Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](O)=[O:28].C(Cl)(=O)C(Cl)=O.Cl.[CH3:40][NH:41][CH3:42].C(N(CC)CC)C>C(Cl)(Cl)Cl.CN(C)C=O.ClCCl>[CH3:40][N:41]([CH3:42])[C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([CH2:23][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]3([C:22]4[C:13](=[CH:14][C:15]5[O:20][CH2:19][CH2:18][O:17][C:16]=5[CH:21]=4)[O:12][CH2:11]3)[C:2]2=[O:1])[CH:25]=1
Reactant: CNC
Reactant: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C(=O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.6 %

Procedure:
To a solution of 3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoic acid (0.50 g, 1.16 mmol) in anhydrous chloroform (25 mL) was added oxalyl chloride (0.25 mL, 2.9 mmol) and anhydrous N,N-dimethylformamide (1 drop). The reaction mixture was stirred at ambient temperature for 2 h and concentrated in vacuo. The residue was dissolved in anhydrous dichloromethane (10 mL) and the resultant solution was added dropwise to a cooled (0° C.) solution of dimethylamine hydrochloride (1.56 g, 18.9 mmol) and triethylamine (5.27 mL, 37.8 mmol) in anhydrous dichloromethane (10 mL). The reaction mixture was stirred at 0° C. for 45 min and at ambient temperature for 3 h, filtered and concentrated in vacuo. The residue was recrystallized from hexanes to afford N,N-dimethyl-3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzamide (0.04 g, 8%) as a light brown solid: mp: 90-96° C. (hexanes); 1H NMR (300 MHz, CDCl3) δ 7.37-7.34 (m, 4H), 7.21-7.14 (m, 2H), 7.04-7.00 (m, 1H), 6.77-6.75 (m, 1H), 6.49 (s, 1H), 6.19 (s, 1H), 5.08-5.03 (m, 1H), 4.93-4.82 (m, 2H), 4.67-4.64 (m, 1H), 4.20-4.09 (m, 4H), 3.08 (s, 3H), 2.90 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.6, 171.1, 155.3, 144.7, 141.9, 138.3, 137.0, 136.0, 132.1, 129.1, 128.9, 128.3, 126.6, 126.0, 124.0, 123.6, 120.9, 111.5, 109.2, 99.5, 80.2, 64.5, 63.9, 58.0, 43.9, 39.6, 35.3; MS (ES+) m/z 456.8 (M+1).
Reaction SMILES: [CH:1]([C:4]1[C:5]([C:30]([C:32]2[CH:33]=[C:34]([CH:38]=[CH:39][C:40]#[N:41])[CH:35]=[CH:36][CH:37]=2)=[O:31])=[N:6][C:7]([O:20]CC2C=CC(OC)=CC=2)=[N:8][C:9]=1[O:10]CC1C=CC(OC)=CC=1)([CH3:3])[CH3:2]>C(#N)C>[CH:1]([C:4]1[C:9](=[O:10])[NH:8][C:7](=[O:20])[NH:6][C:5]=1[C:30]([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]#[N:41])[CH:35]=[CH:36][CH:37]=1)=[O:31])([CH3:3])[CH3:2]
Reactant: COc1ccc(COc2nc(OCc3ccc(OC)cc3)c(C(C)C)c(C(=O)c3cccc(C=CC#N)c3)n2)cc1
Solvent: CC#N
Product: CC(C)c1c(C(=O)c2cccc(C=CC#N)c2)[nH]c(=O)[nH]c1=O
Reaction time: 3 h
Yield: 34.8 %

Procedure:
To a stirred solution of 3-{3-[5-isopropyl-2,6-bis-(4-methoxy-benzyloxy)-pyrimidine-4-carbonyl]-phenyl}-acrylonitrile (1.25 g, 2.23 mmol) in acetonitrile (10 ml) at room temperature, was added ceric ammonium nitrate (3.67 g, 6.70 mmol) followed by distilled water (5 ml). After 3 hr., the reaction mixture was diluted with EA, washed with water, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a crude product as a white solid. The crude product was purified by silica gel column chromatography (eluent, EA:hexanes (4:1)) to afford 240 mg (35%) of a white solid. m.p. 210-211° C.; 1H NMR (200 MHz, CD3OD/CDCl3) δ 1.10 (6H, d, J=6.8 Hz), 2.39 (1H, m), 6.03 (1H, d, J=16.8 Hz), 7.45 (1H, d, J=16.8 Hz), 7.58 (3H, m), 8.01 (1H, s); m/z (LC/Mass, EI) 310 (M+H+).
Reaction SMILES: [CH:1]1([NH:7][S:8](Cl)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:12]([NH2:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(N(CC)CC)C.C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH:1]1([NH:7][S:8]([NH:28][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCCCCCCCCCCCCCCN
Reactant: O=S(=O)(Cl)NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCNS(=O)(=O)NC1CCCCC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 78.5 %

Procedure:
A solution of 13.6 g of the cyclohexylsulfamoyl chloride (69 mmol) in 100 mL of dichloromethane is added under argon atmosphere to a solution of 1-hexadecylamine (19.9 g, 82 mmol) and triethylamine (47.5 mL, 340 mmol) in 300 mL of dichloromethane. The reaction mixture is stirred 5 hours at 0° C., neutralized with an aqueous Na2CO3 solution and concentrated under reduced pressure. The residue is taken up in dichloromethane (800 mL). The organic components are successively washed with diluted hydrochloric aqueous solution, NaHCO3 aqueous solution and brine, dried (Na2SO4), and concentrated under reduced pressure. The residue is suspended in ether, filtered through Büchner, and the precipitate is washed two times with 100 ml of ether to yield a white powder of N-cyclohexyl-N′-hexadecylsulfamide (21.8 g, 79%).
Reaction SMILES: C[Si](C)(C)CCOC(=O)[NH:7][N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[CH:11][CH:10]=[C:9]1[C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:12]2[N:8]([NH2:7])[C:9]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:27][CH:28]=3)=[CH:10][CH:11]=2)=[CH:18][CH:17]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1ccc(-c2ccc(-c3ccc(C(C)(C)C)cc3)n2NC(=O)OCC[Si](C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2ccc(-c3ccc(C(C)(C)C)cc3)n2N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
[2,5-Bis-(4-tert-butyl-phenyl)-pyrrol-1-yl]-carbamic acid 2-trimethylsilanyl-ethyl ester (681 mg, 1.39 mmol) was treated with a 1 M solution of TBAF in THF (2.78 mL). The resulting solution was stirred at rt overnight, then quenched with glacial acetic acid (0.155 mL). The solution was passed through a short plug of silica gel, eluting with toluene and concentrated in vacuo to afford 2,5-Bis-(4-tert-butyl-phenyl)-pyrrol-1-ylamine (299 mg, 80% for two steps) as a creamy white solid: 1H NMR (CDCl3, chemical shifts in ppm relative to TMS): 1.36 (s, 18H), 4.60 (s, 2H), 6.24 (s, 2H), 7.46 (d, 4H, J=8.7 Hz), 7.52 (d, 4H, J=8.7 Hz).
Reaction SMILES: C([Li])(CC)C.[F:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)[CH:10]=[CH:11][CH:12]=1.[CH:23](N1CCOCC1)=[O:24].Cl>C1COCC1.C1CCCCC1>[F:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)[CH:10]=[CH:11][C:12]=1[CH:23]=[O:24]
Reactant: O=CN1CCOCC1
Reactant: Fc1cccc(-c2ccc3ccccc3c2)c1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccc3ccccc3c2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
A 86.86 ml cyclohexane solution of sec-butyl lithium in a concentration of 1.01M was dropped into a 300 ml THF solution of 15.00 g (=67.49 mmol) of 2-(3-fluorophenyl)naphthalene at −70° C. After the dropping was finished, the reaction solution was stirred at the same temperature for 1 hour, added with a 150 ml THF solution of 10.88 g (=94.49 mmol) of 4-formylmorpholine through dropping and then slowly heated to room temperature. After being stirred for 18 hours, 25 ml of 6N HCl(aq) was dropped into the reaction solution, and then the reaction mixture was extracted thrice with toluene. The extract was washed with water and an aqueous solution of NaHCO3, and then dried with anhydrous MgSO4. After the solvent was evaporated under a reduced pressure, the obtained yellow solid of 16.83 g was purified with silica gel chromatography using toluene as the eluent to obtain a yellowish solid of 13.26 g, which was further recrystallized with toluene to obtain 10.09 g of 2-fluoro-4-naphthalene-2-yl-benzaldehyde as yellowish crystals.
Reaction SMILES: [CH2:1]([C:7](=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:8]=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(OCC)(OCC)OCC.[C:27]([C@@H:32]([C@H:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[OH:35])O)([O:29][CH2:30][CH3:31])=[O:28]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:10](=[C:7]([CH:8]1[O:35][C@@H:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C@H:32]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[O:9]1)[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Reactant: CCCCCCC(C=O)=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(OCC)OCC
Product: CCCCCCC(=Cc1ccccc1)C1O[C@@H](C(=O)OCC)[C@H](C(=O)OCC)O1
Yield: 108.9 %

Procedure:
A solution of α-hexylcinnamaldehyde (62.19 g, 0.288 mole), triethyl orthoformate (42.61 g, 0.288 mole), diethyl L-tartrate (51.5 g, 0.25 mole) in toluene (180 ml) containing p-toluene sulfonic acid (0.8 g) was refluxed for 1 hour. About 100 ml of ethanol-toluene mixture was distilled over a period of 2 hours, and after cooling the remaining solvent was removed on a rotary evaporator. The residue was dissolved in toluene (200 ml) and the solution was washed with aqueous NaHCO3 and then with water. The solution was dried over Na2SO4, and the solvent was evaporated under reduced pressure to provide a brown liquid (110.1 g).
Reaction SMILES: [CH:1]1([NH:6][NH2:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C[O-].[Na+].C(O[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17])C>C(O)C>[NH2:19][C:18]1[N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:7]=[CH:14][C:15]=1[C:16]#[N:17]
Reactant: CCOC=C(C#N)C#N
Reactant: NNC1CCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cnn(C2CCCC2)c1N
Temperature: 70 °C
Yield: 34 %

Procedure:
Alternate Synthesis of 3: Cyclopentylhydrazine hydrochloride1 (1.08 g, 10 mmol) was dissolved in 100 mL anhydrous ethanol. Sodium methoxide (540 mg, 10 mmol) was added in one portion and the reaction mixture was stirred for ten minutes. Ethoxymethylenemalononitrile (Acros, 1.22 g, 10 mmol) was then added in small portions over several minutes. The reaction mixture was heated at 70° C. under argon overnight. The reaction mixture was concentrated and subjected to flash chromatography on silica gel (stepwise elution: dichloromethane followed by 1:1 hexane: ethyl acetate) to afford 600 mg (34%) of compound 3—identical in all respects with the material obtained above.
Reaction SMILES: O[Li].O.C([O:6][C:7]([C:9]1[CH:10]=[N:11][N:12]([C:14]2[NH:18][C:17]3[CH:19]=[C:20]([Cl:25])[C:21]([Cl:24])=[C:22]([Br:23])[C:16]=3[N:15]=2)[CH:13]=1)=[O:8])C.C1COCC1>O>[Br:23][C:22]1[C:16]2[N:15]=[C:14]([N:12]3[CH:13]=[C:9]([C:7]([OH:8])=[O:6])[CH:10]=[N:11]3)[NH:18][C:17]=2[CH:19]=[C:20]([Cl:25])[C:21]=1[Cl:24]
Reactant: CCOC(=O)c1cnn(-c2nc3c(Br)c(Cl)c(Cl)cc3[nH]2)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnn(-c2nc3c(Br)c(Cl)c(Cl)cc3[nH]2)c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 82.2 %

Procedure:
LiOH.H2O (0.046 g, 1.09 mmol) was added to a mixture of 1-(4-Bromo-5,6-dichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.088 g, 0.22 mmol), THF (1 mL), and water (0.33 mL), and the mixture was stirred 18 h at 23° C. The solvent was evaporated, water (3 mL) was added and the mixture acidified with 1M HCl. The resulting white precipitate was filtered and dried to yield the titled compound (0.068 g, 83%). MS (ESI/CI): mass calcd. for C11H5BrCl2N4O2, 374.9; m/z found, 375.9 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 8.89 (s, 1H), 8.32 (s, 1H), 7.74 (s, 1H).
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH2:33])=[O:32])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH2:33])=[O:32])=[CH:26][CH:25]=2)=[CH:7][CH:6]=1
Reactant: NC(=O)Nc1ccc(Br)cc1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2ccc(NC(N)=O)cc2)cc1)[C@H](O)CCc1cccnc1
Temperature: 100 °C
Yield: 23.6 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.15 g, Example 33), 4-bromophenylurea (0.16 g), 2M aqueous sodium carbonate (0.25 ml) and tetrakis(triphenylphosphine)palladium (0) (0.1 g) in ethanol (3 ml). The reaction mixture was heated at 100° C. for 3 hours. After cooling, the solution was concentrated under reduced pressure. The residue was triturated with acetone and then filtered through silica gel. The filtrate was concentrated under reduced pressure and purified by flash column chromatography eluting with 10% methanol in dichloromethane give the title compound as a solid (0.046 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]1([CH3:17])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1B(O)O.[F-].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1([B-](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.O1CCCC1>[C:8]1([CH3:17])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: Clc1ccccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccccn1
Yield: 84 %

Procedure:
A 50-ml four-necked flask was equipped with a stirrer, a thermometer and a reflux condenser. 0.568 g (5 mmol) of 2-chloropyridine, 0.748 g (5.5 mmol) of ortho-tolylboronic acid, 0.011 g (0.05 mmol) of palladium (II) acetate, 0.959 g (17 mmol) of potassium fluoride and 10 ml of tetrahydrofuran were weighed in the flask, followed by stirring. Further, 0.026 g (0.05 mmol) of tri-tert-butylphosphonium tetraphenylborate obtained in Example A-1 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 25° C. for 24 hours. After the completion of the reaction, 10 ml of 10% aqueous sodium hydroxide solution was added, followed by separation. The organic phase was purified by column chromatography to afford 0.711 g of 2-ortho-tolylpyridine (yield: 84 mol % based on 2-chloropyridine). The identification of the product was made by mass spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][N:25]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([O:20]CC)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.[OH-].[Na+]>O1CCCC1.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][N:25]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=[O:19])[CH2:15][N:16]=1)=[CH:8]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cn4)cc(OC)c3[nH]2)S1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 95.5 %

Procedure:
Ethyl [2-(7-methoxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetate (500 mg) was dissolved in a mixture of tetrahydrofuran (5 mL) and ethanol (5 mL). To the mixture was added 1M aqueous sodium hydroxide solution (3 mL) and the mixture was stirred at room temperature for 50 min. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in water and the mixture was washed with diethyl ether. The aqueous layer was acidified with 1M hydrochloric acid (3 mL). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual solid was washed with diethyl ether to give the title compound (450 mg, 96%) as a pale yellow solid. MS 462 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4](Cl)[N:3]=1.C(O)CCC.[CH2:21]([NH2:24])[CH2:22][CH3:23]>C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4]([NH:24][CH2:21][CH2:22][CH3:23])[N:3]=1
Reactant: CCCN
Reactant: CCC(C)n1cnc2c(Cl)nc(Cl)nc21
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: CCCNc1nc(Cl)nc2c1ncn2C(C)CC
Reaction time: 22 h

Procedure:
The operation is carried out as in Stage 2 of Example 9 starting from 200 mg of the product obtained in Stage 1 of Example 9 and 4 ml of butanol and using 0.132 ml 1-propanamine in place of the benzylamine. Agitation is carried out at ambient temperature then the reaction medium is taken to a temperature of 80 to 85° C. for approximately 22 hours, left to return to ambient temperature, followed by taking up in 5 ml of ethyl acetate, evaporating to dryness, impasting in 5 ml of pentane at ambient temperature, separating, washing with 5 ml of pentane and drying at a temperature of approximately 50° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[NH:11][CH2:12][CH2:13][CH2:14][OH:15].[H][H]>[Ni].C(O)C>[NH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:11][CH2:12][CH2:13][CH2:14][OH:15]
Reactant: O=[N+]([O-])c1cccc(Cl)c1NCCCO
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1cccc(Cl)c1NCCCO
Yield: 20 %

Procedure:
A mixture of 115 parts of 3-[(2-chloro-6-nitrophenyl)amino]-1-propanol and 400 parts of ethanol is hydrogenated at normal pressure and at room temperature with 12 parts of a Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding 20 parts (20%) of 3-[(2-amino-6-chlorophenyl)amino]-1-propanol as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9](=[O:11])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cc1ccc(Cl)cc1)c1ccccc1
Yield: 142.4 %

Procedure:
A benzene solution containing 51.2 g 4-chlorophenylacetic acid and 39.3 g thionyl chloride is refluxed for 6 hours and the solvent removed. The crude reaction product is added dropwise to a slurry of 40 g aluminum chloride in 200 ml benzene maintaining the temperature below 50° C. After addition the reaction is refluxed for 1.5 hours. After cooling, the mixture is poured into ice and the resulting white solid is separated yielding 61.3 g of crude product. The product is taken up in methylene chloride and washed with 5% sodium hydroxide solution followed by water, dried over sodium sulfate and stripped yielding 49.3 g (71%) of >95% pure 4'-chlorodeoxybenzoin. 15 g of 4-chlorodeoxybenzoin is dissolved in 105 ml pyridine. An aqueous solution containing 15 g potassium permanganate is added and the reaction stirred for 6 hours at room temperature using dry ice to buffer the pH near 7. The mixture is extracted with methylene chloride, the extract washed with water, dried over Na2SO4 and stripped. The residue is recrystallized from ethanol yielding 6.1 g of white plate-like crystals which is identified as starting material. Concentration of the mother liquor yields 4 g of 4-chlorobenzil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:11][CH2:12][CH2:13][C:14]2[N:15]=[C:16]([CH3:19])[S:17][CH:18]=2)[CH3:10])=[CH:4][CH:3]=1.[C:20]([O:24][CH3:25])(=[O:23])[CH:21]=[O:22]>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:11]2[CH2:12][CH:13]([C:14]3[N:15]=[C:16]([CH3:19])[S:17][CH:18]=3)[O:22][CH:21]2[C:20]([O:24][CH3:25])=[O:23])[CH3:10])=[CH:4][CH:3]=1
Reactant: Cc1nc(CCNC(C)Cc2ccc(O)cc2)cs1
Reactant: COC(=O)C=O
Product: COC(=O)C1OC(c2csc(C)n2)CN1C(C)Cc1ccc(O)cc1

Procedure:
Prepared by analogy to Example 18 by reaction of N-[2-(4-hydroxyphenyl)-1-methylethyl]-2-(2-methyl-thiazol-4-yl)ethanamine with methyl glyoxylate, followed by purification of the base on a silica gel column using ether/petroleum ether =8:2 as eluant.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[C:14]3[CH2:13][S:12][N:11]=[C:10]([N:15](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:9]4=[N:30][N:31]([CH2:33][C:34]5[C:39]([CH3:40])=[C:38]([O:41][CH3:42])[C:37]([CH3:43])=[CH:36][N:35]=5)[N:32]=[C:7]([C:8]=34)[CH2:6]2)[CH2:3][CH2:2]1.CO.C=O.[C:48]([BH3-])#N.[Na+]>C(O)(=O)C>[CH:1]1([N:4]([CH3:48])[CH:5]2[C:14]3[CH2:13][S:12][N:11]=[C:10]([NH2:15])[C:9]4=[N:30][N:31]([CH2:33][C:34]5[C:39]([CH3:40])=[C:38]([O:41][CH3:42])[C:37]([CH3:43])=[CH:36][N:35]=5)[N:32]=[C:7]([C:8]=34)[CH2:6]2)[CH2:2][CH2:3]1
Reactant: [BH3-]C#N
Reactant: COc1c(C)cnc(CN2N=C3CC(NC4CC4)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1c(C)cnc(CN2N=C3CC(N(C)C4CC4)C4=C3C(=N2)C(N)=NSC4)c1C
Temperature: 25 °C
Reaction time: 14 h
Yield: 83.7 %

Procedure:
A mixture composed of di-tert-butyl {8-(cyclopropylamino)-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 60 (400 mg), methanol (2 mL), a 35% formalin solution (111 μL), acetic acid (156 μL) and molecular sieves 3A was stirred at room temperature for 40 minutes. Then, sodium cyanoborohydride (163 mg) was added, and the mixture was stirred at room temperature for 14 hours. The molecular sieves were separated off by filtration, and then the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with a saturated sodium bicarbonate solution and then with brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. Dichloromethane (2 mL) and trifluoroacetic acid (2 mL) were added to the resulting residue, and the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue under ice-cooling, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (233 mg, 84%) as an oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.S(Cl)(Cl)=O.C1C2C(=CC=CC=2)C=C(C(Cl)=O)N=1.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:34][CH:33]=1>>[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][N:40]2[CH2:41][CH2:42][N:43]([C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])[CH2:44][CH2:45]2)=[CH:34][CH:33]=1
Reactant: O=C(O)c1cc2ccccc2cn1
Reactant: Fc1ccc(CCN2CCNCC2)cc1
Agent: O=C(Cl)c1cc2ccccc2cn1
Solvent: O=S(Cl)Cl
Product: O=C(c1cc2ccccc2cn1)N1CCN(CCc2ccc(F)cc2)CC1

Procedure:
Analogously to Example 3, firstly isoquinoline-3-carboxylic acid is reacted with thionyl chloride, and the resultant isoquinoline-3-carbonyl chloride is reacted with 1-[2-(4-fluorophenyl)ethyl]piperazine, giving {4-[2-(4-fluoro-phenyl)ethyl]piperazin-1-yl}isoquinolin-3-ylmethanone.