Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[CH2:9](O)[CH2:10][OH:11]>C1C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[N:3]=[C:4]([CH:7]2[O:11][CH2:10][CH2:9][O:8]2)[S:5][CH:6]=1
Reactant: OCCO
Reactant: O=Cc1nc(Br)cs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Brc1csc(C2OCCO2)n1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
To a rb flask with an attached Dean-Stark trap containing molecular sieves, 4A (0.25g) was added 4-bromothiazole-2-carbaldehyde (4.4 g, 22.91 mmol). The starting material was dissolved in Benzene (45 ml) and Ethylene glycol (1.406 ml, 25.2 mmol) was added followed by pTsOH (0.218 g, 1.146 mmol). The mixture was heated to reflux for 3 h. The mixture was cooled to rt, and was partitioned with sat. aq. NaHCO3. The mixture was washed 2× with sat. NaHCO3 (40 mL), then once with sat. NaCl (40 mL). The organic layer was dried with Na2SO4. The drying agent was removed by filtration, and the mixture was concentrated under reduced pressure. The residue was purified by biotage flash chromatography using a 40+M column and a 0 to 20% EtOAc in hexanes gradient. The product, 4-bromo-2-(1,3-dioxolan-2-yl)thiazole (5.1 g, 21.60 mmol, 94% yield), was collected as a light-yellow oil.
Reaction SMILES: ClC(Cl)C.[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:18]2[CH:19]=[C:20]([N:23]=[C:24]=[O:25])[CH:21]=[CH:22][C:17]=2[N:16]([CH3:26])[C:15](=[O:27])[CH2:14][N:13]=1.NC1C=CC2N(C)C(=O)CN=C(C3C=CC=CC=3F)C=2C=1.[NH2:49][CH2:50][CH:51]([OH:53])[CH3:52]>ClCCCl>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:18]2[CH:19]=[C:20]([NH:23][C:24]([NH:49][CH2:50][CH:51]([OH:53])[CH3:52])=[O:25])[CH:21]=[CH:22][C:17]=2[N:16]([CH3:26])[C:15](=[O:27])[CH2:14][N:13]=1
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc(N=C=O)ccc21
Reactant: CC(O)CN
Agent: CN1C(=O)CN=C(c2ccccc2F)c2cc(N)ccc21
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: CC(O)CNC(=O)Nc1ccc2c(c1)C(c1ccccc1F)=NCC(=O)N2C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A dichloroethane solution of [5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]isocyanate, prepared as described in paragraph (a) of Example 1 from 12.5 g (0.044 M) of 7-amino-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one, is added to a solution of 8 g of 1-amino-2-propanol in 100 ml of 1,2-dichloroethane, the mixture is stirred at room temperature for 15 minutes and then concentrated. The residue is purified on a 300 g silica gel column using methylene chloride and then acetone as the eluting agent. This operation is repeated once using ethyl acetate as the eluting agent. After crystallisation from ethyl acetate, there is obtained rac-1-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-(2-hydroxypropyl)urea which melts at 149°-151° C. with decomposition.
Reaction SMILES: C1([NH2+]C2CCCCC2)CCCCC1.[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH2:32])[C:23]([O-:25])=O)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(Cl)(=O)C(C)(C)C.[CH2:40]([O:42][C:43]([C@@:45]1([NH:50][C:51]([C@H:53]2[NH:57][CH2:56][C@H:55]([O:58][C:59]([N:61]3[CH2:69][C:68]4[C:63](=[CH:64][CH:65]=[CH:66][C:67]=4[F:70])[CH2:62]3)=[O:60])[CH2:54]2)=[O:52])[CH2:47][C@H:46]1[CH:48]=[CH2:49])=[O:44])[CH3:41]>C1COCC1>[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH2:32])[C:23]([N:57]1[C@H:53]([C:51](=[O:52])[NH:50][C@:45]2([C:43]([O:42][CH2:40][CH3:41])=[O:44])[CH2:47][C@H:46]2[CH:48]=[CH2:49])[CH2:54][C@@H:55]([O:58][C:59]([N:61]2[CH2:69][C:68]3[C:63](=[CH:64][CH:65]=[CH:66][C:67]=3[F:70])[CH2:62]2)=[O:60])[CH2:56]1)=[O:25])=[O:20])([CH3:15])([CH3:16])[CH3:17]
Reactant: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)[O-]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(F)c3C2)CN1)C(=O)OCC
Agent: C1CCC([NH2+]C2CCCCC2)CC1
Agent: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](OC(=O)N2Cc3cccc(F)c3C2)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 98.4 %

Procedure:
A solution of 57.7 g (128 mmol) (S)-2-tert-butoxycarbonylamino-non-8-enoic acid dicyclohexylammonium salt (commercially available from Synthetech Oregon, USA) in 350 mL of THF was added dropwise to a solution of 15.1 g (125 mmol) pivaloyl chloride in 200 mL of THF while maintaining the temperature at 0-5° C. The dosing funnel was rinsed with 50 mL of THF and the suspension was stirred for 90 min at 5° C. jacket temperature. The temperature was decreased to −5° C. and 50.0 g (116 mmol) of 4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid (3R,5S)-5-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-pyrrolidin-3-yl ester was added in five portions within 30 min to the mixed anhydride at −5° C. to 0° C. The funnel was rinsed with 25 mL of THF. The suspension was first stirred for 30 min at 0° C., then for 6 h at 23° C. After complete conversion 150 mL of water was added. The reaction mixture was concentrated at 50° C. jacket temperature under reduced pressure to a residual volume of 300 mL. After cooling to 23° C. 500 mL of toluene and 58 mL of aqueous HCl (1M) were added. The suspension was filtered and the reaction vessel and filter cake were washed with 220 mL of toluene. The phases of the filtrate were separated and the aqueous layer was extracted with 150 mL of toluene. The organic layers were washed separately with 200 mL of aqueous Na2CO3 (10 wt %) and 58 mL of aqueous HCl (1M). The combined organic layers were concentrated at 50° C. under reduced pressure using a rotary evaporator to afford 143.3 g of crude (54.5 wt %) 4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid (3R,5S)-1-((S)-2-tert-butoxycarbonylamino-non-8-enoyl)-5-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropyl-carbamoyl)-pyrrolidin-3-yl ester in a yield of 98.4%.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:32]([OH:35])[C:33]#[CH:34].C(Cl)Cl>N(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:34]#[C:33][CH2:32][OH:35])[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: ClCCl
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(C#CCO)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
To a solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (264 mg), PdCl2(PPh3)2 (17.3 mg), and CuI (4.7 mg) in 9.6 mL Et2NH is added propargyl alcohol (0.029 mL, 0.492 mmol). Distilled CH2Cl2 (14 mL) is added to help solublize the reactants. The reaction is stirred at room temperature overnight, then condensed to remove the solvents. The crude product is adsorbed onto silica and chromatographed (eluent 1% MeOH in CH2Cl2 (1L), 2% MeOH in CH2Cl2 (1L), and 3% MeOH in CH2Cl2 (2L)). Product-containing fractions are combined and condensed to afford 148.2 mg (63%) of the desired product as a tan solid.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][NH:10][C:11]2[O:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][C:6]([CH2:20][CH3:21])=[C:5]([CH3:22])[N:4]=1.Cl.N1C=CC=CC=1>O>[O:12]1[C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=[C:11]1[NH:10][CH2:9][C:8]1[C:3](=[O:2])[NH:4][C:5]([CH3:22])=[C:6]([CH2:20][CH3:21])[CH:7]=1
Reactant: CCc1cc(CNc2nc3ccccc3o2)c(OC)nc1C
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCc1cc(CNc2nc3ccccc3o2)c(=O)[nH]c1C
Temperature: 150 °C

Procedure:
A mixture of 2-methoxy-3-{[(benzoxazol-2-yl)amino]methyl}-5-ethyl-6-methylpyridine (80 mg, 0.269 mmol) and pyridine hydrochloride (335 mg, 2.9 mmol), under a nitrogen atmosphere, was warmed in an oil bath pre-heated to 150° C. for 5 minutes. This solidified mixture was cooled, diluted with water and the crude precipitated product collected by filtration. This material was dissolved in methylene chloride, filtered through a charcoal pad and then diluted with hexane. As the methylene chloride was boiled off the product crystallized out to give 40 mg (53%), m.p. 211°-213° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:12][C:13]2[S:17][C:16]([C:18]3[CH:33]=[CH:32][C:21]([CH2:22][NH:23][CH:24]4[CH2:29][O:28]C(C)(C)[O:26][CH2:25]4)=[CH:20][CH:19]=3)=[CH:15][CH:14]=2)[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.CO.Cl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:12][C:13]2[S:17][C:16]([C:18]3[CH:19]=[CH:20][C:21]([CH2:22][NH:23][CH:24]([CH2:25][OH:26])[CH2:29][OH:28])=[CH:32][CH:33]=3)=[CH:15][CH:14]=2)[CH:9]([CH3:10])[CH3:11])=[CH:6][CH:7]=1
Reactant: CC(C)N(Cc1ccc(-c2ccc(CNC3COC(C)(C)OC3)cc2)s1)c1ccc(F)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC(C)N(Cc1ccc(-c2ccc(CNC(CO)CO)cc2)s1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
A solution of the product of Step A (0.025 g, 0.05 mmol) in a mixture of solvents (CH3OH, CH2Cl2, 30% HCl: 1 ml, 3 ml, 15 drops) was stirred for 3 h at room temperature. The solvents were evaporated and co-evaporated with iPrOH to give the title compound (0.012 g, 48%) as creamy paste. 1H-NMR (CDCl3) 7.45 (d, 2H, J=8.12 Hz); 7.23-7.33 (m, 4H); 7.16-7.09 (m, 3H); 6.88 (d, 2H, J=3.68 Hz); 4.95 (bs, 1H); 4.21 (s, 2H); 4.07-4.02 (m, 1H); 3.92-3.68 (m, 6H); 3.29-3.26 (m, 1H); 1.03 (d, 6H, J=6.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:19])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[N:5]=[CH:6][C:7]=1[Cl:8].[N+](C1C=CC(CCl)=CC=1)([O-])=O.NC1C=CC(CN2C(=O)C(Cl)=C(Cl)C=N2)=CC=1.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>C(O)(=O)C.N1C=CC=CC=1.[Fe]>[Cl:1][C:2]1[C:3](=[O:19])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:49]([CH3:48])(=[O:51])=[O:50])=[CH:12][CH:11]=2)[N:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CS(=O)(=O)Cl
Reactant: O=c1c(Cl)c(Cl)cnn1Cc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: Nc1ccc(Cn2ncc(Cl)c(Cl)c2=O)cc1
Agent: O=[N+]([O-])c1ccc(CCl)cc1
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(Cn2ncc(Cl)c(Cl)c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
4.5 g (15 mmoles) of 4,5-dichloro-2-(4-nitrobenzyl)-3(2H)-pyridazinone (prepared according to method III but using 4-nitrobenzyl chloride instead of 3-phenyl-2-propenyl chloride (M.P. 128-130 celsius)) are dissolved in 150 ml of 99.5% acetic acid solution. Then 7.5 g of iron dust are added to the solution at such a rate that the temperature should not exceed 20° C., and the suspension is stirred at room temperature for 8 hours. By working up the reaction mixture in the usual manner 3.15 g (77%) of 2-(4-aminobenzyl)-4,5-dichloro-3(2H)-pyridazinone melting at 187°-189° C. are obtained, which is dissolved in 34 ml of anhydrous pyridine. To the solution 1.24 ml (16 moles) of methanesulfonyl chloride are dropped under stirring and cooling at such a rate that the inner temperature should remain between 0° C. and 5° C. The mixture is then stirred at room temperature for 4 hours and poured onto water. The separated crystals are filtered and washed with water. Thus 2.34 g (57%) of the desired compound are obtained. M.p.: 152°-154° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH:14]=2)=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.Cl[C:39]1[O:40][C:41]2[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=2[N:43]=1>CN(C)C=O>[O:40]1[C:41]2[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=2[N:43]=[C:39]1[N:11]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][Si:20]([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:21])[CH3:22])[CH:14]=1)[CH2:10][CH2:9][CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=1
Reactant: Clc1nc2ccccc2o1
Reactant: COc1ccc(OCCCNCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(OCCCN(Cc2cccc(O[Si](C)(C)C(C)(C)C)c2)c2nc3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N-3-(4-methoxyphenoxy)propyl-3-tert-butyldimethylsilyloxybenzylamine (1.9 g, 5.0 mmol) was dissolved in N,N-dimethylformamide (3.0 mL). Subsequently, N,N-diisopropylethylamine (768 mg, 5.9 mmol) was added dropwise thereto. To the solution, 2-chlorobenzoxazole (912 mg, 5.94 mmol) was added. The mixture was stirred for 15 minutes at room temperature, and then stirred overnight at 70° C. The resultant mixture was extracted with ethyl acetate, followed by washing the organic layer with brine, drying over anhydrous sodium sulfate, and concentration under reduced pressure. The resultant mixture was subjected to purification by silica gel column chromatography (n-hexane/ethyl acetate=10/1), whereby the target compound was obtained (1.9 g, 73%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.[NH3:26]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](=[O:13])[NH2:26])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17]([NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=[O:25]
Reactant: N
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1C(=O)Nc1ccncc1
Product: NC(=O)c1ccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)cc1

Procedure:
Reaction of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid with ammonia gives “A88”; method 1: HPLC/MS: 1.10 min, [M+H]=334;
Reaction SMILES: [C:1]([C:5]1[C:10]2[CH2:11][C:12]([CH3:17])([C:14](O)=[O:15])[O:13][C:9]=2[CH:8]=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[O:22][Si:23]([CH3:26])([CH3:25])[CH3:24])([CH3:4])([CH3:3])[CH3:2].[CH2:27]([N:29](CC)[CH2:30][CH3:31])[CH3:28].N1CCCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl>[C:1]([C:5]1[C:10]2[CH2:11][C:12]([CH3:17])([C:14]([N:29]3[CH2:30][CH2:31][CH2:28][CH2:27]3)=[O:15])[O:13][C:9]=2[CH:8]=[C:7]([C:18]([CH3:20])([CH3:19])[CH3:21])[C:6]=1[O:22][Si:23]([CH3:25])([CH3:26])[CH3:24])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC1(C(=O)O)Cc2c(cc(C(C)(C)C)c(O[Si](C)(C)C)c2C(C)(C)C)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCNC1
Product: CC1(C(=O)N2CCCC2)Cc2c(cc(C(C)(C)C)c(O[Si](C)(C)C)c2C(C)(C)C)O1
Reaction time: 4 h
Yield: 92 %

Procedure:
In 3 ml of dichloromethane were dissolved 0.20 g of 4,6-di-t-butyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran-2-carboxylic acid, 0.20 ml of triethylamine and 0.06 ml of pyrrolidine at room temperature, and 0.35 g of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate was added and the mixture was stirred for 4 hours. The mixture was extracted with water and diethyl ether, and the combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography eluting with n-hexane containing 33% ethyl acetate to give 0.21 g of 1-(4,6-di-t-butyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran-2-carbonyl)pyrrolidine as a colorless solid (yield 92%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([O:13][CH2:14][C:15](O)=[O:16])=[C:8]([Cl:12])[C:9]=2[CH3:11])[S:4][C:3]=1[C:18](=[O:23])[NH:19][CH:20]1[CH2:22][CH2:21]1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.[CH2:56]([CH2:58][NH2:59])[OH:57]>CN(C=O)C.C1COCC1>[OH:57][CH2:56][CH2:58][NH:59][C:15](=[O:16])[CH2:14][O:13][C:7]1[N:6]=[C:5]2[S:4][C:3]([C:18](=[O:23])[NH:19][CH:20]3[CH2:21][CH2:22]3)=[C:2]([NH2:1])[C:10]2=[C:9]([CH3:11])[C:8]=1[Cl:12]
Reactant: NCCO
Reactant: Cc1c(Cl)c(OCC(=O)O)nc2sc(C(=O)NC3CC3)c(N)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1c(Cl)c(OCC(=O)NCCO)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 33.5 %

Procedure:
To a solution of (3-amino-5-chloro-2-cyclopropylcarbamoyl-4-methyl-thieno[2,3-b]pyridin-6-yloxy)-acetic acid (0.200 g, 0.562 mmol) in a 1:1 mixture of THF:DMF (1.5 ml each) are added 1-hydroxybenzotriazole hydrate (0.099 g, 0.73 mmol), N,N-diisopropylethylamine (0.109 g, 0.843 mmol), 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (0.162 g, 0.843 mmol), and ethanolamine (0.103 g, 1.69 mmol). The resulting solution is stirred at room temperature for 24 hours, then at 50° C. for 24 hours. The reaction is cooled to room temperature and quenched by the addition of water. The mixture is partitioned between water and EtOAc (40 ml each), and the layers are shaken and separated. The aqueous layer is acidified to pH 3 with 1 N HCl and then extracted with EtOAc (40 ml). The combined organic layers are dried (anhydrous magnesium sulfate), filtered, concentrated, and flashed (100% EtOAc) to give the title compound as a cream solid (0.075 g, 34%). Mass (m/z): 399.2 (M++1), 397.2 (M+−1).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]#[N:11].C([O-])([O-])=O.[K+].[K+].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1.[Cl:34][C:35]1[CH:36]=[CH:37][C:38]2[S:42][C:41]([CH2:43]Cl)=[N:40][C:39]=2[CH:45]=1>CN(C=O)C.O>[Cl:34][C:35]1[CH:36]=[CH:37][C:38]2[S:42][C:41]([CH2:43][O:8][C:7]3[C:2]([F:1])=[C:3]([C:10]#[N:11])[C:4]([F:9])=[CH:5][CH:6]=3)=[N:40][C:39]=2[CH:45]=1
Reactant: ClCc1nc2cc(Cl)ccc2s1
Reactant: N#Cc1c(F)ccc(O)c1F
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(F)ccc(OCc2nc3cc(Cl)ccc3s2)c1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79 %

Procedure:
A mixture of 2,6-difluoro-3-hydroxybenzenecarbonitrile (4.5 g, 29.0 mmol), K2CO3 (6.01 g, 43.5 mmol) and Nal (0.78 g 5.8 mmol) in DMF (75 ml) was stirred at room temperature for 5 minutes. 5-chloro-2-(chloromethyl)-1,3-benzothiazole was then added and the mixture heated at 40° C. for 18 hours, cooled to room temperature and poured into water (450 ml). Buff solid was filtered off and dried (9.46 g). This was the recrystallised from acetonitrile (30 ml) and dried in vacuo at 40° C. to give a beige solid. Yield 79%, mp 145-147° C., HPLC (Gemini C18, 50×4.6 mm): m/z 337 [M+H]+, Rt=4.93 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Br[CH:14]([CH3:27])[CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26]>>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH:14]([CH3:27])[CH2:15][N:16]3[C:17](=[O:26])[C:18]4[C:19](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]3=[O:21])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: CC(Br)CN1C(=O)c2ccccc2C1=O
Product: CC(CN1C(=O)c2ccccc2C1=O)N1CCN(c2ccncc2)CC1

Procedure:
The title compound was prepared from 1-pyridin-4-yl-piperazine [Org. Lett. 4 (2002) 737-740] and N-(2-bromopropyl)-phthalimide according to the method described in Reference Example 1/a.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[CH3:21][O:22][CH2:23][CH2:24][NH2:25].CN1CCOCC1>CO>[CH3:21][O:22][CH2:23][CH2:24][NH:25][S:17]([C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:3]3[C:4]([CH3:7])=[N:5][NH:6][C:2]=3[NH2:1])[S:9][C:10]=2[CH:16]=1)(=[O:19])=[O:18]
Reactant: COCCN
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: CO
Solvent: CN1CCOCC1
Product: COCCNS(=O)(=O)c1ccc2nc(-c3c(C)n[nH]c3N)sc2c1
Yield: 39 %

Procedure:
the title compound (33 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (75 mg, 0.23 mmol), 2-methoxyethylamine (39 mg, 0.43 mmol) and the polystyrene resin bound base N-3-(morpholino)propyl polystyrene sulfonamide (PS-NMM) (0.24 g, 0.45 mmol) in 4 mL of methanol. MS (m/z, ES+): 368.5 (M+1, 100%); 1H NMR (500 MHz, ppm, DMSO-d6): δ 11.8-12.1 (br s, 1H), 8.5 (s, 1H), 7.99 (br d, 1H), 7.83 (d, 1H), 7.73 (t, 1H), 5.9-6.7 (br s, 2H), 3.30 (t, 2H), 3.15 (s, 3H), 2.94 (dt, 2H), 2.41 (br s, 3H). Yield=46%.
Reaction SMILES: Cl[C:2]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][C:10]#[N:11])=[CH:6][CH:5]=1)=O.[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=C)=[CH:17][CH:16]=1.C(N(C)C)C1C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC(C)=CC=1>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH:2][C:4]2[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][C:10]#[N:11])=[CH:6][CH:5]=2)=[CH:17][CH:16]=1
Reactant: C=Cc1ccc(Br)cc1
Reactant: N#CC=Cc1ccc(C(=O)Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)Cc1ccccc1
Solvent: Cc1ccc(C)cc1
Product: N#CC=Cc1ccc(C=Cc2ccc(Br)cc2)cc1
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 11 %

Procedure:
2.13 g (11.1 mmols) of 4-chloroformylcinnamonitrile, 2.24 g (11.1 mmols) of 4-bromostyrene, 1.51 g (11.1 mmols) of N-benzyldimethylamine and 0.0246 g (0.11 mmol) of palladium acetate are added under argon to 30 ml of p-xylene, and the reaction mixture is stirred at 130° C. for 1.5 hours. The crude product which has been precipitated is filtered off at room temperature and is recrystallised from methanol and then from carbon tetrachloride. 0.38 g (11% of theory) of 4-bromostilbene-4'-acrylonitrile are obtained; melting point 258° C.
Reaction SMILES: CO.[OH-].[Li+].[C:5]([O:9][C:10]([NH:12][C:13]([CH3:29])([CH3:28])[CH2:14][C:15]1[N:19]([CH2:20][CH2:21][CH3:22])[N:18]=[C:17]([C:23]([O:25]CC)=[O:24])[CH:16]=1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>C(O)(=O)C.O>[C:5]([O:9][C:10]([NH:12][C:13]([CH3:28])([CH3:29])[CH2:14][C:15]1[N:19]([CH2:20][CH2:21][CH3:22])[N:18]=[C:17]([C:23]([OH:25])=[O:24])[CH:16]=1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CCCn1nc(C(=O)OCC)cc1CC(C)(C)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCCn1nc(C(=O)O)cc1CC(C)(C)NC(=O)OC(C)(C)C
Reaction time: 5.5 h
Yield: 89.5 %

Procedure:
Methanol (39.9 mL), lithium hydroxide (5.06 g, 121 mmol), and water (13.3 mL) were added to ethyl 5-{2-[(tert-butoxycarbonyl)amino]-2-methylpropyl}-1-propyl-1H-pyrazole-3-carboxylate (10.65 g, 30.1 mmol) in a 500 mL round bottom flask. The mixture was stirred vigorously for 5.5 hours. Acetic acid (8.0 mL) and water (200 mL) were added. A white solid formed and more acetic acid (61 mL) was added. The solid was isolated by filtration, washed with water, and dried. A second crop of solid was isolated from the filtrate. The crops were combined to yield 8.77 g of 5-{2-[(tert-butoxycarbonyl)amino]-2-methylpropyl}-1-propyl-1H-pyrazole-3-carboxylic acid as a white solid, mp 151-152° C. MS (APCI) m/k 326 (M+H)+; Anal. calcd for C16H27N3O4: C, 59.06; H, 8.36; N, 12.91. Found: C, 58.93; H, 8.59; N, 12.94.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[CH2:20][N:19]3[CH2:26][CH:27]([NH2:29])[CH3:28])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[C:30](OC(=O)C)(=[O:32])[CH3:31].C([O-])(=O)C.[NH4+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@@H:18]3[CH2:23][O:22][C:21]([CH3:24])([CH3:25])[CH2:20][N:19]3[CH2:26][C@@H:27]([NH:29][C:30](=[O:32])[CH3:31])[CH3:28])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CC(N)CN1CC(C)(C)OCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(=O)N[C@@H](C)CN1CC(C)(C)OC[C@H]1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12

Procedure:
The desired compound was prepared according to the previous example from 4-(2-Amino-propyl)-6,6-dimethyl-morpholine-3-carboxylic acid (6-chloro-9H-β-carbolin-8yl)-amide (3 CF3COOH salt) and acetic anhydride. 1H-NMR (300 MHz, methyl-d3 alcohol-d): δ 1.15 (d, 3H), 1.23 (s, 3H), 1.39 (s, 3H), 1.98 (s, 3H), 2.24 (d, 1H), 2.38 (m, 1H), 2.68 (m, 1H), 2.92 (d, 1H), 3.24 (m, 1H), 3.98 (m, 2H), 4.22 (m, H), 7.78 (d, 1H), 7.98 (m, 2H), 8.27 (d, 1H), 8.84 (s, 1H). Retention Time (LC, method: ammonium acetate standard): 1.54 min. MS (M+H+): 458.