Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]5([C:30]#[N:31])[CH2:29][CH2:28]5)[CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>CN(C)C1C=CN=CC=1>[C:30]([C:27]1([C:23]2[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=2)[C:20]([NH:19][C:14]2[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([O:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH:1][C:36]([CH:33]5[CH2:35][CH2:34]5)=[O:37])[S:3][C:4]=4[CH:10]=3)[CH:13]=2)=[O:32])[CH2:29][CH2:28]1)#[N:31]
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(N)sc2c1
Agent: CN(C)c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2c1
Yield: 33 %

Procedure:
Using N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-methylphenyl}-3-(1-cyanocyclopropyl)benzamide (0.11 g, 0.25 mmol), cyclopropanecarbonyl chloride (0.21 g, 2.0 mmol), and N,N-dimethylpyridine-4-amine (0.24 g, 2.0 mmol), and in the same manner as in Example A29(vi), the title compound (42 mg, 33%) was obtained as a pale-yellow powder.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@@H:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:11]([CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:10][C@@H:7]([O:8][CH3:9])[C@@H:6]1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:40]I>CN(C=O)C>[CH3:40][N:4]([C@H:5]1[C@@H:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:11]([CH2:21][O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:10][C@@H:7]([O:8][CH3:9])[C@@H:6]1[O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:1](=[O:3])[CH3:2]
Reactant: CO[C@@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](NC(C)=O)[C@H]1OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](N(C)C(C)=O)[C@H]1OCc1ccccc1

Procedure:
Dissolve methyl 3-acetamido-3-deoxy-2,4,6-tri-O-benzyl-β-D-galactopyranoside (5.05 g.) in dry DMF (100 ml.). With stirring in an atomsphere of dry nitrogen add 0.25 g. of sodium hydride and allow the mixture to stir for 1 hour. Add methyl iodide (2.0 g.) and continue stirring at room temperature for 16 hours. Evaporate the mixture in vacuo to ca 10 ml. then dilute with chloroform. Cautiously add water and shake, separate the layers and re-extract the chloroform layer 3 times with water. Dry the chloroform solution and evaporate to 50 ml. Add hexane to precipitate the title product of this example. Yield ca 4.7 g.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.Br[C:13]1[CH:22]=[N:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]>>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([CH2:3][NH:2][C:19]2[CH:20]=[N:21][CH:22]=[CH:13][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[CH:5][CH:6]=1)#[N:9]
Reactant: COC(=O)c1ccncc1Br
Reactant: N#Cc1ccc(CN)cc1
Agent: Cl
Product: COC(=O)c1ccncc1NCc1ccc(C#N)cc1
Yield: 4 %

Procedure:
The title compound was prepared in 4% yield from 4-(aminomethyl)-benzonitrile hydrochloride and methyl 3-bromoisonicotinate according to the procedure for Preparation 4A. 1H NMR (500 MHz, CDCl3): δ 8.07 (s, 1H), 7.97 (d, 2H, J=5.0 Hz), 7.63-7.70 (m, 3H), 7.46 (d, 2H, J=8.3 Hz), 4.61 (d, 2H, J=6.1 Hz), 3.94 (s, 3H). [M+H] calc'd for C15H13N3O2, 268. Found 268.
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[N:16]=[N:15][CH:14]=1>O.C(O)C>[Cl:23][C:19]1[CH:18]=[C:17]2[C:22]([C:13]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([S:1]([OH:11])(=[O:10])=[O:2])=[CH:8][CH:7]=3)=[CH:14][N:15]=[N:16]2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Reactant: Clc1ccc2c(Cl)cnnc2c1
Solvent: O
Solvent: CCO
Product: O=S(=O)(O)c1ccc(Nc2cnnc3cc(Cl)ccc23)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Sulphanilic acid (1.95 g) in water (75 ml) and ethanol (10 ml) at 70° C. was treated with 4,7-dichlorocinnoline (2.2 g) and ethanol (10 ml) was added. The resultant green suspension was stirred vigorously overnight at 70° C. The mixture was cooled, and the solid was filtered, washed with water and dried at room temperature to give 3.45 g of the title compound as the monohydrate, melting point greater than 280° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH3:13].CO>>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:13])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: FC(F)(F)c1cnc(Cl)cc1I
Reactant: N
Solvent: CO
Product: Nc1cc(Cl)ncc1C(F)(F)F
Temperature: 130 °C

Procedure:
2-chloro-4-iodo-5-(trifluoromethyl)pyridine was dissolved in 7 M Ammonia/Methanol. It was heated in a Biotage Initiator microwave synthesizer at 130° C. for 1 h. A mixture of the 2- and 4-substituted products was obtained. The solvent was removed and the residue was purified by silica gel chromatography (DCM/MeOH) gradient. The pure title compound was isolated.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:31])[C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23]CC3C=CC=CC=3)=[CH:19][CH:18]=2)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.C(O)(=O)C.[Pd]>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([CH:14]([CH3:31])[C:15]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[O:16])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C(=O)c1ccc(OCc2ccccc2)cc1)N1CCC(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C(=O)c1ccc(O)cc1)N1CCC(Cc2ccccc2)CC1

Procedure:
25 g of 2-(4-benzylpiperidino)-4'-benzyloxypropiophenone are debenzylated in 200 ml of ethanol and 10 ml of acetic acid, in a Parr apparatus, in the presence of 1 g of 10% palladium-on-charcoal under a pressure of 0.1 MPa for 3 hours. The product obtained is isolated by filtering off the catalyst and evaporating off the solvent.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([NH:7][CH2:8][CH2:9][CH3:10])=[N:4][N:3]=1.[CH:11]1([C:15](Cl)=[O:16])[CH2:14][CH2:13][CH2:12]1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][C:2]1[O:6][C:5]([N:7]([CH2:8][CH2:9][CH3:10])[C:15]([CH:11]2[CH2:14][CH2:13][CH2:12]2)=[O:16])=[N:4][N:3]=1
Reactant: O=C(Cl)C1CCC1
Reactant: CCCNc1nnc(C)o1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCN(C(=O)C1CCC1)c1nnc(C)o1

Procedure:
5-Methyl-2-n-propylamino 1,3,4-oxadiazole (6 g, 0.04 mol) prepared as in (b) above, was refluxed with cyclobutanecarboxylic acid chloride (5.5 g, 0.05 mol) in benzene (25 ml) in the presence of triethylamine (4.72 g, 0.05 mol) for 2 hours. The mixture was filtered and the filtrate washed with dilute HCl, saturated solution NaCHO3 and water; dried over magnesium sulphate, filtered, solvent evaporated off to yield a reddish brown liquid which was distilled twice in a vigreux flask to yield the title compound as a slightly pink liquid (b.p. 110°-111° C./0.27 mm Hg).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][C:16]3=[O:20])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:21](/B(O)O)=[CH:22]\[CH2:23][CH2:24][CH2:25][CH3:26].[ClH:30]>CCOCC>[ClH:30].[CH:21](/[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][C:16]3=[O:20])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)=[CH:22]\[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCC/C=C/B(O)O
Reactant: O=C1CCCN1CCCNc1ccc2ncc(Br)n2n1
Agent: Cl
Solvent: CCOCC
Product: CCCC/C=C/c1cnc2ccc(NCCCN3CCCC3=O)nn12
Yield: 52 %

Procedure:
Prepared from the product of step A and (E)-1-hexeneboronic acid according to general procedure 2. The free-base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (68 mg, 52%) as a brown solid; 1H NMR (500 MHz, CD3OD) δ 7.90 (s, 1H), 7.86 (d, J=9.8 Hz, 1H), 7.16 (d, J=9.8 Hz, 1H), 6.89 (dt, J=6.1, 16.2 Hz, 1H), 6.68 (d, J=16.2 Hz, 1H), 3.50 (t, J=7.0 Hz, 2H), 3.44-3.40 (m, 4H), 2.38-2.32 (m, 4H), 2.09-2.03 (m, 2H), 1.98-1.93 (m, 2H), 1.56-1.50 (m, 2H), 1.46-1.40 (m, 2H), 0.98-0.96 (t, J=6.3 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 177.8, 157.1, 139.0, 133.3, 130.1, 121.2, 120.6, 117.9, 114.3, 41.3, 39.9, 34.3, 32.4, 32.1, 26.9, 23.3, 18.9, 14.3 (one signal overlapping with solvent); HPLC tR=11.4 min (Luna), 97.3%; ES-MS: (M+H)=342 m/z.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].[Cl:9][C:10]1[C:11]([O:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)=[N:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[CH2:1]([N:3]([CH2:7][CH3:8])[C:4]([N:23]1[C:24]([CH3:26])=[CH:25][C:21]([O:20][C:11]2[C:10]([Cl:9])=[CH:15][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:13][N:12]=2)=[N:22]1)=[O:5])[CH3:2]
Reactant: Cc1cc(Oc2ncc(C(F)(F)F)cc2Cl)n[nH]1
Reactant: CCN(CC)C(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)n1nc(Oc2ncc(C(F)(F)F)cc2Cl)cc1C
Temperature: 70 °C
Reaction time: 9 h
Yield: 11.1 %

Procedure:
Diethylcarbamoyl chloride (1.52 g, 7.8 mmol) was added to a solution of 3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole (1.39 g, 5.0 mmol) and potassium carbonate (1.98 g, 14.3 mmol) in DMF (15 ml), the mixture was stirred at 70° C. for 9 hours and further stirred at room temperature for 2 days. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid, and the mixture was extracted with ethyl acetate (20 ml×3). An organic-layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant. The solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/5), to give a colorless viscous substance of N,N-diethyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole-1-carboxamide (0.21 g, yield: 11.2%). 1H-NMR (CDCl3, TMS, ppm): δ 1.21 (t, J=7.0 Hz, 6H), 2.48 (d, J=0.6 Hz, 3H), 3.47 (q, J=7.0 Hz, 4H), 6.00 (q, J=0.6 Hz, 1H), 7.99 (d, J=2.1 Hz, 1H), 8.33 (m, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:16]=[CH:15][C:7]([C:8]([O:10]C(C)(C)C)=[O:9])=[CH:6][C:5]=1[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH:1]([C:4]1[CH:16]=[CH:15][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(C(=O)OC(C)(C)C)cc1Oc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc(C(=O)O)cc1Oc1ccccc1
Yield: 81.3 %

Procedure:
To a solution of tert-butyl 4-isopropyl-3-phenoxybenzoate (150 mg, 0.48 mmol) in dichloromethane (10 mL) was added 2,2,2-trifluoroacetic acid (2 mL). The resultant mixture was stirred at room temperature for 30 minutes. Thin layer chromatography showed that starting material was consumed completely. The solution was concentrated to give 4-isopropyl-3-phenoxybenzoic acid (100 mg, 81.3%) as a white solid which was used in the next step directly. LRMS (M+H+) m/z: calcd 257.11. found 257. 1H NMR (300 MHz, DMSO) δ 12.94 (s, 1H), 7.71 (m, 1H), 7.68 (m, 1H), 7.40 (m, 2H), 7.38 (s, 1H), 7.36 (m, 1H), 7.11 (m, 2H), 1.22 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[N:4][C:5]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][N:14]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:15]3=[O:18])=[CH:11][C:10]=2[O:25][CH:26]([CH3:28])[CH3:27])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:49][N:50]([CH3:54])[C:51](Cl)=[O:52]>CN(C=O)C>[CH3:49][N:50]([CH3:54])[C:51]([N:22]1[CH2:21][CH2:20][CH:19]([N:14]2[CH2:13][C:12]3[C:16](=[CH:17][C:9]([NH:8][C:5]4[N:4]=[C:3]([NH:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[C:2]([Cl:1])=[CH:7][N:6]=4)=[C:10]([O:25][CH:26]([CH3:28])[CH3:27])[CH:11]=3)[C:15]2=[O:18])[CH2:24][CH2:23]1)=[O:52]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)Oc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)C(=O)N(C1CCNCC1)C2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)Oc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)C(=O)N(C1CCN(C(=O)N(C)C)CC1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-2-piperidin-4-yl-2,3-dihydro-isoindol-1-one (Example 1, 20 mg, 0.033 mmol) and triethylamine (23 uL, 0.165 mmol) in DMF (1.5 mL) is added dimethylcarbamyl chloride (11 mg, 0.1 mmol). The mixture is stirred at room temperature for 1 hour. The reaction is filtered and the filtrate is purified by mass-trigger preparative RP LC-MS to afford the title compound 4-(6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylic acid dimethylamide (155) as a white solid: 1H NMR (400 MHz, MeOD-d4) δ 8.29 (s, 1H), 8.26 (br, 1H), 7.96 (dd, 1H), 7.93 (s, 1H), 7.72 (dd, 1H), 7.48 (dd, 1H), 7.35 (s, 1H), 4.50 (s, 2H), 4.35-4.29 (m, 1H), 3.83 (d, 2H), 3.38-3.30 (m, 2H), 3.02-2.95 (m, 3H), 2.88 (s, 6H), 1.88-1.84 (m, 3H), 1.36 (d, 6H), 1.25 (d, 6H); ESMS m/z 670.2 (M+H+).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH3:9])[C:4]1=[O:10].C(N(CC)CC)C.S=[C:19]1[CH2:23][S:22][C:21](=[O:24])[NH:20]1>C(O)C>[CH3:9][N:5]1[CH2:6][CH2:7][CH2:8][CH:3]([NH:2][C:19]2[CH2:23][S:22][C:21](=[O:24])[N:20]=2)[C:4]1=[O:10]
Reactant: O=C1NC(=S)CS1
Reactant: CN1CCCC(N)C1=O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1CCCC(NC2=NC(=O)SC2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the crude product containing 3-amino-1-methylpiperidin-2-one hydrochloride obtained in C) and triethylamine (3 mL) in ethanol (15 mL) was added 4-thioxothiazolidin-2-one (666 mg) at room temperature. The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (220 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([Cl:21])[C:19]=1[OH:20])[NH2:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:14]=[C:13]([Cl:12])[C:19]([OH:20])=[C:18]([Cl:21])[CH:17]=1)=[O:9]
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: O=C(Nc1cc(Cl)c(O)c(Cl)c1)c1cc(Br)ccc1O

Procedure:
Using 5-bromosalicylic acid and 3,5-dichloro-4-hydroxyaniline as the raw materials, the same operation as the example 16 gave the title compound. 22.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[OH:11].Cl.CCCCCCC>C(O)C.[Fe]>[NH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[OH:11]
Reactant: O=[N+]([O-])c1cccc(Cl)c1O
Agent: [Fe]
Agent: Cl
Solvent: CCCCCCC
Solvent: CCO
Product: Nc1cccc(Cl)c1O
Temperature: 25 °C
Yield: 57.6 %

Procedure:
A solution of 2-chloro-6-nitrophenol (1.210 g, 6.972 mmol) in ethanol (50 mL) was treated with iron powder (1.947 g, 34.86 mmol) and concentrated HCl (3 mL). The yellow mixture was heated to reflux for 18 h and then cooled to room temperature. The reaction mixture was filtered through a pad of Celite, and the filtrate was neutralized with satd aq NaHCO3 solution. The resulting gray suspension was filtered through a pad of Celite, and the filtrate was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to give a black solid. Trituration with heptane afforded 2-amino-6-chlorophenol (0.577 g, 58%) as a dark brown solid. RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 100 Å, 5 μm, 250×4.6 mm column) tr=7.30 min., 91%; m/z 143 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]=[C:7]([C:12]([CH:14]([O:17][CH3:18])[O:15][CH3:16])=O)[C:8]([O:10][CH3:11])=[O:9])([O-:3])=[O:2].[NH2:23]/[C:24](/[CH3:30])=[CH:25]\[C:26]([O:28][CH3:29])=[O:27]>>[CH3:30][C:24]1[NH:23][C:12]([CH:14]([O:17][CH3:18])[O:15][CH3:16])=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:6]([C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[N+:1]([O-:3])=[O:2])[C:25]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)C(=Cc1ccccc1[N+](=O)[O-])C(=O)C(OC)OC
Reactant: COC(=O)/C=C(/C)N
Product: COC(=O)C1=C(C)NC(C(OC)OC)=C(C(=O)OC)C1c1ccccc1[N+](=O)[O-]
Yield: 60.3 %

Procedure:
A mixture of methyl 2-(2-nitrobenzylidene)-4,4-dimethoxyacetoacetate (15.19 g) and methyl 3-aminocrotonate (6.50 g) was heated at 60° to 63° C. for 6 hours and at 100° to 105° C. for 4 hours and 45 minutes. The resulting crystalline mass was triturated with methanol and collected by filtration to give crystals of dimethyl 2-methyl-4-(2-nitrophenyl)-6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (12.04 g). Thus obtained crystals (1.07 g) were recrystallized from methanol (5 ml) to give pure crystals (0.93 g), m.p. 132° to 133° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[N-:8]=[C:9]=[O:10].[K+].[Na+].[Cl-]>O>[O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:9]([NH2:8])=[O:10])[CH2:3][CH2:2]1
Reactant: [N-]=C=O
Reactant: NC1CCOCC1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: NC(=O)NC1CCOCC1
Temperature: 25 °C
Yield: 18 %

Procedure:
A mixture of tetrahydro-2H-pyran-4-amine (5.0 g, 49.4 mmol, 1.0 equiv.) and potassium isocyanate (4.0 g, 49.5 mmol, 1.0 equiv.) was refluxed in H2O (50 mL) overnight. The reaction was cooled to room temperature and excess NaCl was added to help saturate the aqueous layer. The precipitate was isolated by filtration to provide the desired product (1.28 g, 8.88 mmol). The aqueous layer was washed with EtOAc (3×15 mL) and then was concentrated and azeotroped with toluene (3×100 mL). The resulting solid was suspended in 1:4 CH3OH:EtOAc (100 mL) and filtered a total of four times. The combined organics were concentrated under reduced pressure and combined with the isolated precipitate to provide 5.01 g (70%) of the title compound. LC/MS: m/z (ES+) 145 (M+H)+. 1H-NMR (400 MHz, DMSO-d6): δ 6.14 (d, J=7.5 Hz, 1H), 5.47 (s, 2H), 3.85 (dt, J=11.6, 3.6 Hz, 2H), 3.65-3.52 (m, 1H), 3.38 (td, J=11.4, 2.2 Hz, 2H), 1.80-1.72 (m, 2H), 1.42-1.27 (m, 2H).
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:25]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28])[CH3:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][N:33]3[CH2:32][CH2:31][N:30]([S:27]([CH2:25][CH3:26])(=[O:28])=[O:29])[CH2:35][CH2:34]3)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: CCS(=O)(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: CCS(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)CC1
Yield: 44.2 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (100 mg, 0.30 mmol), ethanesulfonyl-piperazine hydrochloride (128 mg, 0.60 mmol) and sodium triacetoxyborohydride (83 mg, 0.39 mmol) to afford 66 mg (44%) of the desired product after purification.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][C:6]=1[O:15][CH2:16][CH3:17])[CH2:3][OH:4].C(N(CC)CC)C.[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:27]=1[C:28](Cl)=[O:29]>O1CCCC1>[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:27]=1[C:28]([NH:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:7][C:6]=1[O:15][CH2:16][CH3:17])[CH2:3][OH:4])=[O:29]
Reactant: CCOc1cc(C(C)(C)C)ccc1C(N)CO
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOc1cc(C(C)(C)C)ccc1C(CO)NC(=O)c1c(F)cccc1F
Yield: 86.1 %

Procedure:
A mixture of 23.6 g (0.10 mole) of 2-amino-2-(2-ethoxy-4-tert-butylphenyl)ethanol, 12.2 g (0.12 moles) of triethylamine and 200 ml of tetrahydrofuran was cooled and stirred, 17.7 g (0.10 mole) of 2,6-difluorobenzoyl chloride was added dropwise, and the mixture was stirred at room temperature for 5 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give 32.5 g of N-(2,6-difluorobenzoyl)-2-amino-2-(2-ethoxy-4-tert-butylphenyl)ethanol.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:26]([NH:28][C:29](=[N:37][CH2:38][CH2:39][S:40][CH2:41][C:42]1[N:43]=[C:44]([NH:47][C:48]([NH2:50])=[NH:49])[S:45][CH:46]=1)OC1C=CC=CC=1)#[N:27]>>[C:26]([NH:28][C:29]([NH:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:7]([CH2:6][C:5]1[CH:24]=[CH:25][C:2]([F:1])=[CH:3][CH:4]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:23])=[N:37][CH2:38][CH2:39][S:40][CH2:41][C:42]1[N:43]=[C:44]([NH:47][C:48]([NH2:50])=[NH:49])[S:45][CH:46]=1)#[N:27]
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Reactant: CN(CCCCCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Product: CN(CCCCCNC(=NCCSCc1csc(NC(=N)N)n1)NC#N)CCN(Cc1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.51 g (1.5 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,5-pentanediamine and the equimolar amount of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=626 ([M+H]+, 3), 154 ([m-NO2 benzylOH] 100); IR (KBr): 2162 cm- (C≡N). For further analysis, a portion of the compound is converted into the tartaric acid salt and recrystallised from isopropanol/petroleum ether; m.p.: 103° C. (isopropanol/petroleum ether).
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([CH2:15][CH:16]=O)=[CH:10][C:9]=2[F:18])[C:6](=[O:19])[CH:5]=[CH:4][C:3]=1[C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28].Cl.[CH3:31][C:32]([C:35]([O:37][CH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1)=[O:36])([CH3:34])[NH2:33]>>[NH2:1][C:2]1[N:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([CH2:15][CH2:16][NH:33][C:32]([CH3:31])([C:35]([O:37][CH:38]3[CH2:39][CH2:40][CH2:41][CH2:42]3)=[O:36])[CH3:34])=[CH:10][C:9]=2[F:18])[C:6](=[O:19])[CH:5]=[CH:4][C:3]=1[C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28]
Reactant: CC(C)(N)C(=O)OC1CCCC1
Reactant: Nc1c(C(=O)c2ccc(F)cc2F)ccc(=O)n1-c1c(F)cc(CC=O)cc1F
Agent: Cl
Product: CC(C)(NCCc1cc(F)c(-n2c(N)c(C(=O)c3ccc(F)cc3F)ccc2=O)c(F)c1)C(=O)OC1CCCC1

Procedure:
Example 2 was synthesised using Intermediate 4 and Intermediate 7 in a similar manner to Example 1.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:13])([F:12])[C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.[C:14]([C:16]1[CH:21]=[C:20](Cl)[N:19]=[C:18](Cl)[CH:17]=1)#[N:15]>CN1CCCC1=O>[C:14]([C:16]1[CH:21]=[C:20]([O:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:4]([F:12])([F:13])[F:3])[CH:6]=2)[N:19]=[C:18]([O:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:4]([F:3])([F:12])[F:13])[CH:6]=2)[CH:17]=1)#[N:15]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: N#Cc1cc(Cl)nc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N#Cc1cc(Oc2cccc(C(F)(F)F)c2)nc(Oc2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C

Procedure:
Sodium hydride (0.31 g (ca. 60% in mineral oil), 0.0035×2.2 mol) was suspended in 20 ml of N-methyl-2-pyrrolidinone, then meta-trifluoromethyl phenol (1.24 g, 0.0035×2.2 mol) was added thereto, and the resultant solution was heated to about 60° C. and stirred for several minutes. After allowed to cool to room temperature, to the reaction solution was added 4-cyano-2,6-dichloropyridine (0.60 g, 0.0035 mol), and then the mixture was allowed to react for 1 hour at about 90° C.