Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[C:4]1=[O:20].[C:21]1([CH2:27][CH:28]=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[ClH:1].[C:21]1([CH2:27][CH2:28][NH:2][C@H:3]2[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[C:4]2=[O:20])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N[C@H]1CCCN(CC(=O)OCc2ccccc2)C1=O
Reactant: O=CCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(CN1CCC[C@H](NCCc2ccccc2)C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.8 %

Procedure:
To a mixture of 41 (1.50 g, 5.02 mmol) and phenylacetaldehyde (0.724 g, 6.03 mmol) in 35 mL of 1, 2-dichloroethane was added triethylamine (2.03 g, 21.1 mmol, 2.80 mL). After stirring at ambient temperature for 10 min, sodium triacetoxyborohydride (1.49 g, 7.03 mmol) was added rapidly over a 5 min period. The reaction mixture was stirred at room temperature for 15 hrs and quenched with 30 mL of water. The mixture was diluted with 50 mL of CH2Cl2 and the organic phase was separated, washed with 30 mL portions of saturated NaHCO3, water, brine, dried over MgSO4, filtered, and evaporated. The residue was purified by flash chromatography on silica gel eluting with CH2C12, ethanol: 95, 5 to afford 1.21 g (66% yield) of product 42 as a pale yellow oil; TLC (silica gel; CH2Cl2, ethanol: 9, 1): Rf=0.4
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([O-:3])=[O:2].C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.[S:32](Cl)(=[O:35])(=[O:34])[NH2:33].O>C(Cl)Cl>[S:32](=[O:35])(=[O:34])([O:16][C:13]1[CH:12]=[CH:11][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1)[NH2:33]
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(O)cc1
Reactant: NS(=O)(=O)Cl
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: O
Solvent: ClCCl
Product: NS(=O)(=O)Oc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.9 %

Procedure:
108 mg of 2′-nitrobiphenyl-4-ol was dissolved in 9.5 ml of methylene chloride, and 312 mg of 2,6-di-tert-butyl-4-methylpyridine and 347 mg of sulfamoyl chloride were successively added thereto under cooling with ice, followed by stirring at room temperature for 5 hours. After water was added to the reaction mixture, the product was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the resulting crude product was purified by TLC (using a 1:1 mixture of ethyl acetate and hexane as the developing solvent) to obtain 149 mg of 2′-nitrobiphenyl-4-yl sulfamate.
Reaction SMILES: C(OC(=O)COC1C=CC(S)=CC=1C)C.[CH2:16]([O:18][C:19](=[O:36])[CH2:20][O:21][C:22]1[C:31]2[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=2[C:25]([S:32](Cl)(=O)=O)=[CH:24][CH:23]=1)[CH3:17]>>[CH2:16]([O:18][C:19](=[O:36])[CH2:20][O:21][C:22]1[C:31]2[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=2[C:25]([SH:32])=[CH:24][CH:23]=1)[CH3:17]
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)Cl)c2c1CCCC2
Agent: CCOC(=O)COc1ccc(S)cc1C
Product: CCOC(=O)COc1ccc(S)c2c1CCCC2

Procedure:
The title compound was prepared according to the method described for preparing compound 10.3, using compound 22.2 as the starting material. 1H NMR (300 MHz) (CDCl3) δ 7.11 (1H, d, J=8.5 Hz); 6.46 (1H, d, J=8.4 Hz); 4.59 (2H, s); 4.26 (2H, q, J=7.1 Hz); 3.10 (1H, s); 2.76-2.65 (4H, m); 1.82-1.74 (4H, m); 1.30 (3H, t, J=7.1 Hz).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][NH:5][C:6]1[C:18]2[C:17](=O)[C:16]3[CH:15]=[N:14][CH:13]=[CH:12][C:11]=3[C:10]=2[C:9]2[CH:20]=[CH:21][C:22]([OH:25])=[C:23]([CH3:24])[C:8]=2[N:7]=1.[CH3:27][O:28][NH2:29]>>[CH3:27][O:28][N:29]=[C:17]1[C:18]2[C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:26])[CH3:1])=[N:7][C:8]3[C:23]([CH3:24])=[C:22]([OH:25])[CH:21]=[CH:20][C:9]=3[C:10]=2[C:11]2[CH:12]=[CH:13][N:14]=[CH:15][C:16]1=2
Reactant: Cc1c(O)ccc2c3c(c(NCCN(C)C)nc12)C(=O)c1cnccc1-3
Reactant: CON
Product: CON=C1c2cnccc2-c2c1c(NCCN(C)C)nc1c(C)c(O)ccc21

Procedure:
This compound was prepared from the compound of 6-(2-dimethylamino-ethylamino)-3-hydroxy-4-methyl-5,9-diaza-benzo[c]fluoren-7-one (Example 46) and O-methylhydroxylamine in a similar manner to 52. The desired product was obtained as an orange powder. ESI−MS: m/z 378 (MH+); 1H-NMR (CDCl3): δ2.45 (6H, s), 2.56 (3H, s), 2.79 (2H, t, J=6 Hz), 3.86 (2H, quartet like, J=ca 6 Hz), 4.31 (3H, s), 6.78 (1H, d, J=9 Hz), 7.10 (1H, brt, J=ca 6 Hz), 7.72 (1H, d, J=9 Hz), 7.76 (1H, d, J=5 Hz), 8.66 (1H, d, J=5 Hz), 9.41 (1H, s).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH2:3]1.[CH2:13](I)[CH3:14]>>[CH2:13]([N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH2:3][C:2]1=[O:1])[CH3:14]
Reactant: CCI
Reactant: O=C1CCNc2ccccc2N1
Product: CCN1C(=O)CCNc2ccccc21

Procedure:
2-Oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (1.95 g, 11.96 mmol) was reacted with ethyl iodide (1.4 ml, 17.5 mmol) according to the procedure in Example 18A. The product was purified by flash chromatography on silica (eluant EtOAc); yield 1.70 g (75%).
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:16])[NH:10][C:11](=[O:15])[NH:12][C:13]=1Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH2:30][CH2:29][CH:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:27][CH:26]=2)O1.[F-].[Cs+]>O1CCOCC1.O.[Cl-].[NH4+]>[CH2:1]([C:8]1[C:9](=[O:16])[NH:10][C:11](=[O:15])[NH:12][C:13]=1[C:34]1[CH2:35][CH2:36][CH:31]([C:28]2[CH:27]=[CH:26][CH:25]=[CH:30][CH:29]=2)[CH2:32][CH:33]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(Cl)c(Cc2ccccc2)c(=O)[nH]1
Reactant: CC1(C)OB(C2=CCC(c3ccccc3)CC2)OC1(C)C
Agent: [Cl-]
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]c(C2=CCC(c3ccccc3)CC2)c(Cc2ccccc2)c(=O)[nH]1
Temperature: 140 °C
Yield: 31.7 %

Procedure:
A mixture of 5-benzyl-6-chloro-1H-pyrimidine-2,4-dione (WO06014394) (1.0 g), 4,4,5,5-tetramethyl-2-(4-phenylcyclohex-1-enyl)-[1,3,2]dioxaborolane (1.4 g), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (0.06 g) and cesium fluoride (1.92 g) in 1,4-dioxane (18 mL) and water (2 mL) was heated at 140° C. in a microwave reactor for 20 minutes. The resulting mixture was diluted with saturated aqueous ammonium chloride and filtered to remove the precipitate. The filtrate was extracted with dichloromethane and the combined organic layers washed with water and brine, then dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel, eluting with a mixture of methanol and dichloromethane (0:1 to 1:20 by volume) to afford the title compound 2a as an off-white solid (0.48 g). LCMS (Method A): Rt=3.56 min. (M+H)+=359. 1H NMR (DMSO-D6): δ 11.06 (1H, s), 10.69 (1H, s), 7.23-7.21 (10H, m), 5.84-5.79 (1H, m), 3.61 (2H, s), 3.57 (1H, s), 2.77-2.67 (1H, m), 2.19-2.16 (3H, m), 1.84-1.81 (1H, m), 1.68-1.67 (1H, m).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([CH2:22][C:23]([NH2:25])=[O:24])=[CH:9][N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+].C(OCC)(=O)C>CO>[NH2:25][C:23](=[O:24])[CH2:22][C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:26])=[O:2])[N:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1
Reactant: COC(=O)COc1cccc2c1c(CC(N)=O)cn2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: NC(=O)Cc1cn(Cc2ccccc2)c2cccc(OCC(=O)O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.3 %

Procedure:
A mixture of 100 mg (0.26 mmol) of 2-[[3-(2-amino-2-oxoethyl)-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid methyl ester and 2 mL of 1N NaOH in 6 mL of MeOH was stirred at room temperature for 2 hours. Hater and ethyl acetate were added and the aqueous layer separated, made acidic to pH 3 with 1N HCl and ethyl acetate added. The ethyl acetate solution was washed with brine, dried (MgSO4), and concentrated at reduced pressure. The residue was stirred with methylene chloride and filtered to give 17 mg (56% yield) of 2-[[3-(2-amino-2-oxoethyl)-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid, mp, 207-208° C.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C@H:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:9]1)C1C=CC=CC=1.C(O)(=O)C>C(O)C.[Pd]>[CH2:22]([O:21][C:19]([C@H:10]1[C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:12][NH:8][CH2:9]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccccn1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)[C@@H]1CNC[C@H]1c1ccccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1-benzyl-trans-3-ethoxycarbonyl-4-(2-pyridyl)pyrrolidine from step 2 above (5.0 g, 16 mmol) and 10% Pd on carbon (750 mg) in ethanol (30 mL) containing acetic acid (3 mL) was shaken under an atmosphere of hydrogen (40 psi) on a Parr apparatus at ambient temperature for 18 h. The catalyst was removed by filtration and the filtrate solvents were removed in vacuo. The residue was partitioned between CH2Cl2 and aqueous NaHCO3. The organic phase was separated, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as an oil (3.3 g; HPLC RT=2.43 min, method A).
Reaction SMILES: [F:1][C:2]1[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:4][N:5]([C:7]2[N:17]=[CH:16][CH:15]=[CH:14][C:8]=2[C:9]([O:11]CC)=[O:10])[CH:6]=1.[OH-].[Na+]>CO>[F:1][C:2]1[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:4][N:5]([C:7]2[N:17]=[CH:16][CH:15]=[CH:14][C:8]=2[C:9]([OH:11])=[O:10])[CH:6]=1
Reactant: CCOC(=O)c1cccnc1-n1cc(F)c(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccnc1-n1cc(F)c(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To ethyl 2-(4-fluoro-3-phenyl-1H-pyrazol-1-yl)nicotinate (1.49 g, 4.79 mmol) in methanol (40 ml) 8.5 ml of an aqueous 2 m NaOH-solution (17 mmol) was added dropwise at 10° C., and the mixture was stirred for 2 h at room temperature and then for 3 h at 65° C. After completion of the reaction the mixture was concentrated under reduced pressure, dissolved in water and acidified using 2 n HCl. The precipitate formed was filtered off, washed with water and dried to give 1.23 g of a white amorphous solid; ESI-MS [M+H]+: 284.1.
Reaction SMILES: O1CCCC1.[CH2:6]([NH2:8])[CH3:7].CS([C:12]1[N:13]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[CH:26][CH:25]=2)[C:14](=[O:23])[C:15]2[CH:21]=[CH:20][C:19](=[O:22])[NH:18][C:16]=2[N:17]=1)=O.Cl>O1CCCC1>[CH2:6]([NH:8][C:12]1[N:13]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[CH:28][CH:29]=2)[C:14](=[O:23])[C:15]2[CH:21]=[CH:20][C:19](=[O:22])[NH:18][C:16]=2[N:17]=1)[CH3:7]
Reactant: CCN
Reactant: CS(=O)c1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCNc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Ethylamine tetrahydrofuran solution (2M, 2 ml) was diluted with tetrahydrofuran (2 ml), 2-(methylsulfinyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (100 mg) was added thereto at room temperature, and the mixture was stirred at room temperature for 10 min. The pH of the reaction mixture was adjusted to about 7 with 0.5M hydrochloric acid (about 4 ml), and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained white residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (52 mg) as a white solid.
Reaction SMILES: CC1C=CC(S(O[C:12]2[C:21]3[C:20](=[O:22])[N:19]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[C:18](=[O:32])[N:17]([C:33]4[CH:38]=[CH:37][C:36]([I:39])=[CH:35][C:34]=4[F:40])[C:16]=3[N:15]([CH3:41])[C:14](=[O:42])[C:13]=2[CH3:43])(=O)=O)=CC=1.N1C(C)=CC=CC=1C.[NH2:52][C:53]1[CH:54]=[C:55]([CH:60]=[CH:61][CH:62]=1)[C:56]([O:58][CH3:59])=[O:57].O>CC(N(C)C)=O>[F:40][C:34]1[CH:35]=[C:36]([I:39])[CH:37]=[CH:38][C:33]=1[N:17]1[C:16]2[N:15]([CH3:41])[C:14](=[O:42])[C:13]([CH3:43])=[C:12]([NH:52][C:53]3[CH:54]=[C:55]([CH:60]=[CH:61][CH:62]=3)[C:56]([O:58][CH3:59])=[O:57])[C:21]=2[C:20](=[O:22])[N:19]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[C:18]1=[O:32]
Reactant: COC(=O)c1cccc(N)c1
Reactant: COc1ccc(Cn2c(=O)c3c(OS(=O)(=O)c4ccc(C)cc4)c(C)c(=O)n(C)c3n(-c3ccc(I)cc3F)c2=O)cc1
Solvent: Cc1cccc(C)n1
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1cccc(Nc2c(C)c(=O)n(C)c3c2c(=O)n(Cc2ccc(OC)cc2)c(=O)n3-c2ccc(I)cc2F)c1
Temperature: 130 °C
Yield: 49.7 %

Procedure:
To a stirred solution of 1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl 4-methylbenzene sulfonate (3a) (8.70 gm, 12.13 mmol) in DMA (10 ml) was added 2,6-lutidine (3.5 ml, 30.3 mmol) and methyl 3-aminobenzoate (5.5 g, 36.4 mmol). The reaction mixture was heated at 130° C. for 16 h. The reaction mixture was cooled to room temperature and water was added followed by extraction with Ethyl acetate. The organic phase was dried over sodium sulphate. The solvent was evaporated in vacuo and the residual solid was purified by silica gel column chromatography, eluting with Hexane:Ethyl acetate, to yield the titled compound (3b) (4.2 g)
Reaction SMILES: C([NH:5][C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([C:18]1[O:19][C:20]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:21]=3[CH:22]=1)[C:12]([N:28]([CH3:32])[CH:29]([CH3:31])[CH3:30])=[N:11]2)=O)(C)(C)C.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>ClCCl>[F:27][C:24]1[CH:25]=[CH:26][C:20]2[O:19][C:18]([C:13]3[C:12]([N:28]([CH3:32])[CH:29]([CH3:31])[CH3:30])=[N:11][C:10]4[C:15](=[CH:16][CH:17]=[C:8]([C:6]#[N:5])[CH:9]=4)[N:14]=3)=[CH:22][C:21]=2[CH:23]=1
Reactant: CC(C)N(C)c1nc2cc(C(=O)NC(C)(C)C)ccc2nc1-c1cc2cc(F)ccc2o1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)N(C)c1nc2cc(C#N)ccc2nc1-c1cc2cc(F)ccc2o1
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To a solution of N-tert-butyl-2-(5-fluorobenzofuran-2-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxamide (600 mg, crude) in dichloromethane (30 ml) was added TFAA (3 ml) with stifling overnight at room temperature. The reaction mixture was quenched with water (80 ml) and adjusted to pH 8 with sodium bicarbonate solution, extracted with dichloromethane (4×50 ml), and the organic layers combined and concentrated in vacuo to give the residue, which was purified by silica gel column chromatography (1% ethyl acetate in petroleum ether) to afford 2-(5-fluorobenzofuran-2-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carbonitrile as a yellow solid (400 mg, 80%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:15]2[CH2:24][C:23]([CH3:26])([CH3:25])[C:22]3[C:17](=[C:18]([C:27](O)=[O:28])[CH:19]=[CH:20][CH:21]=3)[CH2:16]2)=[N:6][C:7]=1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[S:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[NH2:39].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[S:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[NH:39][C:27]([C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[CH2:16][N:15]([C:5]1[N:6]=[C:7]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:24][C:23]2([CH3:25])[CH3:26])=[O:28]
Reactant: CC(C)(C)OC(=O)c1nc(N2Cc3c(C(=O)O)cccc3C(C)(C)C2)ccc1Br
Reactant: Nc1nc2ccccc2s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)(C)OC(=O)c1nc(N2Cc3c(C(=O)Nc4nc5ccccc5s4)cccc3C(C)(C)C2)ccc1Br
Temperature: 40 °C

Procedure:
An ambient solution of EXAMPLE 14B (182 mg), benzo[d]thiazol-2-amine (71.1 mg), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (113 mg), 1-hydroxybenzotriazole hydrate (91 mg), and N-methylmorpholine (0.065 mL) was stirred overnight. An additional 1 equivalent each of 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride, N-methylmorpholine, 1-hydroxybenzotriazole hydrate, and 2-aminobenzothiazole were added, and the reaction was heated to 40° C. for 4 hours. The reaction mixture was cooled to room temperature and quenched by the addition of saturated aqueous bicarbonate solution and ethyl acetate. The layers were separated, and the aqueous was extracted with additional 2× ethyl acetate. The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel with 0-50% ethyl acetate/hexanes to provide the title product.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=1)[NH2:32]>>[N:1]1([C:7]([N:9]2[CH2:10][CH:11]([C:26]3[O:27][N:32]=[C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:40])([F:41])[F:42])[CH:34]=4)[N:30]=3)[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=3)[CH2:14]2)=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: NC(=NO)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3cccc(C(F)(F)F)c3)no2)C1

Procedure:
150 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 114 mg (0.56 mmol, 1.5 eq.) of N′-hydroxy-3-(trifluoromethyl)benzenecarboximidamide were reacted according to the General Method 2. Yield: 123 mg (58% of theory).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)=[O:4].[OH-].[K+].[N:22]1[N:23]([C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=2[O-:38])[N:24]=[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=12>C(#N)C>[N:22]1[N:23]([C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=2[O:38][CH2:2][C:3]([C:5]2[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=2)=[O:4])[N:24]=[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=12
Reactant: Cc1ccc([O-])c(-n2nc3ccccc3n2)c1
Reactant: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1ccc(OCC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(-n2nc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
6.54 g (20 mmol) of 2-bromo-1-(4-hydroxy-3,5-di-tert-butylphenyl)-ethanone and 1.98 g (30 mmol) of potassium hydroxide are dissolved in 150 ml of acetonitrile and stirred under inert atmosphere at room temperature for 30 minutes. Then 5.27 g (20 mmol) of 2-benzotriazol-2-yl-4-methyl-phenolate is added in portions. Stirring at room temperature is continued for additional 3 hours. After adjusting the pH to 6-7 the mixture is extracted with ethyl acetate. The collected organic phases are washed with water, dried and evaporated. Crystallization of the crude product from methanol gives 6.85 g of compound 106, m.p. 155-157° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1.N1C=C(C(O)=O)C=NC=1.[C:25]([O:29][C:30](N1CCC(N)CC1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(NC1CCNCC1)c1cncnc1
Agent: O=C(O)c1cncnc1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cncnc2)CC1

Procedure:
In analogy to the procedure described in example 50k), pyrimidine-5-carboxylic acid piperidin-4-ylamide [prepared in analogy to the procedures described in examples 50 h) and 50i) by condensation of pyrimidine-5-carboxylic acid with 4-amino-piperidine-carboxylic acid tert-butyl ester to give 4-[(pyrimidine-5-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester followed by Boc cleavage with trifluoroacetic acid] was reacted with 3,5-diethoxy-4-fluoro-benzaldehyde (example 50 g), sodium cyano-borohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as light yellow solid. MS: 403.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[N+:13]([O-])=O>C(O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[NH2:13]
Reactant: Cc1cc(-n2cncn2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(-n2cncn2)ccc1N
Yield: 99.6 %

Procedure:
2-Methyl-4-(1,2,4-Triazol-1-yl)nitrobenzene (1.0 g, 4.9 mmol) and Pd/C (200 mg) in ethanol (50 ml) were hydrogenated at rtp for 3 days. The suspension was filtered through celite, evaporated under reduced pressure to afford a white solid (850 mg, 100%).
Reaction SMILES: [CH3:1][C:2]1[C:14]([OH:15])=[C:13]([CH3:16])[C:12]([CH3:17])=[C:11]2[C:3]=1[CH2:4][CH2:5][C:6]1([O:10]2)[CH2:9][CH2:8][CH2:7]1.[OH-].[Na+].[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(Cl)Cl>[Cl:20][CH2:21][C:22]([O:15][C:14]1[C:2]([CH3:1])=[C:3]2[C:11](=[C:12]([CH3:17])[C:13]=1[CH3:16])[O:10][C:6]1([CH2:7][CH2:8][CH2:9]1)[CH2:5][CH2:4]2)=[O:23]
Reactant: O=C(Cl)CCl
Reactant: Cc1c(C)c2c(c(C)c1O)CCC1(CCC1)O2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1OC(=O)CCl)CCC1(CCC1)O2
Temperature: 0 °C

Procedure:
A solution of 5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol (500 mg) in anhydrous CH2Cl2 (3 mL) was mixed with a 15% aq. NaOH solution (2.0 mL). The resulting mixture was cooled to 0° C. and stirred vigorously while being treated with slow addition of a solution of chloroacetyl chloride (0.534 mL) in CH2Cl2 (2 mL). The reaction mixture was allowed to warm up to ambient temperature and stirred for an additional 6 h. Upon layer separation, organic phase was collected and dried over Na2SO4, followed by solvent evaporation. Column chromatography (SiO2: hexane:EtOAc, 95:5 v/v) yielded 5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-yl chloroacetate as a pale yellow solid (204 mg).
Reaction SMILES: C[O:2][C:3]([C:5]([C@H:27]1[CH2:30][C@@H:29]([C:31]([O:33]C)=[O:32])[CH2:28]1)([CH2:9][CH2:10][CH:11]1[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:18](=[O:26])(=[O:25])[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)C(O)=O)=[O:4].C([N:37](CC)CC)C>C1(C)C=CC=CC=1>[NH2:37][C:5]([C@H:27]1[CH2:30][C@@H:29]([C:31]([OH:33])=[O:32])[CH2:28]1)([CH2:9][CH2:10][CH:11]1[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:18](=[O:26])(=[O:25])[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:3]([OH:2])=[O:4]
Reactant: COC(=O)C(CCC1c2ccccc2S(=O)(=O)c2ccccc21)(C(=O)O)[C@H]1C[C@@H](C(=O)OC)C1
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Product: NC(CCC1c2ccccc2S(=O)(=O)c2ccccc21)(C(=O)O)[C@H]1C[C@@H](C(=O)O)C1
Temperature: 75 °C

Procedure:
A mixture of cis-2-methoxycarbonyl-2-(3-methoxy carbonylcyclobutyl)-4-(10,10-dioxido-9-thioxanthyl)butanoic acid (0.87 g, 1.79 mmol), triethylamine (0.19 g, 1.88 mmol) and diphenyl phosphonic azide (0.33 g, 1.88 mmol) in toluene (30 ml) were heated at 75° C. and worked up following the procedure described in Example 17(iii). The crude product was purified by chromatography on flash silica eluting with diethyl ether-hexane (7:3) to give a colourless oil and then crystallised from diethyl ether to give the title compound.