Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:18])([CH3:17])[C:12](OCC)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O.[NH2:20][NH2:21]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:18])([CH3:17])[C:12]([NH:20][NH2:21])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)C(C)(C)c1ccc(OC)c(OC)c1
Reactant: NN
Solvent: CO
Solvent: O
Product: COc1ccc(C(C)(C)C(=O)NN)cc1OC
Reaction time: 12 h
Yield: 102.5 %

Procedure:
A solution of ethyl 2-(3,4-dimethoxyphenyl)-2-methylpropanoate (2.84 g, 11.26 mmol) and hydrazine hydrate (7.00 mL, 112.56 mmol) in MeOH (15 mL) was heated at 110° C. in a sealed tube. After 12 h, additional hydrazine hydrate (10 mL) was added to the reaction mixture, which then was heated for additional 6 h. The cooled mixture was concentrated to afford 2-(3,4-dimethoxyphenyl)-2-methylpropanehydrazide (2.75 g, quant) as a liquid. 1H NMR (400 MHz, CDCl3) δ 6.94-6.91 (m, 1H), 6.87-6.81 (m, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 3.69 (br s, 3H), 1.56 (s, 6H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]([F:17])([F:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH3:6])=[O:4].N1C=CC=CC=1.[C:24](Cl)(Cl)=[O:25].C1(C)C=CC=CC=1>ClCCl>[F:17][C:8]([F:16])([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][C@H:2]([N:1]=[C:24]=[O:25])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)[C@@H](N)CC(F)(F)Cc1ccccc1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](CC(F)(F)Cc1ccccc1)N=C=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Under argon, methyl (S)-2-amino-4,4-difluoro-5-phenylpentanoate (400 mg, 1.64 mmol) was dissolved in 20 ml of dichloromethane. At RT, pyridine (520 mg, 4 eq.) was added dropwise and the resulting solution was stirred for 15 minutes. The mixture was then cooled to 0° C. and admixed with 20% phosgene solution in toluene (2.16 ml, 4.1 mmol, 2.5 eq.). The mixture was stirred at RT for 90 minutes and then the solvent was removed under reduced pressure. The mixture was codistilled with 10 ml of toluene twice more. The crude product thus obtained was used for the reactions which followed without further purification.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[C:1]1([NH:7][C:8](=[N:10][C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[S:9][CH3:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(NC(=S)Nc1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CSC(=NC(=O)c1ccccc1)Nc1ccccc1

Procedure:
12.8 g (0.05 M) of N-phenyl-N'-benzoyl-thiourea, 5.3 g (0.038M) of potassium carbonate, 4.7 ml (0.075 M) of methyliodide and 200 ml of acetone are boiled in a reflux and constantly mixed for five hours. After cooling the sediment is filtered. The filtrate is washed with 150 ml of water. The separated sediment is ground and filtered. 12.4 g (93.3% of the theoretical yield) of N-phenyl-N'-benzoyl-S-methylisothiourea with a melting point of 78°-94° are obtained. After recrystallization twice from ethanol and ethylacetate 7.4 g (54.8 % of the raw one) of product with a melting temperature of 102°-104° C. are obtained.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:32])[N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH:20]=[N:21]2)=[CH:16][C:15]=1[O:33][CH3:34].[N:35]1([CH2:40][CH2:41]O)[CH:39]=[CH:38][N:37]=[CH:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[N:35]1([CH2:40][CH2:41][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](=[O:32])[N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:28])([CH3:29])[CH3:30])[CH:20]=[N:21]3)=[CH:16][C:15]=2[O:33][CH3:34])[CH:39]=[CH:38][N:37]=[CH:36]1
Reactant: OCCn1ccnc1
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCn1ccnc1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 79.9 %

Procedure:
Diethyl azodicarboxylate (435 mg, 2.5 mmol) was added dropwise to a suspension of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (612 mg, 2 mmol), (prepared as described for the starting material in Example 85), 2-(imidazol-1-yl)ethanol (280 mg, 2.5 mmol), (J. Med. Chem. 1993, 25 4052-4060), and triphenylphosphine (655 mg, 2.5 mmol) in methylene chloride (10 ml) at 5° C. The mixture was stirred for 10 minutes at 5° C. and then 1 hour at ambient temperature. The mixture was poured directly on to a silica column and eluted with methylene chloride/methanol (95/5) to give 7-(2-(imidazol-1-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (640 mg, 80%). 1H NMR Spectrum: (CDCl3) 1.19(s, 9H); 3.98(s, 3H); 4.34(m, 2H); 4.45(m, 2H); 5.94(s, 2H); 7.02(s, 1H); 7.07(s, 1H); 7.11(s, 1H); 7.64(s, 1H); 7.67(s, 1H); 8.17(s, 1H) MS-ESI: 423 [MNa]+
Reaction SMILES: [Cl:1][C:2]([CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]2[C:16]=1[CH:17]=[CH:18][C:19](=[O:28])[N:20]2[CH3:27])(C(OCC)=O)[C:3]([O:5]CC)=[O:4].C(O)(=O)C.Cl.O>C(O)C>[Cl:1][CH:2]([CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]2[C:16]=1[CH:17]=[CH:18][C:19](=[O:28])[N:20]2[CH3:27])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(Cl)(CCc1ccc(OC)c2c1ccc(=O)n2C)C(=O)OCC
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(CCC(Cl)C(=O)O)c2ccc(=O)n(C)c12
Temperature: 25 °C
Yield: 55 %

Procedure:
Diethyl 2-chloro-2-[2-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]malonate (2.38 g) was added to a mixture of acetic acid (10 ml) and 6N hydrochloric acid (15 ml), and the resulting mixture was heated under reflux overnight. After cooling to room temperature, water and a small quantity of ethanol was added to the reaction mixture, followed by ice cooling. The precipitated solid was collected by filtration, washed with water and dried to thereby obtain 0.99 g (yield: 55%) of 2-chloro-4-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-yl)butyric acid as a gray powder.
Reaction SMILES: [BH4-].[Na+].C(OC(=O)[O:7][C:8]1[CH:13]=[C:12]([O:14]C(OCC)=O)[CH:11]=[CH:10][C:9]=1[C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)C.Cl>O.C1COCC1.[OH-].[Na+]>[CH2:20]([C:9]1[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=1[OH:7])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)Oc1ccc(C(=O)c2ccccc2)c(OC(=O)OCC)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc(Cc2ccccc2)c(O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of sodium borohydride (1.85 g, 49 mmol) in water (30 ml) was added to an ice cooled solution of carbonic acid 2-benzoyl-5-ethoxycarbonyloxy-phenyl ester ethyl ester (3.6 g, 10 mmol) in THF (30 ml). The mixture was stirred for ˜60 mins. at 0° C., and for ˜60 hrs. at room temperature, to give a pale red suspension. Water (150 ml) was added and the mixture extracted with diethyl ether (150 ml). The extracts were washed with water (2×100 ml) and saturated aqueous sodium chloride solution (50 ml). The solution was dried over anhydrous magnesium sulphate and concentrated to give a pale yellow gum. The gum was taken up in aqueous sodium hydroxide (20 ml, 10%), and the solution heated under reflux for ˜60 mins. The solution was allowed to cool and acidified with hydochloric acid (5 ml, 37%). The mixture was extracted with diethyl ether (50 ml). The extracts were washed with water (3×40 ml) and saturated aqueous sodium chloride solution (30 ml). The solution was dried over anhydrous magnesium sulphate and concentrated to give 4-benzyl-benzene-1,3-diol as a dark red gum, (2.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:4]2[CH:3]=1.C([Li])CCC.[CH2:35]([S:37]SCC)[CH3:36].O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([S:37][CH2:35][CH3:36])[N:5]2[N:8]=[C:9]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22]4)[N:12]=3)=[C:4]2[CH:3]=1
Reactant: CCSSCC
Reactant: Fc1ccc(-c2nn3ccc(Cl)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCSc1cc(Cl)cc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn12
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (150 mg, 0.37 mmol) in anhydrous tetrahydrofuran (5 mL) at −78° C. was added n-butyllithium (0.7 mL, 1.1 mmol of 1.6 M solution in hexane). The resulting solution was stirred for 10 minutes at −78° C., followed by addition of diethyldisulfide (0.14 mL, 1.1 mmol). The reaction was stirred at −78° C. for 20 minutes and then allowed to warm to room temperature. Water and ethyl acetate were added to the reaction mixture The phases were separated, the aqueous phase washed with ethyl acetate and the combined organic phase dried (magnesium sulfate), filtered and concentrated in vacuo. The resulting solid was purified by flash chromatography (1:1 ethyl acetate-hexane) to give, after recrystallization from ethyl acetate N-{4-[5-chloro-7-(ethylsulfanyl)-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinyl}-N-cyclopentylamine (90 mg, 52%) as a solid. 1H-NMR (CDCl3): δ 8.42(broad s, 1H), 8.08 (d, 1H), 7.66 (q, 2H), 7.17 (t, 2H), 6.73 (d, 1H), 6.31 (d, 1H), 5.18 (d, 1H), 4.20 (m, 1H), 3.22 (q, 2H), 2.0–2.1 (m, 2H), 1.4–1.9 (m, 9H); 19F-NMR (CDCl3): δ112.8; MS m/z 468(M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH:4]([N:16]1[CH2:21][CH2:20][NH:19][CH:18]([CH2:22][O:23][CH3:24])[CH2:17]1)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.[C:26]([NH:33][C@H:34]([C:43](O)=[O:44])[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.O.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:25])[CH:4]([N:16]1[CH2:21][CH2:20][N:19]([C:43](=[O:44])[CH:34]([NH:33][C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:35][C:36]2[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=2)[CH:18]([CH2:22][O:23][CH3:24])[CH2:17]1)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)O
Reactant: COCC1CN(C(Cc2ccc3ccccc3c2)C(=O)OC)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCC1CN(C(Cc2ccc3ccccc3c2)C(=O)OC)CCN1C(=O)C(Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 92 %

Procedure:
2-(3-Methoxymethyl-piperazine-1yl)-3-naphthalen2-yl-propionic acid methyl ester, 62, (2.2 g, 6.4 mmol) and N-Boc-(4-flouro)phenylalanine (1.9 g, 6.8 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (4.9 g, 12.9 mmol) are dissolved in anhydrous DMF (20 mL). This reaction mixture is cooled to 0° C. then N-methylmorpholine (0.75 mL, 6.8 mmol) is added. This reaction mixture is placed in a refrigerator overnight. EtOAc (75 mL) and water (300 mL) are added, and the organic layer is separated. The aqueous layer is extracted with EtOAc (3×150 mL). All organic layers are combined and washed with water (100 mL), and dried over Na2SO4. The solution is concentrated in vacuo and the residue purified over silica (EtOAc/Hexane, 1:1) to afford 3.6 g (92% yield) of the desired product. 1H NMR (CDCl3, δ): 7.72–7.58 (m, 3H), 7.44 (s, 1H), 7.40–7.22 (m, 2H), 7.15 (d, J=8.2 Hz, 1H), 7.10–6.98 (m, 2H), 6.82 (t, J=8.2 Hz, 2H), 5.88–5.64 (m, 1H), 4.82–4.50 (m, 1.5H), 4.18 (d, J=12.3 Hz, 0.5H), 3.58–3.44 (m, 3H), 3.42–3.30 (m, 1.5H), 3.08–3.72 (m, 10H), 2.68–2.45 (m, 2H), 2.40–2.18 (m, 1H), 1.70 (d, J=12.3 Hz, 0.5H), 1.35–1.25 (m, 1H), 1.30 (s, 9H); 13C NMR, δ 171.8, 171.4, 170.4, 163.9, 160.2, 153.0, 152.8, 136.0, 133.6, 132.6, 132.3, 131.4, 127.9, 127.7, 127.5, 126.2, 125.6, 115.5, 115.2, 115.1, 115.0, 79.5, 79.2, 69.6, 68.9, 68.3, 68.1, 60.3, 58.6, 58.3, 53.7, 52.0, 51.2, 48.8, 46.5, 45.6, 42.3, 40.0, 38.7, 35.3, 28.4.
Reaction SMILES: C(O[C:4]([CH2:6][O:7][C:8]1[CH:28]=[CH:27][C:11]([NH:12][C:13]2[CH:18]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[CH:10][CH:9]=1)=[O:5])C.[NH:29]([CH2:33][CH2:34][OH:35])[CH2:30][CH2:31][OH:32]>C(O)C>[OH:32][CH2:31][CH2:30][N:29]([CH2:33][CH2:34][OH:35])[C:4]([CH2:6][O:7][C:8]1[CH:28]=[CH:27][C:11]([NH:12][C:13]2[CH:18]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[CH:10][CH:9]=1)=[O:5]
Reactant: OCCNCCO
Reactant: CCOC(=O)COc1ccc(Nc2cc(Nc3cccc(C)c3)ncn2)cc1
Solvent: CCO
Product: Cc1cccc(Nc2cc(Nc3ccc(OCC(=O)N(CCO)CCO)cc3)ncn2)c1
Yield: 21 %

Procedure:
A mixture of 4-[4'-(ethoxycarbonylmethoxy)anilino]6-(3'-methylanilino)pyrimidine (0.30 g) and diethanolamine (0.5 g) in ethanol (10 ml) was refluxed for 8 hours. The product so obtained was chromatographed on silica to give 4-[4'-{N,N-di-(2-hydroxyethyl)carbamoylmethoxy}anilino]6-(3'-methylanilino)pyrimidine in 21% yield, m.p. 160°-162° C.;
Reaction SMILES: C([O:3][C:4](=O)[NH:5][CH2:6][CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O=P(Cl)(Cl)Cl>[C:4]1(=[O:3])[C:9]2[C:8](=[CH:17][CH:16]=[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]3=2)[CH2:7][CH2:6][NH:5]1
Reactant: CCOC(=O)NCCc1ccc2ccccc2c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1NCCc2ccc3ccccc3c21
Temperature: 110 °C
Reaction time: 3 h
Yield: 39.3 %

Procedure:
Using an analogous procedure and workup as described in Example 1, step 4, (2-naphthalen-2-yl-ethyl)-carbamic acid ethyl ester (I-10c: 1.3 g, 5.349 mmol) in POCl3 (16 mL) was reacted with P2O5 (1.58 g, 11.205 mmol). The resulting mixture was stirred at 110° C. for 3 hours to afford the crude product. Purification by column chromatography on silica gel (20% ethylacetate in hexane) afforded 415 mg of the product (40% yield).
Reaction SMILES: [NH2:1][CH:2]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:3][CH2:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1.O>C(Cl)Cl>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH:1][CH:2]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:3][CH2:4][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=2)(=[O:40])=[O:39])=[CH:34][CH:33]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)COc1ccc(CCC(N)c2cccnc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(CCC(NS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 28.3 %

Procedure:
Ethyl 4-[3-amino-3-(3-pyridyl)propyl]phenoxyacetate (50 mg) and 30 mg of triethylamine were dissolved in 10 ml of methylene chloride, followed by addition of 50 mg of p-chlorobenzene sulfonylchloride, and stirred at room temperature for 2.5 hours. To the reaction mixture was added water, and the organic phase was then separated which was extracted with methanol-methylene chloride (5:95 v/v) from the aqueous phase. The organic phases were combined and washed in saturated aqueous sodium chloride followed by drying over magnesium sulfate and distillation of the solvent. The obtained residue was subjected to chromatography on a silica gel column, and from a fraction eluted with methanol-methylene chloride (5:95 v/v) was obtained 22 mg of ethyl 4-[3-(4-chlorobenzenesulfonamido)-3-(3-pyridyl)propyl]phenoxyacetate. The spectrometric data supports the structure of [38] as follows.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][C@@H:7]1[CH3:19])=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][C@@H:7]1[CH3:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCNC[C@@H]1C
Reaction time: 12 h

Procedure:
A solution of 2.05 g (S)-2-Methyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester 1-ethyl ester in 15 ml dichloromethane was treated with 11.2 ml TFA and the resulting solution stirred for 12 h. The solvents were removed in vacuum and the crude hydrotrifluoroacetate transformed to the free amine by treatment with (Polystyrylmethyl)trimethylammonium bicarbonate in MeCN. Yield: 1.70 g.
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1C(C2SC3C=CC=C(C(N)=O)C=3C=2)=NC(NCCC2CCN(C)CC2)=NC=1.[CH:32]1([NH:35][C:36]([C:38]2[C:46]3[CH:45]=[C:44]([C:47]4[C:52]([Cl:53])=[CH:51][N:50]=[C:49]([NH:54][CH2:55][CH2:56][CH2:57][N:58]5[CH2:63][CH2:62][NH:61][CH2:60][C@@H:59]5[CH3:64])[N:48]=4)[S:43][C:42]=3[CH:41]=[CH:40][CH:39]=2)=[O:37])[CH2:34][CH2:33]1>>[ClH:3].[ClH:53].[ClH:1].[CH:32]1([NH:35][C:36]([C:38]2[C:46]3[CH:45]=[C:44]([C:47]4[C:52]([Cl:53])=[CH:51][N:50]=[C:49]([NH:54][CH2:55][CH2:56][CH2:57][N:58]5[CH2:63][CH2:62][N:61]([CH3:4])[CH2:60][C@@H:59]5[CH3:64])[N:48]=4)[S:43][C:42]=3[CH:41]=[CH:40][CH:39]=2)=[O:37])[CH2:34][CH2:33]1
Reactant: C[C@H]1CNCCN1CCCNc1ncc(Cl)c(-c2cc3c(C(=O)NC4CC4)cccc3s2)n1
Reactant: CN1CCC(CCNc2ncc(Cl)c(-c3cc4c(C(N)=O)cccc4s3)n2)CC1
Agent: Cl
Product: C[C@H]1CN(C)CCN1CCCNc1ncc(Cl)c(-c2cc3c(C(=O)NC4CC4)cccc3s2)n1

Procedure:
Using the method of 2-{5-chloro-2-[2-(1-methylpiperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid amide di-hydrochloride, the title compound is synthesized from (S)-2-{5-chloro-2-[3-(2-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and isolated as a yellow solid. ES+(m/z) 499 (35Cl) and 501 (37Cl) [M(free base)+H].
Reaction SMILES: Br[C:2]1[C:3]([O:23][CH3:24])=[C:4]([CH:10]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([NH2:21])=[C:15]3[C:14]([CH3:22])=[N:13]2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[CH3:25][N:26]([CH3:44])[C:27](=[O:43])[C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[NH2:21][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:12]([CH:10]([C:4]3[C:3]([O:23][CH3:24])=[C:2]([C:32]4[CH:31]=[N:30][CH:29]=[C:28]([CH:33]=4)[C:27]([N:26]([CH3:25])[CH3:44])=[O:43])[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=3)[CH3:11])[N:13]=[C:14]([CH3:22])[C:15]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1Br
Reactant: CN(C)C(=O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1cncc(C(=O)N(C)C)c1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
A mixture of 1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (25 mg, 0.061 mmol) (chiral pure, first peak from Example 20, Step 2), N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide (from PepTech) (25 mg, 0.091 mmol), sodium carbonate (13 mg, 0.12 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (1:1) (9.9 mg, 0.012 mmol) in acetonitrile (0.8 mL)/water (0.3 mL) was degassed with N2 and then stirred at 95° C. for 2 h. The mixture was filtered and the filtrate purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. The product was isolated as a single enantiomer. LCMS calculated for C24H27ClN7O2 (M+H)+: m/z=480.2; Found: 480.2. 1H NMR (500 MHz, DMSO-d6) δ 8.64 (1H, s), 8.54 (1H, br s), 8.13 (1H, s), 7.82 (1H, m), 7.53 (1H, s), 7.42 (2H, br s), 6.28 (1H, q, J=6.5 Hz), 3.22 (3H, s), 2.95 (6H, m), 2.58 (3H, s), 2.04 (3H, s), 1.77 (3H, d, J=6.5 Hz) ppm.
Reaction SMILES: [N:1]#[N:2].[CH3:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([S:15]([NH:18][C@H:19]([C:27]([OH:29])=[O:28])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:26])[NH2:25])(=[O:17])=[O:16])=[CH:12]2)=[CH:7][CH:6]=1.[ClH:30].[CH3:31]O>>[N:1]#[N:2].[ClH:30].[CH3:31][O:28][C:27](=[O:29])[C@H:19]([CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:25])[NH2:26])[NH:18][S:15]([C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[CH:14][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[CH:12]=1)(=[O:16])=[O:17]
Reactant: CO
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cc2c1
Agent: Cl
Agent: N#N
Product: COC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2ccc(OC)cc2c1
Yield: 95 %

Procedure:
A suspension of 1.0 gram of N2 -(7-methoxy-2-naphthalenesulfonyl) -L-arginine in 15 ml of anhydrous methanol was saturated with dry hydrogen chloride for one hour. The reaction mixture was refluxed for an additional one hour. After cooling, the reaction mixture was concentrated in vacuo. The residue was triturated with cold ethyl ether to give a cyrstalline product. After crystallization from methanolethyl ether, N2 -(7-methoxy-2-naphthalenesulfonyl)-L-arginine methyl ester hydrochloride was obtained in 95% yield; mp. 115° - 118°C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[CH:5]=1)=O.C([NH2:13])=O>C(O)=O>[Br:10][C:6]1[CH:5]=[C:4]([CH:2]([NH2:13])[CH3:1])[CH:9]=[CH:8][CH:7]=1
Reactant: NC=O
Reactant: CC(=O)c1cccc(Br)c1
Solvent: O=CO
Product: CC(N)c1cccc(Br)c1
Temperature: 220 °C

Procedure:
A mixture of commercially available 3-bromoacetophenone (30 g, 0.1508 mol), formic acid (47 mL) and formamide (70 mL) was heated to 220° C. for 5 h. The brown liquid obtained was cooled to RT, quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine and concentrated. The resulting brown liquid was dissolved in ethanol (375 mL) and conc.HCl (75 mL) and the mixture was refluxed over night. Ethanol was removed completely and the aqueous layer was washed with ether and ethyl acetate to remove all non-basic impurities. The aqueous layer was basified with a 10% aqueous sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, and concentrated to provide 26 g (86.65%) of A56.1. This compound was taken to the next step with out further purification. 1H NMR (CDCl3, 300 MHz) δ 1.38 (d, 3H), 4.1 (q, 1H), 7.2 (m, 1H), 7.27 (m, 1H), 7.37 (m, 1H), 7.51 (s, 1H). LS-MS (M−H)+=200.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[CH2:12]([NH:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:19]([CH2:20][CH2:21][CH2:22][CH3:23])[C:10]([NH:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCCNCc1ccccc1
Reactant: Cc1ccc(N=C=O)c(C)c1
Product: CCCCN(Cc1ccccc1)C(=O)Nc1ccc(C)cc1C

Procedure:
Many of the novel ureas and thioureas of this invention are prepared by reacting arylisocyanates and arylisothiocyanates with secondary amines. These reactions may be performed in aprotic solvents such as hexane, diethyl ether, toluene, tetrahydrofuran, and the like at temperatures from room temperature or below up to the boiling point of the solvent used. The ureas and thioureas are isolated by filtration or by evaporation of the solvent, and they may be purified by recrystallization, absorption chromatography, or distillation under reduced pressure Examples of this process are the reaction of 2,4-dimethylphenylisocyanate with N-benzyl-N-(n-butyl)amine to yield 1-benzyl-1-(n-butyl)-3-(2,4-dimethylphenyl)urea and the reaction of 6-[[(4-butylphenyl)methyl]amino]-1-hexanol with 2,4-dimethylphenyl isocyanate in hexane at room temperature to yield 1-[(4-butylphenyl)methyl]-3-(2,4-dimethylphenyl)-1-(6-hydroxyhexyl)urea.