Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[C:8]#[N:9].[OH-:18].[K+].Cl>CCO>[NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[C:8]([NH2:9])=[O:18]
Reactant: [OH-]
Reactant: COc1cc(-c2ccccc2)cc(N)c1C#N
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: COc1cc(-c2ccccc2)cc(N)c1C(N)=O
Temperature: 100 °C
Reaction time: 18 h
Yield: 40.4 %

Procedure:
A mixture of 3-amino-5-methoxy-[1,1′-biphenyl]-4-carbonitrile (4, 0.64 g, 2.86 mmol) and KOH (1.12 g, 20 mmol) in EtOH (24 mL) in a sealed tube was heated at 100° C. for 18 h. Additional KOH (0.56 g, 10 mmol) was added and heating was continued for another 18 h. After this time, the mixture was cooled to room temperature, and the pH was adjusted to ˜2 by addition of concentrated HCl. After concentration, the residue was partitioned between ethyl acetate (100 mL) and water (50 mL). The extracts were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography eluting with methanol in dichloromethane (0-20%) to afford the title compound (0.28 g, 40%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 7.62-7.60 (m, 2H), 7.58 (s, 1H), 7.47-7.44 (m, 2H), 7.39-7.36 (m, 1H), 7.28 (s, 1H), 6.61 (d, J=1.5 Hz, 1H), 6.56 (s, 2H), 6.43 (d, J=1.5 Hz, 1H), 3.87 (s, 3H); ESI MS m/z 243 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([C:9]([O:11]CC)=[O:10])[O:6][N:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>>[CH:1]([C:4]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[O:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1nc(C(C)C)no1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1noc(C(=O)O)n1

Procedure:
The title compound was prepared from ethyl 3-isopropyl-1,2,4-oxadiazole-5-carboxylate (0.4 g, 2.17 mmol) and sodium hydroxide solution (6 mL) using the method of Example 225(b). Yield 0.25 g. 1H NMR (400 MHz; D2O): δ 1.33 (d, 6H), 3.17 (m, 1H).
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:7])[CH2:5][Cl:6].[CH2:8]([C:11]1[CH:12]=[C:13]([N:17]=[C:18]=[O:19])[CH:14]=[CH:15][CH:16]=1)[CH:9]=[CH2:10]>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.C1C=CC=CC=1>[Cl:6][CH2:5][C:4]([O:7][C:18](=[O:19])[NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:8][CH:9]=[CH2:10])[CH:12]=1)=[N:3][O:2][CH3:1]
Reactant: CONC(=O)CCl
Reactant: C=CCc1cccc(N=C=O)c1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: c1ccccc1
Product: C=CCc1cccc(NC(=O)OC(CCl)=NOC)c1
Temperature: 25 °C

Procedure:
N-Methoxychloroacetamide (12.3 grams; 0.1 mole), benzene (80 ml) and dibutyltin dilaurate (1 drop) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. 3-Allylphenylisocyanate (16 grams; 0.1 mole) dissolved in benzene (30 ml) is incrementally added to the reaction mixture, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 2 hours. After this time the reaction mixture is distilled to remove benzene and unreacted starting material thereby yielding the desired product 1-chloro-2-(N-3-allylphenylcarbamoyloxy)-2-methoxyiminoethane.
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:8]=[C:9]([C:17]([O:19]C)=O)[CH:10]=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13])[S:3]([CH3:6])(=[O:5])=[O:4].C(Cl)CCl.[CH:25]1[CH:26]=[CH:27][C:28]2N(O)N=N[C:29]=2[CH:30]=1.[CH3:35][CH2:36][N:37](C(C)C)C(C)C.CNCC1C=CC=CC=1>>[CH3:1][N:2]([C:7]1[CH:16]=[C:11]([CH:10]=[C:9]([C:17](=[O:19])[NH:37][CH:36]([C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:30]=2)[CH3:35])[CH:8]=1)[C:12]([O:14][CH3:15])=[O:13])[S:3]([CH3:6])(=[O:4])=[O:5]
Reactant: On1nnc2ccccc21
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1cc(C(=O)OC)cc(N(C)S(C)(=O)=O)c1
Agent: CNCc1ccccc1
Solvent: ClCCCl
Product: COC(=O)c1cc(C(=O)NC(C)c2ccccc2)cc(N(C)S(C)(=O)=O)c1

Procedure:
Dimethyl 5-aminoisophthalate was mesylated by treating with methane sulfonylchloride and pyridine in dichloromethane. Then N-alkylation with methyl iodide under NaH/DMF condition gave dimethyl 5-(N-methylmethylsulfonamnido)isophthalate. Selective hydrolysis of dimethyl 5-(N-methylmethylsulfonamido)isophthalate, followed by EDC/HOBT/DIPEA mediated coupling with cc-methylbezylamine provided methyl 3-(N-methylmethylsulfonamido)-5-(1-phenylethylcarbamoyl)benzoate. Ester hydrolysis using aq. 1N NaOH in presence of THF/MeOH provided pure 3-(N-methylmethylsulfonamido)-5-(1-phenylethylcarbamoyl)benzoic acid as white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:27]([O-:29])=[O:28])=[C:6]([CH:26]=1)[C:7]([NH:9][C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[CH:12][N:11]=1)=[O:8].[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[N+:27]([C:5]1[CH:4]=[CH:3][C:2]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:26][C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[CH:12][N:11]=1)=[O:8])([O-:29])=[O:28]
Reactant: C1CCNCC1
Reactant: O=C(Nc1cnc(-c2cccc(C(F)(F)F)c2)cn1)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1cnc(-c2cccc(C(F)(F)F)c2)cn1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 5-chloro-2-nitro-N-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)benzamide (2.0 g, 4.73 mmol, 1.00 equiv) in N,N-dimethylformamide (30 mL), piperidine (1.0 g, 11.74 mmol, 2.50 equiv), and potassium carbonate (2 g, 14.47 mmol, 3.00 equiv). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting solution was diluted with 150 mL of ethyl acetate. The resulting mixture was washed with 1×50 mL of water and 3×50 of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.7 g (76%) of product as a yellow solid.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](/[CH3:11])\[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9].[H][H]>C1C=CC=CC=1>[CH3:9][C:8](=[CH:7][CH2:6][CH2:5][C@@H:4]([CH2:3][CH2:2][OH:1])[CH3:11])[CH3:10]
Reactant: CC(C)=CCC/C(C)=C\CO
Reactant: [H][H]
Solvent: c1ccccc1
Product: CC(C)=CCC[C@H](C)CCO
Yield: 93.4 %

Procedure:
In a 100 ml stainless steel-made autoclave whose atmosphere had been displaced with nitrogen were charged 1.54 g (10 mmole) of nerol, 0.0837 g (0.1 mmole) of Rh(COD)((+)-cBINAP)Cl obtained in Example 4, and 10 ml of benzene, and hydrogenation reaction was carried out at room temperature and at a hydrogen pressure of 30 kg/cm2 for 17 hours. There was obtained 1.46 g of (S)-(-)-citronellol at a conversion of 99% and a selectivity of 99%. From the results of optical rotation [α]25D =-3.65° (c=10.1, chloroform), the optical yield was found to be 70%ee.
Reaction SMILES: CO[C:3](=[O:20])[CH2:4][C:5]1([C:16]([O:18][CH3:19])=[O:17])O[N:12]2[C:7]([C:8]([CH3:15])([CH3:14])[O:9][CH2:10][CH2:11]2)=[N:6]1.[OH2:21]>CC1C=CC(C)=CC=1C>[OH:21][C:4]1[C:3](=[O:20])[N:12]2[C:7]([C:8]([CH3:14])([CH3:15])[O:9][CH2:10][CH2:11]2)=[N:6][C:5]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)CC1(C(=O)OC)N=C2N(CCOC2(C)C)O1
Reactant: O
Agent: Cc1ccc(C)c(C)c1
Product: COC(=O)c1nc2n(c(=O)c1O)CCOC2(C)C
Temperature: 10 °C

Procedure:
A solution of the above crude methyl 2-(2-methoxy-2-oxoethyl)-8,8-dimethyl-2,5,6,8-tetrahydro-[1,2,4]oxadiazolo[3,2-c][1,4]oxazine-2-carboxylate (8.34 g) in 1,2,4-trimethylbenzene (80 mL) was heated at 155° C. for 9 h. The resulting dark mixture was cooled to 20–25° C. and diluted with water (50 mL). The product was extracted into 0.5M Na2CO3 (2×50 mL). The organic layer was discarded. The aqueous phases were combined and washed with CH2Cl2 (40 mL). The organic wash was discarded. The aqueous solution was acidified to pH 2.0 with 6M sulfuric acid (9.0 mL) and the product extracted into CH2Cl2 (2×20 mL). The combined CH2Cl2 layers were evaporated in vacuo. The residue was redissolved in isopropanol (75 mL) at 75° C. and the solution was treated with activated charcoal (0.85 g) at 75–80° C. for 20 min. The charcoal was removed by filtration and washed with hot isopropanol. The combined filtrate and wash was concentrated in vacuo to 40 mL. The resulting slurry was cooled slowly with stirring to 10° C. and stirred for 1 h. The solid was filtered, washed with cold isopropanol (10 mL) and dried in vacuo at 40–45° C. to afford methyl 3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate as an off-white crystalline solid (3.68 g).
Reaction SMILES: C(COC)OC.[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:26]([C:28]3[N:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)=[CH:30][N:29]=3)=O)[CH2:22][CH2:21]1)(=[O:19])=[O:18])=[CH:11]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:49])=CC=1>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:26]([C:28]3[N:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)=[CH:30][N:29]=3)=[S:49])[CH2:22][CH2:21]1)(=[O:19])=[O:18])=[CH:11]2
Reactant: O=C(c1ncc(-c2ccncc2)cn1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: O=S(=O)(c1cc2cc(Cl)ccc2[nH]1)N1CCN(C(=S)c2ncc(-c3ccncc3)cn2)CC1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
In a mixed solvent of dimethoxyethane (10 ml) and toluene (10 ml) was suspended 1-[(5-chloroindol-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine (100 mg) at room temperature, followed by the addition of Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide, 42 mg). The resulting mixture was heated under reflux for 2 days. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by chromatography on a silica gel column (3→5% methanol—methylene chloride). 1N hydrochloric acid (in ethanol) was added to make acidic the purified product. After concentration, ethyl acetate was added. Yellow powder so precipitated was collected by filtration and dried, whereby the title compound (34 mg) was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[O:17][CH:18]=[C:19]([CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30](=O)[CH3:31])=[CH:26][CH:25]=3)[N:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[Na+].[CH3:37][NH:38][CH3:39].[ClH:40]>C(Cl)Cl>[ClH:40].[C:12]([C:9]1[CH:8]=[C:7]([C:16]2[O:17][CH:18]=[C:19]([CH2:21][CH2:22][O:23][C:24]3[CH:25]=[CH:26][C:27]([CH:30]([N:38]([CH3:39])[CH3:37])[CH3:31])=[CH:28][CH:29]=3)[N:20]=2)[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:10]=1[OH:11])([CH3:13])([CH3:15])[CH3:14]
Reactant: CC(=O)c1ccc(OCCc2coc(-c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)n2)cc1
Reactant: CNC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Product: CC(c1ccc(OCCc2coc(-c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)n2)cc1)N(C)C
Temperature: 60 °C
Yield: 80 %

Procedure:
Title compound was prepared substantially in accordance with the procedure in Example 1E above using the compound of Step A, 1.23 g (19.5 mmole) of sodium cyanoborohydride and dimethylamine (19.4 ml, 293 mmole), heating to 60° C. for 24 hours. The organic layer was chromatographed on silica gel using a methylene chloride/methanol gradient to give the free base which was dissolved in methylene chloride, treated with hydrogen chloride gas, and evaporated to give 8.31 g (80%) of the title product.
Reaction SMILES: C=O.[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:14][CH2:15][C:16]2[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[C:18]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)=[CH:29][CH:28]=3)[N:17]=2)=[C:8]([CH2:10][C:11]([NH2:13])=[O:12])[CH:9]=1.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:14][CH2:15][C:16]2[C:21]([C:22]([F:24])([F:25])[F:23])=[CH:20][N:19]=[C:18]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)=[CH:29][CH:28]=3)[N:17]=2)=[C:8]([CH2:10][C:11]([NH2:13])=[O:12])[CH:9]=1
Reactant: NC(=O)Cc1cc(F)ccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccc(F)cc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.5 %

Procedure:
Formaldehyde (37 wt. % in H2O; 29 μL, 0.39 mmol) was added to a suspension of 2-(5-fluoro-2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (9) (0.065 g, 0.13 mmol) in MeOH (8 mL) under an atmosphere of nitrogen. The resulting mixture was stirred for 10 minutes at room temperature then sodium triacetoxyborohydride (0.110 g, 0.518 mmol) was added in one portion and stirring continued for 3 hours The volatiles were removed in vacuo, then the residue was partitioned between EtOAc (20 mL) and saturated aqueous NaHCO3 (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4. The volatiles were removed under reduced pressure to yield the title compound 10 as an off-white solid (58 mg, 87%); 1H NMR (400 MHz, d6-DMSO) δ 10.13 (s, 1H), 8.65 (s, 1H), 7.64 (d, J=8.6 Hz, 2H), 7.49 (s, 1H), 7.22-7.16 (m, 3H), 7.08 (dd, J=10.2, 2.8 Hz, 1H), 7.04-6.95 (m, 2H), 3.50 (s, 2H), 3.12-3.04 (m, 2H), 3.04-2.95 (m, 2H), 2.87 (d, J=11.3 Hz, 2H), 2.46-2.36 (m, 1H), 2.20 (s, 3H), 2.02-1.92 (m, 2H), 1.76-1.58 (m, 4H). LCMS-A: rt 4.867 min; m/z 516 [M+H]+.
Reaction SMILES: Cl/[CH:2]=[CH:3]/[C:4]#[N:5].[C:6]1([C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[SH:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>O1CCCC1>[C:12]([S:13]/[CH:2]=[CH:3]/[C:4]#[N:5])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: N#C/C=C/Cl
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#C/C=C/SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
To a solution of (E)-3-chloroacrylonitrile (0.1 g) in tetrahydrofuran (2 ml) were added triphenylmethanethiol (0.332 g) and triethylamine (0.175 ml) under ice-cooling. The mixture was stirred at ambient temperature for 16 hours and poured into ice-water. The mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give (E)-3-tritylthioacrylonitrile (0.37 g).
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:25][CH2:24][CH2:23][N:22](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:21][CH2:20][N:19](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:18][CH2:17][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:15][CH2:14][N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][CH2:11]2)(=O)=O)=CC=1.OS(O)(=O)=O.C(O)C>C(OCC)C>[NH:10]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: Cc1ccc(S(=O)(=O)N2CCCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CCO
Product: C1CNCCNCCNCCNCCNC1
Temperature: 100 °C
Reaction time: 69 h
Yield: 15 %

Procedure:
A mixture of 1,4,7,10,13-penta(p-toluenesulfonyl)-1,4,7,10,13-pentaazacyclohexadecane prepared as in Example 1D (30 g, 0.030 mole) and concentrated H2SO4 (100 ml) was heated at 100° C. with stirring under a dry argon atmosphere for 69 h. To the resulting brown solution, ethanol (200 mL) was added dropwise with stirring at 5° C., followed by ethyl ether (500 ml). The tan solid was filtered and washed thoroughly with ethyl ether. The solid was then dissolved in H2O (75 ml), the pH was adjusted to 10 with 10N NaOH, and the solution was extracted with CHCl3 (6×200 ml). The extracts were combined and dried (Na2SO4), and the solvent was removed in vacuo. The resulting yellow solid was purified by recrystallization from hexane to give 1.0 g (15% yield) of the product as colorless needles: mp 109-110.5° C.; 1H NMR (CDCl3)δ 1.72 (quint, J=5.4 Hz, 2 H), 1.76 (br s, 5 H), 2.73 (m, 20 H); Anal. calcd. for C11H27N5: C, 57.60; H, 11.86; N, 30.53. Found: C, 57.77; H, 12.35; N, 30.57.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[C:15]1([N:6]2[C:5]3[CH:21]=[CH:22][C:2]([NH:1][S:30]([C:27]4[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=4)(=[O:32])=[O:31])=[CH:3][C:4]=3[N:8]=[C:7]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: O=S(=O)(Nc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)c1ccc(F)cc1

Procedure:
5-Amino-1,2-diphenyl-1H-benzimidazole was reacted with 4-fluorobenzenesulfonic acid chloride according to general operating instructions 13.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH:13]([NH2:15])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[C:17](N1C=CC=N1)(=[NH:19])[NH2:18]>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][CH:13]([NH:15][C:17]([NH2:19])=[NH:18])[CH2:14]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NC1CCN(c2ccc([N+](=O)[O-])cc2)C1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CN(C)C=O
Product: N=C(N)NC1CCN(c2ccc([N+](=O)[O-])cc2)C1
Yield: 891.5 %

Procedure:
2.07 g (0.01 mol) of [1-(4-nitrophenyl)pyrrolidin-3-yl]amine (2) was heated to 90° C. in 10 ml of DMF. 1.32 g (0.0009 mol) of 1-amidinopyrazole monohydrochloride was added slowly to the reaction medium. The mixture was heated for 8 hours. A yellow solid was thus precipitated. The solid thus obtained was filtered off, washed with ethanol and dried under vacuum to give 2 g of a yellow powder (3) (70%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][N:8]=1.O[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.NC1C=CC=CC=1.C(O)C(N)(CO)CO>CN(C=O)C>[C:21]1([NH:17][C:13]([C:10]2[CH:11]=[N:12][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:8][CH:9]=2)=[O:15])[CH:22]=[CH:23][CH:24]=[CH:25][CH:20]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cnc(-c2ccccn2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(CO)(CO)CO
Solvent: Nc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1cnc(-c2ccccn2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23 %

Procedure:
A mixture of 2-pyridin-2-yl-pyrimidine-5-carboxylic acid (100 mg, 0.5 mmol, prepared according to the general procedure described in Example 2, steps 1 and 2), 1-hydroxybenzotriazole (76.1 mg, 0.56 mmol) and PS-DCC (518 mg, 1.28 mmol/g, 0.66 mmol) in 8 mL of DMF is shaken at room temperature for 15 minutes, and aniline (31 mg, 0.33 mmol) is added. After shaking at room temperature for 18 hours, PS-trisamine (400 mg, 3.75 mmol/g, 1.5 mmol) is added and the mixture is continually shaken at room temperature for 18 hours. The solid is filtered and washed with DCM. The filtrate is concentrated to yield 2-pyridin-2-yl-pyrimidine-5-carboxylic acid phenylamide (21 mg, 23%) as a solid. MS: 277 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[Br:17][CH2:18][CH2:19][CH2:20]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[O:15][CH2:20][CH2:19][CH2:18][Br:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCCBr
Reactant: Cc1cccc(O)c1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc(OCCCBr)c1NC(=O)OC(C)(C)C
Temperature: 55 °C

Procedure:
To (2-hydroxy-6-methyl-phenyl)-carbamic acid tert-butyl ester (5.5 g, 24.6 mmol) in acetonitrile (200 mL) was added 1,3-dibromopropane (17.5 mL, 172 mmol), and potassium carbonate (27.0 g, 196 mmol). The mixture was heated at 55° C. for 2.5 hrs, followed by a filtration to remove solids. The filtrate was concentrated and repartitioned with ethyl acetate (250 mL) and water (150 mL). The organic layer was then washed with brine (150 mL), dried over MgSO4, and evaporated affording [2-(3-bromo-propoxy)-6-methyl-phenyl]-carbamic acid tert-butyl ester (quantitative yield). MS: 243.8 (M+H-Boc)+; tR=2.62 min (method 1).
Reaction SMILES: C=[C:2]1[CH:7]([CH2:8][CH2:9][CH2:10][CH:11]=C)[CH2:6][CH2:5][O:4][CH2:3]1>C(Cl)Cl>[CH2:3]1[C:2]2[CH:7]([CH2:8][CH2:9][CH2:10][CH:11]=2)[CH2:6][CH2:5][O:4]1
Reactant: C=CCCCC1CCOCC1=C
Solvent: ClCCl
Product: C1=C2COCCC2CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-methylidene-4-(pent-4-en-1-yl)tetrahydro-2H-pyran (1320 mg, 7.94 mmol) was added to CH2Cl2 (159.00 ml) at RT. The reaction was degassed three times. Zhan-1b (58.3 mg, 0.079 mmol) was added at 0° C. The reaction mixture was degassed again and then stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure (280 mmhg). The residue was purified by column chromatography on silica gel to provide the title compound. 1H NMR (500 MHz, CDCl3) δ 5.54 (d, 1H, J=2.2 Hz), 4.06 (d, 1H, J=122 Hz), 3.97 (dd, 1H, J=4.4 Hz, 11.2 Hz), 3.84-3.91 (m, 1H), 3.46-3.53 (m, 1H), 2.21 (bs, 1H), 1.92-2.19 (m, 2H), 1.80-1.89 (m, 1H), 1.68-1.86 (m, 2H), 1.36-1.48 (m, 2H), 1.16-1.26 (m, 1H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:34](=[O:37])[CH2:35][CH3:36])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f20) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][CH:2]([F:28])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH:14]([C:16]3[O:20][N:19]=[C:18]([CH2:21][CH2:22][O:23][CH3:24])[N:17]=3)[CH2:13][N:12](C(=O)C)[CH2:11]2)=[CH:6][CH:5]=1.Cl>C(O)C.O>[F:28][CH:2]([F:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH:14]([C:16]3[O:20][N:19]=[C:18]([CH2:21][CH2:22][O:23][CH3:24])[N:17]=3)[CH2:13][NH:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: COCCc1noc(C2CC(c3ccc(CC(F)F)cc3)CN(C(C)=O)C2)n1
Agent: Cl
Solvent: CCO
Solvent: O
Product: COCCc1noc(C2CNCC(c3ccc(CC(F)F)cc3)C2)n1

Procedure:
A solution of 45.0 mg (0.083 mmol, purity 72%) of the compound from Example 60A in ethanol (10.0 ml) was admixed with 69 μl (15 mg, 0.42 mmol) of concentrated hydrochloric acid. Subsequently, the mixture was stirred under reflux for 24 h, and the reaction solution was diluted with water and washed with diethyl ether. The aqueous phase was alkalized and extracted with dichloromethane. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 36.3 mg (87% of theory, purity 70%)