Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=2[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:6]=[CH:7][CH:8]=1.[NH:26]1[CH:30]=[CH:29][CH:28]=[N:27]1>O1CCOCC1>[N:26]1([CH2:2][C:3]2[CH:4]=[C:5]([C:9]3[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=3[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:6]=[CH:7][CH:8]=2)[CH:30]=[CH:29][CH:28]=[N:27]1
Reactant: c1cn[nH]c1
Reactant: CC(C)Cc1cc(-c2cccc(CBr)c2)c(S(=O)(=O)NC(C)(C)C)s1
Solvent: C1COCCO1
Product: CC(C)Cc1cc(-c2cccc(Cn3cccn3)c2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 80 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
To a solution of 3-(3-bromomethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (90.4 mg, 0.203 mmol; see Example 1(e)) in dioxane (2.0 mL) was added pyrazole (41.5 mg, 0.609 mmol) and the reaction mixture was stirred for 18 h at 80° C., after which another portion of pyrazole (60.4 mg, 0.887 mmol) was added and the reaction mixture stirred for a further 3 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography using EtOAc:petroleum ether (2:8) as eluent to give the sub-title compound in 98% yield as a colourless syrup (86 mg, 0.199 mmol).
Reaction SMILES: [NH:1]([C:5]1[C:13]2[C:8](=[C:9]([CH2:14][S:15][C:16]3[NH:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[N:10]=[CH:11][CH:12]=2)[S:7][CH:6]=1)[C:2]([CH3:4])=[O:3].C1C=C(Cl)C=C(C(OO)=[O:33])C=1.[O-]S([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[NH:1]([C:5]1[C:13]2[C:8](=[C:9]([CH2:14][S:15]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[N:17]=3)=[O:33])[N:10]=[CH:11][CH:12]=2)[S:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)Nc1csc2c(CSc3nc4ccccc4[nH]3)nccc12
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(=O)Nc1csc2c(CS(=O)c3nc4ccccc4[nH]3)nccc12
Reaction time: 1.5 h
Yield: 58.6 %

Procedure:
To a solution of 83 mg (0.244 mmol) of 2-[(3-acetaminothieno[2, 3-c]pyridin-7-yl)methylthio]benzimidazole (Ia-12) was dissolved in a mixture of 4 ml of CHCl3 and 2 ml of MeOH. To the solution was added 53 mg (1 equivalent) of 80% m-CPBA at -10° C., and the mixture was stirred for 1.5 hr. at the same temperature. By adding an appropriate quantity each of 10% Na2SO3 and saturated aqueous NaHCO3 to the solution, crystals separated out. The crystals were collected by filtration to give 72 mg of crude crystals. The crystals were recrystallized from a solution of CHCl3 - MeOH, whereby 53 mg (Yield : 60.9%) of 2-[(3-acetaminothieno[2, 3-c]pyridin-7-yl)methylsulfinyl]benzimidazole (Ic-27) was obtained as an objective compound.
Reaction SMILES: [C:1]1([O:7][CH:8]=[CH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10]([CH:12]=[CH2:13])=[O:11].C1(C=CC(O)=CC=1)O>>[O:7]([CH:8]1[CH2:9][CH2:13][CH:12]=[CH:10][O:11]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC=O
Reactant: C=COc1ccccc1
Agent: Oc1ccc(O)cc1
Product: C1=COC(Oc2ccccc2)CC1

Procedure:
45 g (375 mmol) of phenylvinyl ether, 21 g (375 mmol) of acrolein and 0.66 g (6 mmol) of hydroquinone are reacted in a pressure reactor for 1 h at 185° C. After cooling, 2-phenoxy-3,4-dihydro-2H-pyran is isolated by distillation at 80° C./0.0267 kPa in a yield of 30.2 g (172 mmol; 46%) as a clear liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7](N)=[CH:6][C:5]=1[NH:11][C:12](=[O:23])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1.N([O-])=[O:26].[Na+].OS(O)(=O)=O>FC(F)(F)C(O)=O.O>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([OH:26])=[CH:6][C:5]=1[NH:11][C:12](=[O:23])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(N)cc1NC(=O)c1ccc(C(C)(C)C)cc1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(O)cc1NC(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 0.08 h
Yield: 71 %

Procedure:
To a solution of 4-amino-2-(4-tert-butyl-benzoylamino)-benzoic acid methyl ester (0.711 g, 2.18 mmol) in trifluoroacetic acid cooled to 0° C. was added NaNO2 (0.182 g, 2.64 mmol, 1.21 eq) as a solution in water (4 mL) and the reaction was stirred for 5 minutes. It was then added dropwise to a 30% solution of H2SO4 (50 mL) at 65° C. and stirred for 15 minutes. It was extracted with ethyl acetate, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/hexanes (20/80) to afford 2-(4-tert-butyl-benzoylamino)-4-hydroxy-benzoic acid methyl ester (0.508, 71%) as a white solid. mp=146.0-148.4° C.; mass spectrum (−ES, M−H) m/z 326. 1H NMR (400 MHz, DMSO-d6); δ 11.95 (bs, 1H), 10.60 (bs, 1H), 8.26 (d, 1H), 7.88 (m, 3H), 7.62 (d, 2H), 6.58 (dd, 1H), 3.85 (s, 3H), 1.32 (s, 9H). Elemental analysis: Calcd. for C19H21NO4: C, 69.71; H, 6.47; N, 4.28, Found: C, 69.20; H, 6.54; N, 4.17.
Reaction SMILES: [C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](Cl)=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)CCl>[C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](=[O:9])[C:21]2[CH:22]=[CH:23][C:18]([Br:17])=[CH:19][CH:20]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Brc1ccccc1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)N1CCC(C(=O)c2ccc(Br)cc2)CC1
Reaction time: 8 h

Procedure:
32.0 g of 1-acetylisonipecotoyl chloride, Example 1(b) are added portionwise to a stirred mixture of 45.3 g of aluminum chloride, 28.3 g of bromobenzene and 120 ml of ethylene dichloride. The solution is stirred overnight, poured onto ice, the organic phase is collected, and the aqueous layer is extracted with chloroform. The organic solutions are combined, dried, and the solvent is removed under reduced pressure to give a yellow oil which crystallizes to a soft solid. The solid is triturated with ether, collected and dried to give 1-acetyl-4-(4-bromobenzoyl)piperidine.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([OH:27])[CH:23]=[CH:24][C:25]=1[Cl:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][C:25]=1[Cl:26])[O:27][C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N1CCN(C(=O)c2cccc(Br)n2)CC1
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N1CCN(C(=O)c2cccc(Oc3ccc(Cl)c(Cl)c3)n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 10.1 %

Procedure:
To a solution of (6-bromo-pyridin-2-yl)-(4-isopropyl-piperazin-1-yl)-methanone (76.7 mg, 0.25 mmol) in DMF (2.5 mL) was added 3,4 dichlorophenol (40.07 mg, 0.25 mmol) and K2CO3 (101.93 mg, 0.74 mmol). After 18 h at 120° C., the mixture was cooled to rt, diluted with water, and extracted with DCM. Purification by FCC followed by reverse phase HPLC (basic conditions) provided the desired product (10.0 mg, 3.5%). MS (ESI): mass calcd. for C19H21Cl2N3O2, 393.10; m/z found, 394.3 [M+H]+. 1H NMR (CDCl3): 7.82 (dd, J=8.2, 7.4 Hz, 1H), 7.52-7.44 (m, 2H), 7.26 (d, J=2.7 Hz, 1H), 7.06-6.98 (m, 2H), 3.75-3.67 (m, 2H), 3.50-3.44 (m, 2H), 2.70-2.61 (m, 1H), 2.55-2.48 (m, 2H), 2.23-2.15 (m, 2H), 1.01 (d, J=6.6 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:17][CH2:18][C:19]([OH:21])=O)[CH2:14][CH2:13][C:12](=[O:15])[NH:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8].CN(C=O)C.S(Cl)([Cl:29])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:17][CH2:18][C:19]([Cl:29])=[O:21])[CH2:14][CH2:13][C:12](=[O:15])[NH:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCC1(c2ccc(Cl)c(Cl)c2)CCC(=O)NC1=O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)CCC1(c2ccc(Cl)c(Cl)c2)CCC(=O)NC1=O
Temperature: 60 °C

Procedure:
Under a nitrogen atmosphere, 20 g of 3-[3-(3,4-dichlorophenyl)-2,6-dioxopiperidin-3-yl]propionic acid, 200 ml of toluere and 0.5 ml of DMF are mixed. The medium is heated to 60° C and 14.9 g of thionyl chloride and 40 ml of toluene are introduced dropwise. The stirring is maintained for 5 hours at 60° C. The toluene and the excess thionyl chloride are evaporated off and then the reaction medium is dried in an oven (40° C.) overnight.
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:3]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)=[O:4].[H-].[Na+].[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25]Cl>CS(C)=O.C(Cl)(Cl)Cl>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][N:9]1[C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:6]=[C:5]1[C:3]([N:2]([CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:4]
Reactant: CN(C(=O)c1nc2ccccc2[nH]1)c1ccccn1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: CN(C)CCn1c(C(=O)N(C)c2ccccn2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-Methyl-N-(2-pyridyl)benzimidazole-2-carboxamide (1.0 g) prepared in Example 5 was dissolved in dry DMSO (20 ml), 60% sodium hydride (0.17 g) was added and stirred at room temperature for 1 hr in an argon atmosphere. Excess β-dimethylaminoethyl chloride was added to the mixture and reacted at room temperature under agitation for 20 hrs. The reaction solution was diluted with chloroform, washed with water, dried over anhydrous Na2SO4 and the solvent was distilled off. Purification of the residue by column chromatography on silica gel (using silica gel manufactured by Merck Co., Ltd.) gave the title compound (0.88 g) as an oily product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][CH3:25])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1.CCN(CC)CC.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[NH2:17][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][N:24]([CH3:25])[S:34]([CH3:33])(=[O:36])=[O:35])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNCCOCCn1c(CCOC)nc2c(N)nc3ccccc3c21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCN(C)S(C)(=O)=O
Temperature: 0 °C
Yield: 61.4 %

Procedure:
2-(2-Methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 2.92 mmol) was dissolved in 30 mL of anhydrous CH2Cl2 and cooled to 0° C. under N2. To the stirred solution were added Et3N (0.81 mL, 5.81 mmol) and methanesulfonyl chloride (226 μL, 2.92 mmol) and the reaction was allowed to warm to room temperature overnight. The reaction mixture was then quenched by addition of saturated NaHCO3 solution (30 mL) and CH2Cl2 (30 mL). The organic layer was separated and washed with H2O and brine, dried over Na2SO4 and concentrated under reduced pressure. Crystallization of the residue from EtOAc and CH2Cl2 gave 756 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methylmethanesulfonamide as tan crystals. m.p. 145.0-146.5° C.;
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].C([Li])CCC.[C:19](#[N:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH:6][C:19](=[NH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: N#Cc1ccccc1
Agent: [Li]CCCC
Product: CC(C)c1cccc(C(C)C)c1NC(=N)c1ccccc1
Yield: 50 %

Procedure:
Procedure as described for Amidine I using the following amounts: 8.50 mL of 2,6-diisopropylaniline (45.0 mmol); 23.5 mL of 2.0 M butyllithium (47.0 mmol); 4.70 mL of benzonitrile (46.0 mmol). Filtration of the final pentane solution yielded 6.31 g (50%) of white solid. 1H NMR (400 MHz, CDCl3): 7.92 (d, 2H), 7.48 (m, 3H), 7.17 (d, 2H), 7.09 (t, 1 H), 4.59 (s, 2H), 3.06 (septet, 2H), 1.20 (d, 12H).
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:54][O:55][C:56](=[O:68])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[CH2:16][S:17][CH2:18][C@H:19]([NH:36]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:20](=[O:35])[NH:21][C@@H:22]([CH2:33][CH3:34])[CH2:23][O:24][CH2:25][C:26](=[O:32])[O:27]C(C)(C)C)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:36][C@@H:19]([CH2:18][S:17][CH2:16][C@H:15]([O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:54][O:55][C:56](=[O:68])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[C:20](=[O:35])[NH:21][C@@H:22]([CH2:33][CH3:34])[CH2:23][O:24][CH2:25][C:26]([OH:32])=[O:27]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](CC)COCC(=O)OC(C)(C)C)OC(=O)CCCCCCCCCCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)N[C@@H](CC)COCC(=O)O)OC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (8S,11R,15R)-11-(((9H-fluoren-9-yl)methoxy)carbonylamino)-8-ethyl-2,2-dimethyl-4,10-dioxo-3,6-dioxa-13-thia-9-azahexadecane-15,16-diyl didodecanoate (1 eq, from the previous step) in 50% TFA in DCM (0.05 M) was stirred in open air at 40° C. for 1.5 hours. The mixture was dried under a stream of air and briefly evaporated under high vacuum. The resulting oil was dissolved in 20% piperidine in THF (0.1 mL) and stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate. The reaction mixture was concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-10% methanol in DCM to give the product as a solid. 1H NMR (DMSO-d6): δ 8.30 (d, 1H), 5.11 (m, 1H), 4.27 (dd, 1H), 4.09 (dd, 1H), 3.96 (s, 2H), 3.67-3.76 (m, 2H), 3.37-3.48 (m, 2H), 2.71-2.95 (m, 4H), 2.25-2.28 (m, 4H), 1.23-1.62 (m, 41H), 0.83-0.88 (m, 6H). LRMS [M+H]=689.4.
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[I:15][C:16]1[CH:21]=[C:20]([I:22])[CH:19]=[C:18]([I:23])[C:17]=1[OH:24]>C(#N)C>[C:1]([O:24][C:17]1[C:16]([I:15])=[CH:21][C:20]([I:22])=[CH:19][C:18]=1[I:23])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: Oc1c(I)cc(I)cc1I
Solvent: CC#N
Product: CCCCCCCCCCCC(=O)Oc1c(I)cc(I)cc1I
Yield: 83.1 %

Procedure:
Dodecanoyl chloride (2.95 ml, 12.8 mmol) was added to a suspension of 2,4,6-triiodophenol (6.0 g, 12.7 mmol) in refluxing acetonitrile (50 ml) and the mixture was heated under argon for 24 hrs. The reaction mixture was cooled and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness under vacuum to give an off-white solid. The crude product was recrystallized from methanol to give 6.9 g (83%) of the desired ester, mp 68°-69° C.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[NH:11]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19](O)=O)=[N:12]1.N>>[NH:11]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[C:18]([C:19]3[O:1][N:2]=[C:3]([C:4]4[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=4)[N:10]=3)[CH:22]=[CH:23][CH:24]=2)=[N:12]1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1cccc(-c2cc[nH]n2)c1
Agent: N
Product: c1cncc(-c2noc(-c3cccc(-c4cc[nH]n4)c3)n2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-(1H-pyrazol-3-yl)benzoic acid (Maybridge). 1H NMR (300 MHz, DMSO-d6) δ 6.91 (d, J=2.4 Hz, 1H), 7.62-7.69 (m, 1H), 7.72 (t, J=7.8 Hz, 1H), 7.79-7.92 (m, 1H), 7.82-7.88 (m, 1H), 8.10-8.20 (m, 3H), 8.49 (dt, J=8.2, 1.9, 1.7 Hz, 1H), 8.64 (s, 1H), 8.83 (dd, J=4.7, 1.7 Hz, 1H), 9.29 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 290 (M+H)+.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[NH2:5][C:6]1[C:14]2[O:13][C:12]([F:16])([F:15])[O:11][C:10]=2[CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[CH2:1]([NH:5][C:6]1[C:14]2[O:13][C:12]([F:16])([F:15])[O:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)[C:2]#[CH:3]
Reactant: C#CCBr
Reactant: Nc1cccc2c1OC(F)(F)O2
Solvent: Cc1ccccc1
Product: C#CCNc1cccc2c1OC(F)(F)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
At 20-25° C., 53.3 g of an 80% strength solution of propargyl bromide in toluene (=0.36 mol of propargyl bromide) are added dropwise to a solution of 120 g (0.67 mol) of 4-amino-2,2-difluorobenzo-1,3-dioxole in 150 ml of toluene. After 2 hours at 80° C., the reaction mixture is cooled to room temperature and the precipitate is filtered off with suction and washed with n-hexane. The filtrate is concentrated under reduced pressure and the residue is purified over silica gel using cyclohexane/ethyl acetate mixtures and then-crystallized from pentane. 33.2 g (44% of theory) of N-propargyl-4-amino-2,2-difluorobenzo-1,3-dioxole of mp.: 66-68° C. are obtained in this manner. NMR: (CDCl3): 2.25 (t, 1H); 3.9 (2*s, 3H); 6.30 (dd, 1H); 6.50 (d, 1H); 6.85 (d, 1H)
Reaction SMILES: C(OC([NH:8][C@H:9]([C:17]([O:19][CH2:20][C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2)=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(C)(C)C.[ClH:31]>O1CCOCC1>[ClH:31].[NH2:8][C@H:9]([C:17]([O:19][CH2:20][C:21]12[CH2:30][CH:25]3[CH2:24][CH:23]([CH2:29][CH:27]([CH2:26]3)[CH2:28]1)[CH2:22]2)=[O:18])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)OCC12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccccc1)C(=O)OCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
769 mg (1.86 mmol) of adamantan-1-ylmethyl N-(tert-butoxycarbonyl)-L-phenylalaninate (Intermediate 13) were dissolved in 25 ml of a 4 N solution of hydrogen chloride in dioxane and stirred at RT for 1 h. Subsequently, the reaction mixture was concentrated and the residue was dried under reduced pressure. 619 mg (95% of theory) of the title compound were obtained.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)c(F)c2)CC1
Temperature: 150 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
2,4-Difluorobenzonitrile (5.00 g, 35.94 mmol), tert-butyl-1-piperazinecarboxylate (6.69 g, 35.92 mmol) and potassium carbonate (10.0 g, 72.4 mmol) were combined in dimethylsulfoxide (40 mL) and stirred at 150° C. overnight. The reaction mixture was cooled to ambient temperature, poured into water (150 mL) and extracted into ethyl acetate (150 mL). The extract was washed twice with water and once with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography (2″×5″ silica gel). The column was flushed with 500 mL each 10% and 20% ethyl acetate/hexane and the product removed with an additional 500 mL of 20% ethyl acetate/hexane. Concentration gave 4-(4-cyano-3-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester as a white solid (3.28 g, 30%) which had mp 130.5-131.0° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:26]([O:59][CH3:60])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:57][CH3:58])[C@@H:36]([CH3:56])[C:37]([NH:39][C@H:40](/[CH:48]=[CH:49]/[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12].O=[CH:66][CH2:67][CH2:68][C:69]([OH:71])=[O:70].C([BH3-])#N.[Na+].O1CCOCC1>O1CCOCC1.O>[C:69]([CH2:68][CH2:67][CH2:66][N:9]([CH3:8])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:26]([O:59][CH3:60])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:57][CH3:58])[C@@H:36]([CH3:56])[C:37]([NH:39][C@H:40](/[CH:48]=[CH:49]/[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH:11]([CH3:13])[CH3:12])([OH:71])=[O:70]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](/C=C/c1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Reactant: O=CCCC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1COCCO1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](/C=C/c1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C

Procedure:
15.5 mg (10 μmol) N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S,3E)-1,4-diphenylbut-3-en-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide trifluoroacetic acid salt (intermediate 19) was dissolved in 1.0 mL dioxane/water (1:1) and reacted with a 15% aqueous solution of 4-oxobutanoic acid in the presence of sodium cyanoborohydride, by analogy with the synthesis in Example 1. After lyophilization from dioxane, 10.3 mg (68% of the theoretical) of the title compound was obtained in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH2:8][CH3:9].[CH:23]1(C2C(N[C@@H]3C4C(=CC=CC=4)C[C@@H]3O)=NC(CC)=CN=2)CC1>>[Br:1][C:2]1[N:3]=[C:4]([CH:21]2[CH2:23][CH2:22]2)[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: CCc1cnc(C2CC2)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(C2CC2)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting (1R,2S)-1-[(3-cyclopropyl-6-ethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.86–1.08, 1.23–1.30, 1.70–1.79, 2.77–2.84, 3.03–3.09, 3.23–3.30, 4.77–4.81, 5.44, 5.56, 7.23–7.32; MS (ESI+) for C18H20BrN3O m/z 374 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]([CH3:17])[C:11]=1[C:18]([OH:20])=O>O>[CH3:17][N:12]1[C:11]2[C:18](=[O:20])[NH:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[NH:9][C:10]=2[C:14]([CH3:15])=[C:13]1[CH3:16]
Reactant: Cc1c(Nc2ccccc2N)c(C(=O)O)n(C)c1C
Agent: Cl
Solvent: O
Product: Cc1c2c(n(C)c1C)C(=O)Nc1ccccc1N2
Temperature: 140 °C

Procedure:
15 ml of concentrated hydrochloric acid are added to the solution obtained in Example 4, which contains 49.2 g (0.19 mole ) of 3-[(2-aminophenyl)amino]-1,4,5-trimethyl-1H-pyrrole-2-carboxylic acid, and the mixture is heated to an internal temperature of 140° C. for 12 hours. During this heating, the water formed is continuously distilled off. For working up the mixture, as much of the solvent as possible is distilled off on a rotary evaporator under a water-pump vacuum. The residue is taken up in 100 ml of water, and the mixture is adjusted to pH 2, at 80° C., with concentrated hydrochloric acid. The mixture is cooled to 0° C., with stirring. The precipitate formed is filtered off. The filtrate is extracted 3 times with 50 ml of ethyl acetate each time. The combined filtrates are dried with sodium sulfate and concentrated, and the residue is again taken up in 50 ml of water. The resulting mixture is adjusted to pH 2, at 80° C., with concentrated hydrochloric acid. After the mixture has been cooled to 0° C. in an ice-bath, it is filtered. The combined residues on the filter are washed with water and recrystallized from ethyl acetate.