, followed by distilling off chloroform. The residue was recrystallized from a mixed solvent of acetone and methanol to give 4-bromo-3-fluoro-4'-propyltolane (11 g).
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(O)C.[Cl:24][C:25]1[CH:26]=[C:27]([C@@H:32]2[C@H:38]([CH:39]=O)[O:37][CH2:36][CH2:35][N:34]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:33]2)[CH:28]=[CH:29][C:30]=1[Cl:31].C[Si](C=[N+]=[N-])(C)C>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[Cl:24][C:25]1[CH:26]=[C:27]([C@@H:32]2[C@H:38]([CH:39]=[CH2:1])[O:37][CH2:36][CH2:35][N:34]([C:41]([O:43][C:44]([CH3:46])([CH3:47])[CH3:45])=[O:42])[CH2:33]2)[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](C=O)[C@@H](c2ccc(Cl)c(Cl)c2)C1
Agent: [Rh]
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [Cl-]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: C=C[C@@H]1OCCN(C(=O)OC(C)(C)C)C[C@@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.1 %

Procedure:
To a solution of chlorotris(triphenylphosphine)rhodium (I) (52 mg) and triphenylphosphine (620 mg) in tetrahydrofuran (5 mL) was added 2-propanol (0.18 mL), and tert-butyl (6S,7R)-6-(3,4-dichlorophenyl)-7-formyl-1,4-oxazepane-4-carboxylate (800 mg) was added. To the reaction mixture was added trimethylsilyldiazomethane (2 M diethyl ether solution, 2.1 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (224 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:18])[C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[O:21][CH:22]=[CH:23][N:24]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>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].O1CCOCC1>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C:20]2[O:21][CH:22]=[CH:23][N:24]=2)[CH:7]=1)=[O:18]
Reactant: Nc1ncco1
Reactant: O=C(Nc1ccnc(Br)c1)c1c(Cl)cccc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1ccnc(Nc2ncco2)c1)c1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 8.6 %

Procedure:
To a microwave tube was added N-(2-bromopyridin-4-yl)-2,6-dichlorobenzamide (0.30 g, 0.87 mmol), 2-aminooxazole (0.11 g, 1.0 mmol), Pd2(dba)3 (0.078 g, 0.087 mmol), XantPhos (0.096 g, 0.17 mmol), Cs2CO3 (0.57 g, 1.7 mmol) and dioxane (5 mL). The mixture was degassed with N2 for 10 min. The resulting mixture was irradiated in a microwave reactor at 140° C. for 3 hours and then cooled to room temperature. The mixture was filtered through Celite and concentrated under reduced pressure. The residue was dissolved in DMF and purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to give the desired product as a yellow solid (26 mg, yield: 9%). 1H NMR (500 MHz, DMSO-d6): δ 11.2 (s, 1H), 8.28 (s, 1H), 8.17 (d, J=5.5 Hz, 1H), 7.71 (s, 1H), 7.59 (d, J=7.5 Hz, 2H), 7.52 (t, J=3.5 Hz, 1H), 7.41 (m, 1H), 7.03 (s, 1H). LC-MS (ESI) m/z: 349.0 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11](=[O:21])[CH2:12][C:13]1[NH:18][C:17](=[O:19])[CH:16]=[C:15](Cl)[N:14]=1.[N:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CO>O1CCOCC1.O.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(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11](=[O:21])[CH2:12][C:13]1[NH:18][C:17](=[O:19])[CH:16]=[C:15]([C:25]2[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=2)[N:14]=1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: O=C(Cc1nc(Cl)cc(=O)[nH]1)N1CCc2c(F)cccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Cc1nc(-c2ccncc2)cc(=O)[nH]1)N1CCc2c(F)cccc21
Yield: 29.8 %

Procedure:
In a microwave tube, a mixture of 59 mg of 2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-chloro-3H-pyrimidin-4-one, 88 mg of pyridine-4-boronic acid pinacol ester, 32 mg of tetrakis(triphenylphosphine)palladium and 0.26 ml of a 1.5M cesium carbonate solution in 1.25 ml of dioxane is microwave-irradiated for one and a half hours at 100° C. The reaction medium is taken up with a mixture of methanol, ethyl acetate and a few drops of water. The solid formed is filtered off and washed with water and then dried so as to give 20 mg of 2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-pyridin-4-yl-3H-pyrimidin-4-one in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [CH:1]([N:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)([CH3:3])[CH3:2].[N+:17]([O-])([OH:19])=[O:18].O>CC(O)=O>[CH:1]([N:4]1[C:16]2[CH:15]=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(C)n1c2ccccc2c2ccccc21
Solvent: O
Solvent: CC(=O)O
Product: CC(C)n1c2ccccc2c2cc([N+](=O)[O-])ccc21
Reaction time: 0.25 h
Yield: 87 %

Procedure:
A solution of 9-Isopropyl-9H-carbazole (Acros, 1.5 9, 7.2 mmol) in AcOH (50 ml) was treated dropwise with a solution of nitric acid (3.35 ml) in AcOH (10 mL) over 30 minutes. When the reaction was complete the mixture was poured into water and stirred for 15 minutes, then the solid filtered and washed with Et2O to afford the desired product as a solid (1.6 g, 87%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][O:11][CH2:12]Cl.[I:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.[Cl-].[NH4+]>C(Cl)(Cl)Cl>[I:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:10][O:11][CH3:12])=[CH:17][CH:16]=1
Reactant: Oc1ccc(I)cc1
Reactant: COCCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COCOc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.33 ml of N,N-diisopropylethylamine and 900 μl of methoxymethyl chloride were added to a chloroform (20 ml) solution of 2 g of 4-iodophenol, and stirred overnight at room temperature. With cooling with ice, aqueous saturated ammonium chloride solution was added to it, extracted with ethyl acetate, and the organic layer was washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain 1.08 g of the entitled compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[NH2:15][N:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:24][C:19]=2[NH:18][C:17]1=[S:29].C(O)(=O)C>CN(C)C=O.C(N(CC)CC)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:15][N:16]2[C:20]3[CH:21]=[CH:22][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:24][C:19]=3[NH:18][C:17]2=[S:29])=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12]
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=S)n2N
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Solvent: CC(=O)O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)[nH]c(=S)n2NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Reaction time: 8 h
Yield: 55.2 %

Procedure:
2.54 g of 4-chloro-3-sulfamoylbenzoyl chloride were added in little portions to the solution of 2.2 g of 1-amino-5-methoxycarbonylbenzimidazole-2-thione in 8 ml of dimethylformamide and 1.4 ml of triethylamine while stirring. The reaction mixture was set aside overnight, then the pH value was adjusted to 5 by acetic acid and it was diluted with 100 ml of water. The separated gum slowly disaggregated to a powder which was filtered by suction, washed with water and dried at 80° C. The crude product obtained was boiled with 10 ml of glacial acetic acid for 30 minutes, then poured into 50 ml of water. The separated gum disaggregated to a powder by stirring. The precipitate was filtered by suction, washed with water and dried at 80° C. to give 2.4 g (54.5%) of 1-(4'-chloro-3'-sulfamoylbenzoyl)amino-5-methoxycarbonylbenzimidazole-2-thione, as a beige powder, m.p.: 258°-261° C. (with decomposition) after recrystallization from a mixture of dimethylformamide and water (1:2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22](O)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[NH:25]1[CH2:30][CH2:29][CH2:28][CH:27]([CH2:31][CH2:32][NH:33]C(=O)OC(C)(C)C)[CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>CS(C)=O.C(N(CC)CC)C>[NH2:33][CH2:32][CH2:31][CH:27]1[CH2:28][CH2:29][CH2:30][N:25]([C:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][CH2:8][C:9]3[NH:13][C:12]4[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=4[N:10]=3)=[O:6])=[CH:3][C:2]=2[Cl:1])=[O:23])[CH2:26]1
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCC1CCCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: NCCC1CCCN(C(=O)c2ccc(C(=O)NCc3nc4cc(Cl)ccc4[nH]3)cc2Cl)C1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, tert-butyl (2-piperidin-3-ylethyl)carbamate, TBTU, and triethylamine in DMSO at ambient temperature followed by Boc cleaving with trifluoroacetic acid analogously to Example 17. HPLC-MS results: retention time: 3.01 minutes; C23H25Cl2N5O2 (474.39); mass spectrum: (M+H)+=474.2.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:36])[C@@H:15]([NH:25]C(OCC2C=CC=CC=2)=O)[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]>CCO.[Pd]>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:36])[C@@H:15]([NH2:25])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCC(=O)OC(C)(C)C)CC1
Reaction time: 8 h
Yield: 94.9 %

Procedure:
A suspension of 4-((S)-2-benzyloxycarbonylamino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid butyl ester (4.00 g, prepared as described in WO2008050301) and Pd/C (5%, 0.42 g) in EtOH (15 mL) was hydrogenated at RT overnight. The reaction mixture was then stirred under H2 overnight. The mixture was filtered through celite and evaporated off. HV drying afforded the desired compound as light brown oil (2.79 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]([C:20]([F:23])([F:22])[F:21])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=2[C:17]#[C:18][CH3:19])=[O:5])C.C1COCC1.CCO.O.Cl>O>[Cl:16][C:12]1[CH:13]=[C:14]2[C:9](=[C:10]([C:17]#[C:18][CH3:19])[CH:11]=1)[O:8][CH:7]([C:20]([F:23])([F:21])[F:22])[C:6]([C:4]([OH:5])=[O:3])=[CH:15]2
Reactant: CC#Cc1cc(Cl)cc2c1OC(C(F)(F)F)C(C(=O)OCC)=C2
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC#Cc1cc(Cl)cc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 60 °C
Reaction time: 2 h
Yield: 15.6 %

Procedure:
To 0.320 g (1.01 mmole) of ethyl-6-chloro-8-prop-1-ynyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate was added 5 mL of a solvent mixture of THF/EtOH/H2O (7:2:1) followed by 64 mg (1.52 mmole) of LiOH-H20. The mixture was stirred at 60° C. for two hours. The mixture was concd, treated with water and acidified with 0.5N HCl. The product precipitated out of solution and was washed three times with water. The resulting solid was dried to afford 0.050 g (16%) of a brown solid: 1H NMR (CDCl3/400 MHz) 1.83 (s,3H), 5.77 (q, 1H, J=6.8 Hz), 6.89 (d, 1H, J=2.4 Hz), 7.03 (d, 1H, J=2.4 Hz), 7.35 (s, 1H); MS (ES−) 315 (M−1, 100). HRMS (ES−) m/z calcd for (C14H8O3ClF3) 315.0030, found 315.0048.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[S:16][CH:17]=[C:18]([CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([S:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=4)[N:19]=3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].ClC1C=C(C(OO)=[O:41])C=CC=1>C(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[S:16][CH:17]=[C:18]([CH2:20][O:21][C:22]4[CH:23]=[CH:24][C:25]([S:28]([C:29]([F:31])([F:32])[F:30])=[O:41])=[CH:26][CH:27]=4)[N:19]=3)[CH2:11][CH2:10]2)=[N:5][CH:4]=1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1cnc(N2CCC(c3nc(COc4ccc(SC(F)(F)F)cc4)cs3)CC2)nc1
Solvent: ClCCl
Product: CCc1cnc(N2CCC(c3nc(COc4ccc(S(=O)C(F)(F)F)cc4)cs3)CC2)nc1
Reaction time: 1.5 h

Procedure:
To a solution of 5-Ethyl-2-{4-[4-(4-trifluoromethylsulfanyl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine (Example 16) in DCM at room temperature was added 3-chloro-benzenecarboperoxoic acid (2 eq.). The reaction was allowed to stir for 1.5 hours and an additional portion of 3-chloro-benzenecarboperoxoic acid (1 eq.) was added to the reaction mixture. The reaction was stirred at room temperature for an additional 4 hours. The organic solution was washed with sodium bicarbonate; the organic layer was isolated, dried over sodium sulfate and filtered. The filtrate was concentrated and the crude product was purified by column chromatography to afford the desired product. 1H NMR (DMSO-d6): δ 8.40 (2H, s), 7.58 (2H, d), 7.22 (1H, s), 7.02 (2H, d,), 5.17 (2H, s), 3.74 (2H, m), 3.16 (1H, m), 2.96 (2H, m), 2.57 (2H, m), 2.22 (4H, m), 1.24 (3H, m).