Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.I[CH:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH:13]([CH3:15])[CH3:14])[CH:7]=1
Reactant: CC(C)I
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 65.4 %

Procedure:
A mixture of 5-fluoro-2-nitrophenol (91.0 g), 2-iodopropane (103.4 g), potassium carbonate (146 g) and N,N-dimethylformamide (600 mL) was stirred at 50° C. for 3.5 h. The mixture was concentrated under reduced pressure and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=0/100 to 30/70, volume ratio) to give the title compound (75.4 g, 65%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4](Cl)[CH:3]=1.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>CN1C(=O)CCC1.O>[NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])[CH:3]=1
Reactant: CCNCC
Reactant: Nc1cc(Cl)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCN(CC)c1cc(N)c([N+](=O)[O-])cc1C(=O)Nc1ccc2cn[nH]c2c1
Temperature: 25 °C

Procedure:
A solution 4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide (1 mmol; see Example 48) in NMP (2 mL) was added with diethylamine (1.0 mL), and the resulting mixture was subjected to microwave irradiation at 70° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with water (20 mL). The solid formed was collected by filtration, washed with water, and dried in vacuo to provide 4-amino-2-diethylamino-N-(1H-indazol-6-yl)-5-nitrobenzamide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]3=[N:18][S:19](=[O:23])(=[O:22])[CH2:20][CH2:21][N:16]3[CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1>C1COCC1.CO.[Pt](=O)=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[C:17]3=[N:18][S:19](=[O:22])(=[O:23])[CH2:20][CH2:21][N:16]3[CH2:15][CH2:14][CH2:13]2)=[CH:10][CH:11]=1
Reactant: Cc1cccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)c1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cccc(Oc2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 67.5 %

Procedure:
Platinum(IV) oxide (30 mg) was added to a solution of 9-[4-(3-methylphenoxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (357 mg) in THF (dry) (80 mL) and MeOH (80 mL) and the mixture was stirred at 50° C. under hydrogen for 6 hr. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from MeCN-THF/IPE to give the title compound (243.5 mg) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]=2[CH3:15])[O:4][N:3]=1.[H][H]>C(O)C.[Pt]=O>[CH3:15][C:8]1[CH2:9][CH2:10][CH2:11][C:12]([CH3:13])([CH3:14])[C:7]=1[C:5](=[O:4])[CH:6]=[C:2]([NH2:3])[CH3:1]
Reactant: CC1=C(c2cc(C)no2)C(C)(C)CCC1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CC(N)=CC(=O)C1=C(C)CCCC1(C)C
Yield: 99.4 %

Procedure:
30.75 g (0.15 mole) of 3-methyl-5-[2,6,6-trimethyl-cyclohex-1-en-1-yl]-isoxazole were dissolved in 50 ml of dry ethanol and the solution was added to 1.396 g of a mixture of 82.9% of platinum oxide in 600 ml of ethanol, the said mixture having previously been subjected to a hydrogenation. The alcoholic solution was then subjected to a hydrogenation at ordinary temperature and pressure and, after absorption of one equivalent of hydrogen, was filtered through a "Celite" carrier. After having been concentrated under reduced pressure, the residual mixture was recrystallized from hexene containing traces of ethanol to yield 30.91 g (yield 100%) of 2,6,6-trimethyl-1-[3-amino-but-2-enoyl]-cyclohex-1-ene which exists in two interconvertible crystalline structures: m.p. 124.5°-125.0° and 135°-136°.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[C:15]([Cl:16])=[C:14]([O:17][CH3:18])[CH:13]=[CH:12][C:11]=1[C:19](=[O:23])[CH2:20][CH2:21][CH3:22].[OH-].[Na+]>C(O)C>[Cl:16][C:15]1[C:10]([Cl:9])=[C:11]([C:19](=[O:23])[C:20](=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:21][CH3:22])[CH:12]=[CH:13][C:14]=1[O:17][CH3:18]
Reactant: O=Cc1ccccc1
Reactant: CCCC(=O)c1ccc(OC)c(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(=Cc1ccccc1)C(=O)c1ccc(OC)c(Cl)c1Cl

Procedure:
To a mixture of benzaldehyde (19.4 g., 0.183 mole) and 2',3'-dichloro-4'-methoxybutyrophenone (42.2 g., 0.183 mole) in absolute ethanol (350 ml.) a 20% sodium hydroxide solution (35.9 ml.) is added dropwise with stirring. The mixture is stirred for 22 hours. The white solid product that separates is collected and air dried. Yield 55.6 g. (91%), m.p. 127°-130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][O:12][CH2:13][CH3:14])=[CH:9][N:10]=2)[N:7]=1.[NH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.Cl>CCOCC>[ClH:1].[CH2:13]([O:12][CH2:11][C:8]1[N:6]2[N:7]=[C:2]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[CH3:14]
Reactant: CCOCc1cnc2ccc(Cl)nn12
Reactant: NCc1ccccn1
Agent: Cl
Solvent: CCOCC
Product: CCOCc1cnc2ccc(NCc3ccccn3)nn12
Yield: 18 %

Procedure:
Prepared from 6-chloro-3-(ethoxymethyl)imidazo[1,2-b]pyridazine (8b) and 2-(aminomethyl)pyridine according to general procedure 4 (step B). The free-base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (35 mg, 18%) as a white solid; 1H NMR (500 MHz, CD3OD) δ 8.53-8.52 (m, 1H), 7.90 (d, J=9.7 Hz, 1H), 7.86 (dt, J=1.7, 9.5 Hz, 1H), 7.78 (s, 1H), 7.56 (d, J=9.8 Hz, 1H), 7.38-7.36 (m, 1H), 7.26 (d, J=9.8 Hz, 1H), 4.73 (s, 2H), 4.68 (s, 2H), 3.49 (q, J=7.0 Hz, 2H), 1.10 (t, J=7.1 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 158.9, 156.6, 149.3, 139.6, 134.7, 128.7, 124.2, 123.6, 123.0, 122.5, 119.9, 67.5, 60.9, 47.4, 15.4; HPLC tR=7.4 min (Luna), 98.5%; ES-MS: (M+H)=284 m/z.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[CH:4][C:3]=1[N+:13]([O-])=O>CO.[Pd]>[NH2:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[CH:4][C:3]=1[NH2:13]
Reactant: CCNC(=O)c1cncc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CO
Product: CCNC(=O)c1cncc(N)c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.4 %

Procedure:
To a solution of 4-amino-N-ethyl-5-nitronicotinamide (CXXVII) (180 mg, 0.856 mmol) in MeOH (5 mL) was added 10% Pd/C (27 mg, 15% by wt). The solution was purged with hydrogen and stirred for 16 h at room temperature under hydrogen. The suspension was filtered through Celite and concentrated under vacuum. The residue was purified on a silica gel column (100% CHCl3→10:90 MeOH[7N NH3]:CHCl3) to produce 4,5-diamino-N-ethylnicotinamide (CXXVIII) as a dark yellow solid (80 mg, 0.44 mmol, 51.9% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.14 (t, J=7 Hz, 3H), 3.92 (q, J=7 Hz, 2H) 5.56 (brs, 2H), 6.60 (brs, 1H), 7.66 (s, 1H), 8.30 (s, 1H); ESIMS found C8H12N4O m/z 181 (M+H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([CH2:9][NH:10][CH2:11][CH2:12][N:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[C:22]([O:24]C)=[O:23])[CH:15]=[N:14]3)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.O.[OH-].[Li+:28]>O1CCCC1.O>[N:1]12[CH2:8][CH2:7][C:4]([CH2:9][NH:10][CH2:11][CH2:12][N:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[C:22]([O-:24])=[O:23])[CH:15]=[N:14]3)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Li+:28]
Reactant: COC(=O)c1cccc2cnn(CCNCC34CCN(CC3)CC4)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])c1cccc2cnn(CCNCC34CCN(CC3)CC4)c12
Yield: 211.1 %

Procedure:
A mixture of methyl 1-(2-(quinuclidin-4-ylmethylamino)ethyl)-1H-indazole-7-carboxylate (563 mg, 1.7 mmol) from Step F above and lithium hydroxide monohydrate (207 mg, 4.9 mmol) in tetrahydrofuran/water (16 mL; 1:1) was stirred at reflux until the reaction was complete by TLC and/or LC-MS. The solvent was removed under reduced pressure to give lithium 1-(2-(quinuclidin-4-ylmethylamino)ethyl)-1H-indazole-7-carboxylate (1.20 g, crude): 1H NMR (300 MHz, CD3OD) δ 8.03 (s, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.55 (d, J=7.2 Hz, 1H), 7.11 (t, J=7.4 Hz, 1H), 3.28-3.20 (m, 2H); 2.98 (t, J=6.6 Hz, 2H), 2.81 (t, J=7.5 Hz, 6H), 2.28 (s, 2H), 1.36 (t, J=8.1 Hz, 6H).
Reaction SMILES: [C:1]12([O:11][C:12]3[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=3[Cl:19])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH2:21][CH2:22][CH2:23][CH2:24]Br.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:1]12([O:11][C:12]3[CH:18]=[CH:17][C:15]([N:16]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:14][C:13]=3[Cl:19])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: BrCCCCBr
Reactant: Nc1ccc(OC23CC4CC(CC(C4)C2)C3)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Clc1cc(N2CCCC2)ccc1OC12CC3CC(CC(C3)C1)C2

Procedure:
1.7 g. (0.00612 Mole) of 4-(1-adamantyloxy)-3-chloroaniline, 1.32 g. (0.00612 mole) of 1,4 -dibromobutane and 1.86 g. (0.0135 mole) of potassium carbonate were combined in 50 ml. of absolute ethanol and refluxed for 18 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:27])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=2[CH:26]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].Br[C:29]([CH3:36])([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31].[OH-].[Na+].Cl>CC(N(C)C)=O.O>[CH2:33]([O:32][C:30](=[O:31])[C:29]([O:8][C:6]1[CH:5]=[CH:4][C:3]([CH:9]([CH3:27])[C:10]([OH:15])([C:16]2[CH:17]=[CH:18][C:19]3[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=3[CH:26]=2)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=1)([CH3:36])[CH3:35])[CH3:34]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C(C)(C)Oc1ccc(C(C)C(O)(c2ccc3oc(=O)n(C)c3c2)C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5-[2-(2-Chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (80 mg, obtained in Example 172) and ethyl 2-bromoisobutyrate (0.2 mL) were dissolved in dimethylacetamide (2 mL). Powdered sodium hydroxide (54 mg) was added to this solution and the mixture was allowed to stir at r.t. for 12 hours. The mixture was poured into water and ice and was acidified to pH 3 with 2N HCl. The aqueous phase was extracted with ethyl acetate two times and the organic extracts were washed with brine, dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate:hexanes=4:1) to provide the title compound 2-{3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(3-methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl)-propyl]-phenoxy}-2-methyl-propionic acid ethyl ester as a colorless foam (113 mg). MS (m/e, ISP neg. ion)=514.1 [M−H+].
Reaction SMILES: C1(C)C=CC(S([CH:10]([N+:18]#[C-:19])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)(=O)=O)=CC=1.[N:21]1[CH:26]=[CH:25][C:24]([CH:27]=[N:28][CH:29]2[CH2:37][CH:36]3[N:32]([CH2:33][CH2:34][CH2:35]3)[CH2:31][CH2:30]2)=[CH:23][CH:22]=1.C1CCN2C(=NCCC2)CC1>ClCCl>[F:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[N:18]=[CH:19][N:28]([CH:29]3[CH2:37][CH:36]4[N:32]([CH2:33][CH2:34][CH2:35]4)[CH2:31][CH2:30]3)[C:27]=2[C:24]2[CH:23]=[CH:22][N:21]=[CH:26][CH:25]=2)=[CH:16][CH:15]=1
Reactant: C(=NC1CCN2CCCC2C1)c1ccncc1
Reactant: [C-]#[N+]C(c1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: Fc1ccc(-c2ncn(C3CCN4CCCC4C3)c2-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.8 %

Procedure:
α-(p-Toluenesulfonyl)-4-fluorobenzylisocyanide (10.1 g, 34.9 mmol) and (±)-7-(4-pyridylmethyleneamino)-1,2,3,5,6,7,8,8a-octahydroindolizine (8.0 g (34.9 mmol), prepared as described in 2)) were dissolved in dichloromethane (150 ml). To the solution was added 1,8-diazabicyclo[5.4.0]-7-undecene (5.22 ml, 34.9 mmol), and the resulting mixture was stirred at room temperature for 2 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure. To the residue was added a saturated aqueous solution of sodium hydrogencarbonate and this was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel (eluent, ethyl acetate:methanol:isopropylamine=20:1:1), to give the title compound (1.87 g) as a pale yellow powder (yield 14%).
Reaction SMILES: [OH-].[Na+].C1(C)C=CC=CC=1.[C:10]([C:14]1[CH:15]=[C:16]([CH:37]=[C:38]([C:41]([CH3:44])([CH3:43])[CH3:42])[C:39]=1[OH:40])[C:17]([O:19][C:20]1[C:28]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:27][C:23]([C:24]([O-:26])=[O:25])=[CH:22][C:21]=1[C:33]([CH3:36])([CH3:35])[CH3:34])=[O:18])([CH3:13])([CH3:12])[CH3:11].[Na+].Cl>CCOCC>[C:41]([C:38]1[CH:37]=[C:16]([CH:15]=[C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:39]=1[OH:40])[C:17]([O:19][C:20]1[C:21]([C:33]([CH3:34])([CH3:35])[CH3:36])=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:27][C:28]=1[C:29]([CH3:32])([CH3:31])[CH3:30])=[O:18])([CH3:42])([CH3:43])[CH3:44]
Reactant: CC(C)(C)c1cc(C(=O)Oc2c(C(C)(C)C)cc(C(=O)[O-])cc2C(C)(C)C)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C)c1cc(C(=O)Oc2c(C(C)(C)C)cc(C(=O)O)cc2C(C)(C)C)cc(C(C)(C)C)c1O
Temperature: 30 °C

Procedure:
450 ml of 2N sodium hydroxide were added to the toluene filtrate at room temperature and gradually heated to reflux. The reaction was heated at reflux for 41/2 hours. The reaction mixture was cooled to 0° to 5° C. by an ice-water bath whereupon a thick precipitate formed consisting of the intermediate sodium 4-(3,5-di-tert-butyl-4-hydroxybenzoyloxy)-3,5-di-tert-butylbenzoate. 70 ml of concentrated aqueous hydrochloric acid was gradually added dropwise with cooling at 30° C. 150 ml of ether was added with stirring to the reaction mixture at 20° to 25° C. The aqueous phase was separated and the organic phase washed with two 100 ml portions of water. The separated organic phase was then dried over anhydrous sodium sulfate. The residue was isolated from the organic phase by evaporation of the solvent initially at about 20 mm Hg. pressure and finally at 0.5 mm Hg.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH2:4][CH2:3]1.[C:19]1([CH3:30])[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:29])[CH2:27]Cl)=[CH:21][CH:20]=1>>[CH3:30][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([CH2:27][NH:1][CH:2]2[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:12])[CH2:4][CH2:3]2)=[O:29])=[CH:21][CH:20]=1
Reactant: Cc1ccc(NC(=O)CCl)cc1
Reactant: NC1CCN(CCCC(=O)c2ccccc2)CC1
Product: Cc1ccc(NC(=O)CNC2CCN(CCCC(=O)c3ccccc3)CC2)cc1

Procedure:
Using a procedure analogous to Example 1 4-amino-1-(4-phenyl-4-oxobutyl) piperidine may be reacted with N-(p-tolyl) chloro-acetamide to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][NH:15][C:16]([C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23]([C@@H:25]2[CH2:29][C@@H:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][N:26]2[C:35](=[O:62])[CH2:36][C:37]([C:54]2[CH:59]=[CH:58][C:57]([CH:60]=[CH2:61])=[CH:56][CH:55]=2)([C:46]2[CH:51]=[CH:50][C:49]([CH:52]=[CH2:53])=[CH:48][CH:47]=2)[C:38]2[CH:43]=[CH:42][C:41]([CH:44]=[CH2:45])=[CH:40][CH:39]=2)=[O:24])=[O:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[C].[Pd].[H][H]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][NH:15][C:16]([C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23]([C@@H:25]2[CH2:29][C@@H:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][N:26]2[C:35](=[O:62])[CH2:36][C:37]([C:54]2[CH:55]=[CH:56][C:57]([CH2:60][CH3:61])=[CH:58][CH:59]=2)([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][CH3:45])=[CH:40][CH:39]=2)[C:46]2[CH:51]=[CH:50][C:49]([CH2:52][CH3:53])=[CH:48][CH:47]=2)=[O:24])=[O:17])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1ccc(C(CC(=O)N2C[C@H](OC(C)(C)C)C[C@H]2C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(C(=O)OC(C)(C)C)C2)(c2ccc(C=C)cc2)c2ccc(C=C)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(C(CC(=O)N2C[C@H](OC(C)(C)C)C[C@H]2C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(C(=O)OC(C)(C)C)C2)(c2ccc(CC)cc2)c2ccc(CC)cc2)cc1
Reaction time: 4.5 h
Yield: 76.4 %

Procedure:
To a solution of 15.6 mg of (2R)-N-({(3R)-1-(tert-butoxy-carbonyl)-3-piperidyl}methyl)-1-((2S,4R)-4-(tert-butoxy)-1-{3,3,3-tris(4-vinylphenyl)-propanoyl}pyrrolidin-2-yl)carbonylpyrrolidine-2-carboxamide in 0.6 ml of methanol, 5 mg of 10% palladium-carbon catalyst was added at room temperature, followed by 4.5 hours' stirring in hydrogen atmosphere. After filtering the catalyst off, the solvent was distilled off under reduced pressure to provide 12 mg of the title compound.
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16](Cl)[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2].[O:20]1CCOC[CH2:21]1.C[O-].[Na+]>CO>[N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16]([O:20][CH3:21])[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C1COCCO1
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(Cl)nn12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2nnc(-c3ncc([N+](=O)[O-])n3C)n2n1

Procedure:
1.96 g. crude 3-(5-nitro-1-methyl-2-imidazolyl)-6- -chloro-s-triazolo[4,3-b]pyridazine was dissolved in 35 ml. of a mixture of dioxan and methanol (1:1), 0.84 g. sodium methylate added thereto, the reaction mixture heated under reflux for 1 hour, the solution then evaporated in a vacuum, the residue triturated with water, filtered with suction and dried at 120° C. in a vacuum. There was thus obtained 0.64 g. of the desired 3-(5-nitro-1-methyl-2-imidazolyl)-6-methoxy-s-triazolo[4,3-b] pyridazine, which has a melting point of 193° - 198° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:30][CH:19]3[CH2:20][N:21](C(OC(C)(C)C)=O)[CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.Cl.CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:30][CH:19]3[CH2:20][NH:21][CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cn1cc(Nc2ncc(Cl)c(NC3CC4CN(C(=O)OC(C)(C)C)CC4C3)n2)cn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cn1cc(Nc2ncc(Cl)c(NC3CC4CNCC4C3)n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a solution of tert-butyl 5-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (672.6 mg, 1.55 mmol) in DCM (10 mL) was added a solution of HCl in EtOAc (10 mL, 40 mmol). The reaction mixture was stirred at rt overnight and concentrated in vacuo. The residue was dissolved in water (30 mL) and adjusted to pH=10 with saturated Na2CO3 aqueous solution, then extracted with DCM (250 mL×3). The combined organic phases were washed with brine (250 mL), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/5) to give the title compound as a beige solid (410 mg, 79.2%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:26])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])=[CH:7][C:6]=1[Cl:27].[NH:28]1[CH2:32][CH:31]=[CH:30][CH2:29]1>CCN(C(C)C)C(C)C>[Cl:27][C:6]1[CH:7]=[C:8]([NH:11][C:12](=[O:26])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:28]1[CH2:32][CH:31]=[CH:30][CH2:29]1
Reactant: C1=CCNC1
Reactant: O=C(COc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(OCCBr)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(OCCN2CC=CC2)c(Cl)c1

Procedure:
A solution of 0.145 g (0.300 mmol) of N-[4-(2-bromo-ethoxy)-3-chloro-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Z28b) and 30.6 μL (0.400 mmol) 2,5-dihydro-1H-pyrrole in 2 mL Hünig base was stirred for 3h at 80° C. and then evaporated down i. vac. Column chromatography (Alox, neutral, act. II-III, gradient dichloromethane/MeOH 20:0→19:1) yielded the product.
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]([CH2:26][N:27]3[CH2:32][CH2:31][S:30][CH2:29][CH2:28]3)[CH2:24][N:25]=1)=[CH:17]2)[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)(=[O:5])=[O:4].ClC1C=CC=C(C(OO)=[O:41])C=1>ClCCl.C(OCC)(=O)C>[CH3:1][N:2]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]([CH2:26][N:27]3[CH2:32][CH2:31][S:30](=[O:41])[CH2:29][CH2:28]3)[CH2:24][N:25]=1)=[CH:17]2)[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)(=[O:5])=[O:4]
Reactant: CN(c1cccc2cc(C3=NCC(CN4CCSCC4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(c1cccc2cc(C3=NCC(CN4CCS(=O)CC4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Reaction time: 3 h
Yield: 21 %

Procedure:
To a solution of N-methyl-N-{2-[5-(thiomorpholinomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}pyridine-2-sulfonamide (180 mg) in dichloromethane (8 mL) was added m-chloroperbenzoic acid (75 mL) under ice-cooling, and the mixture was stirred for 3 hr under ice-cooling. The reaction solution was diluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to basic silica gel column chromatography (ethyl acetate:hexane=6:4-9:1), and the obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (39 mg, yield: 21%) as colorless needle crystals. MS: 504 (MH+). melting point 193-194° C.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][CH:40]4[CH2:43][CH2:42][CH2:41]4)[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][CH:40]4[CH2:41][CH2:42][CH2:43]4)[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn(CC4CCC4)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(C)cc(-c3cn(CC4CCC4)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-cyclobutylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][NH2:6].[CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:16]=1[N:24]=[C:25]=[O:26])([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:22])[CH3:23])[C:16]=1[NH:24][C:25]([NH:6][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([OH:1])[CH:3]=1)=[O:26])([CH3:13])[CH3:14]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: COc1ccc(CN)cc1O
Solvent: Cc1ccccc1
Product: COc1ccc(CNC(=O)Nc2c(C(C)C)cccc2C(C)C)cc1O

Procedure:
Added to 40 ml of toluene were 600 mg (3.92 mmol) of 3-hydroxy-4-methoxybenzylamine and 810 mg (3.90 mmol) of 2,6-diisopropylphenyl isocyanate, and the mixture was stirred under reflux for 8 hours.