Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:49][OH:50])=[C:7]([CH:48]=1)[C:8]([O:10][C@:11]([C:40]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=1[F:47])([CH2:34][N:35]1[CH:39]=[N:38][CH:37]=[N:36]1)[C@H:12]([S:14][C@@H:15]1[CH2:20][O:19][C@@H:18](/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:26]=2[F:33])[O:17][CH2:16]1)[CH3:13])=[O:9])#[N:2].[CH3:51][N:52]1[CH2:57][CH2:56][N:55]([C:58](=[O:64])[CH2:59][CH2:60][C:61](O)=[O:62])[CH2:54][CH2:53]1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:49][O:50][C:61](=[O:62])[CH2:60][CH2:59][C:58]([N:55]2[CH2:54][CH2:53][N:52]([CH3:51])[CH2:57][CH2:56]2)=[O:64])=[C:7]([CH:48]=1)[C:8]([O:10][C@:11]([C:40]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=1[F:47])([CH2:34][N:35]1[CH:39]=[N:38][CH:37]=[N:36]1)[C@H:12]([S:14][C@@H:15]1[CH2:16][O:17][C@@H:18](/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:26]=2[F:33])[O:19][CH2:20]1)[CH3:13])=[O:9])#[N:2]
Reactant: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@@](Cn1cncn1)(OC(=O)c1cc(C#N)ccc1CO)c1ccc(F)cc1F
Reactant: CN1CCN(C(=O)CCC(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@@](Cn1cncn1)(OC(=O)c1cc(C#N)ccc1COC(=O)CCC(=O)N1CCN(C)CC1)c1ccc(F)cc1F
Reaction time: 2 h

Procedure:
A solution of (1R,2R)-2-[[trans-2-[(1E,3E)-4-(4-cyano-2-fluorophenyl)-1,3-butadienyl]-1,3-dioxan-5-yl]thio]-1-(2,4-difluorophenyl)-1-[(1H-1,2,4-triazol-1-yl)methyl]propyl 5-cyano-2-(hydroxymethyl)benzoate (1.38 g, 1.97 mmol) obtained from Example 33 in dichloromethane (40 ml) was cooled to 0° C., and 4-(N,N-dimethylamino)pyridine (481.3 mg, 3.94 mmol), 4-(4-methyl-1-piperazinyl)-4-oxobutanoic acid (described in Bioorg. Med. Chem., 8, 2693 (2000); 708.0 mg, 3.54 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (830.8 mg, 4.33 mmol) were added thereto. The reaction mixture was stirred at the same temperature for 2 hours, and diluted with dichloromethane, then the organic layer was washed successively with water and a saturated aqueous solution of sodium chloride. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to chromatography on a silica gel (30 g) column (eluent; ethyl acetate:methanol=4:1) to afford a mixture of the title compound and 4-(N,N-dimethylamino)pyridine (component ratio; 6:1, 1.33 g). A part (790.8 mg) of the mixture was separated by recycle preparative HPLC [LC-908; Japan Analytical Industry Co., Ltd.; GPC column JAIGEL-1H (20 mm i.d. ×600 mm) and JAIGEL-2H (20 mm i.d. ×600 mm) connected in series for use; solvent, chloroform] to afford the title target compound (763.0 mg, 44% yield) as a colorless amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH:7]([NH:10][C:11](=[O:20])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[NH2:19])[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:22](O)(=O)C>COC(OC)OC>[C:1]([O:5][C:6](=[O:21])[C@@H:7]([N:10]1[C:11](=[O:20])[C:12]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)[N:19]=[CH:22]1)[CH2:8][CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(NC(=O)c1cc(Cl)ccc1N)C(=O)OC(C)(C)C
Reactant: CC(=O)O
Solvent: COC(OC)OC
Product: CC[C@@H](C(=O)OC(C)(C)C)n1cnc2ccc(Cl)cc2c1=O
Yield: 42 %

Procedure:
2-(2-amino-5-chloro-benzoylamino)-butyric acid-tert-butyl ester (2.82 g) was dissolved in trimethylorthoformate (50 ml). Acetic acid (10 ml) was added, and reaction mixture refluxed for 48 hours. After this time, the solvents were removed and the residue partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous layer was further extracted with ethyl acetate and the combined organic extracts washed with brine, dried (MgSO4) and concentrated under reduced pressure to give a yellow oil. This was purified by flash chromatography (20% EtOAc: Petroleum) to give the sub-title compound as an oil (1.23 g, 42% yield). 1H NMR (400 MHz, CDCl3) δ 8.25 (1H, s), 8.05 (1H, s), 7.7 (2H, m), 5.3 (1H, m), 2.3 (1H, m), 2.0 (1H, m), 1.5 (9H, s), 1.0 (3H, t) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[NH2:14])[CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].C(=O)([O-])O.[Na+].C(=O)(O)[O-].[CH:24]([CH:26]=O)=O.[Na+].[OH-].[Na+]>O.C(OCC)(=O)C>[N:14]1[C:13]2[C:2](=[CH:3][C:4]([CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10])=[CH:11][CH:12]=2)[N:1]=[CH:26][CH:24]=1
Reactant: Nc1ccc(CCOCCO)cc1N
Reactant: O=CC=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: OCCOCCc1ccc2nccnc2c1
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
In 20 mL of water is dissolved 1.50 g of 2-[(3,4-diaminophenethyl)oxy]-1-ethanol. After adjusting pH of the solution to 6.5 with sodium hydrogen carbonate, 2.22 g of sodium glyoxal bicarbonate is added at 60° C., and the mixture thus formed is stirred at the same temperature as above for 30 minutes. Ethyl acetate is added to the reaction mixture, pH is adjusted to 10 with 2 mol/L aqueous solution of sodium hydroxide, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain 0.73 g of 2-[2-(6-quinoxalinyl)-ethoxy]-1-ethanol as an oily product.
Reaction SMILES: Br.[CH3:2][O:3][C:4]([C:6]1[CH2:7][NH:8][CH2:9][CH2:10][CH:11]=1)=[O:5].C(N(C(C)C)C(C)C)C.C1(C)C=CC(S(O[CH2:31][CH2:32][CH:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:35][CH2:34]2)(=O)=O)=CC=1>CN(C)C=O>[CH3:2][O:3][C:4]([C:6]1[CH2:7][N:8]([CH2:31][CH2:32][CH:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:35][CH2:34]2)[CH2:9][CH2:10][CH:11]=1)=[O:5]
Reactant: COC(=O)C1=CCCNC1
Reactant: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc3C2)cc1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1=CCCN(CCC2COc3ccccc3C2)C1
Reaction time: 16 h
Yield: 97.6 %

Procedure:
First 3.3 g (14.8 mmol) of 1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrobromide (guvacoline hydrobromide) and then 6.1 g (47.3 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 4.5 g (13.5 mmol) of 3-[2-(p-toluenesulphonyloxy)ethyl]chroman in 70 ml of absolute dimethylformamide. The mixture is stirred for 16 hours at 60° and, after cooling, is concentrated by evaporation under a high vacuum. Water is added to the oily residue and extraction is carried out with diethyl ether. The combined organic phases are extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 3.97 g (97.7%) of 1-[2-(chroman-3-yl)ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester are obtained in the form of a yellow oil. The 1-[2-(chroman-3-yl)ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from methanol/diethyl ether and melts at 175°-177°.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][C:12]([CH3:15])=[N:11]2)=[CH:6][C:5]=1[Cl:16].[OH-].[Li+]>O1CCCC1>[Cl:16][C:5]1[CH:6]=[C:7]([N:10]2[CH:14]=[CH:13][C:12]([CH3:15])=[N:11]2)[CH:8]=[CH:9][C:4]=1[C:3]([OH:17])=[O:2]
Reactant: COC(=O)c1ccc(-n2ccc(C)n2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccn(-c2ccc(C(=O)O)c(Cl)c2)n1
Yield: 78.3 %

Procedure:
A solution of 2-chloro-4-(3-methyl-1H-pyrazol-1-yl)-benzoic acid methyl ester (1,42 g) from Example 96 and 6 ml of 1 M aqueous lithium hydroxide in tetrahydrofuran (20 ml) was stirred for 18 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic layer was washed with water, brine and was dried over anhydrous sodium sulfate. Evaporation of the solvent in vacuo afforded 1.05 g of the title compound as a colorless solid. m.p. 192-193° C. MS (EI), m/z: 236/238 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1.[C:23]([C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][C@@H:33]2[CH2:35][O:34]2)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][C@@H:33]([OH:34])[CH2:35][N:14]2[CH2:15][CH2:16][C:11]3([O:10][C:9]4[C:19]5[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]=4[S:18][CH2:17]3)=[CH:4][CH:3]=[C:2]([Cl:1])[CH:20]=5)[CH2:12][CH2:13]2)=[CH:29][CH:28]=1)([CH3:24])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CO2)cc1
Reactant: O=C1C(=O)c2ccc(Cl)cc2C2=C1SCC1(CCNCC1)O2
Product: CC(C)(C)c1ccc(OC[C@@H](O)CN2CCC3(CC2)CSC2=C(O3)c3cc(Cl)ccc3C(=O)C2=O)cc1

Procedure:
Compound 192 was synthesized using 9-chlorospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(4-tert-butylphenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=94-97° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.89 (d, J=8.4 Hz, 1H), 7.67-7.62 (m, 2H), 7.28 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 4.86 (d, J=4.4 Hz, 1H), 4.0-3.92 (m, 2H), 3.87-3.83 (m, 1H), 3.08 (s, 2H), 2.84-2.75 (m, 2H), 2.48-2.41 (m, 4H), 2.02-1.94 (m, 2H), 1.86-1.76 (m, 2H), 1.25 (s, 9H); LCMS: 542 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:14]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:12]=[C:11]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:10]=1)[CH2:5][C:6]([CH3:8])=[CH2:7].[F:32][C:33]([F:44])([F:43])[C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C([O-])([O-])=O.[K+].[K+].COCCOC>CCOC(C)=O.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>[CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:14]=[C:13]([C:37]2[CH:38]=[CH:39][C:34]([C:33]([F:44])([F:43])[F:32])=[CH:35][CH:36]=2)[CH:12]=[C:11]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:10]=1)[CH2:5][C:6]([CH3:8])=[CH2:7]
Reactant: C=C(C)CC(C(=O)OC)c1cc(OCc2ccccc2)cc(OS(=O)(=O)C(F)(F)F)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: C=C(C)CC(C(=O)OC)c1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 95 °C

Procedure:
A mixture of 2-(3-benzyloxy-5-trifluoromethanesulfonyloxy-phenyl)-4-methyl-pent-4-enoic acid methyl ester (4.3 g, 9.4 mmol), 4-trifluoromethylphenylboronic acid (2.6 g, 13.7 mmol), K2CO3 solution (2M, 9.4 mL) and DME (50 mL) was purged with N2 three times before adding Pd(PPh3)4 (400 mg, 0.3 mmol). The mixture was heated to 95° C. for 5 h (followed by HPLC). The reaction was diluted with EtOAc (200 mL) and then was washed successively with NaHCO3 solution and brine. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give the title compound as an oil. The residue was used crude in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].C([Li])(CC)C.[B:15](OCCCC)(OCCCC)[O:16]CCCC.Cl>C1COCC1>[F:1][C:2]1[C:3]2[B:15]([OH:16])[O:6][CH2:5][C:4]=2[CH:7]=[CH:8][CH:9]=1
Reactant: OCc1cccc(F)c1
Reactant: CCCCOB(OCCCC)OCCCC
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: OB1OCc2cccc(F)c21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
3-fluorobenzyl alcohol (3.5 parts; 0.028M) was stirred in THF (100 ml) containing tetramethylene ethylenediamine (10.2 ml; 0.067M). After cooling to -78° C., sec-butyl-lithium (77 ml of 0.8M solution in cyclohexane ex Aldrich; 0.061M) was slowly added over 45 min at between -78° and -65° C. with stirring under a nitrogen blanket. After 1 hour at -78° C., tributyl borate (16.78 ml; 0.061M) was added dropwise and the reactants stirred under nitrogen for 16 hrs allowing the temperature to slowly raise to 20° C. Dilute hydrochloric acid was added to bring the pH to about 12 and the aqueous phase separated and washed with diethylether. The pH of the aqueous phase was then acidified to about pH 2 with hydrochloric acid and extracted with ether (3×100 ml). These ether extracts were washed with saturated brine, dried over magnesium sulphate and the ether evaporated whereupon the product separated as a pale solid (2.6 parts; 62% theory) mp=132°-134° C. after recrystallisation from aqueous methanol.
Reaction SMILES: [C@H:1]([NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][N:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)=[O:7])([CH2:3][CH3:4])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C@H:1]([NH:5][C:6](=[O:7])[C:8]1[CH:27]=[CH:26][CH:25]=[C:10]([CH2:11][N:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)[CH:9]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CC[C@@H](C)NC(=O)c1cccc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H](C)NC(=O)c1cccc(CN2CCNCC2)c1
Reaction time: 24 h
Yield: 95.4 %

Procedure:
To a stirred solution of (R)-tert-butyl 4-(3-(sec-butylcarbamoyl)benzyl)piperazine-1-carboxylate (5.33 mmol, 2 g) in dichloromethane (10 mL) was added trifluoroacetic acid (5 mL). The reaction mixture was stirred for 24 hours then was concentrated under reduced pressure. Purification by strong cation exchange column chromatography gave the title compound (1.4 g). MS (ESI) m/z 276.3 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[CH3:12][C:13](OC(C)=O)=[O:14]>C1COCC1>[C:13]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11])(=[O:14])[CH3:12]
Reactant: COc1cc(C=O)ccc1O
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C=O)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 117 %

Procedure:
To a solution of of 4-hydroxy-3-methoxybenzaldehyde (10 g, 66 mmol) in 30 mL of THF was added Ac2O (8 g, 80 mmol) and TEA (20 g, 198 mmol). The reaction was stirred at room temperature overnight. The volatiles were evaporated to afford 15 g of product as an oil, which was used for next step without further purification.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[C:18]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)=[O:19])(=[O:13])=[O:12].[CH:33]1C2C(=CC=CC=2)C=C[C:34]=1S(Cl)(=O)=O>>[CH2:33]([O:26][C:25](=[O:27])[C:24]1[CH:28]=[CH:29][C:21]([NH:20][C:18](=[O:19])[C:17]2[CH:30]=[CH:31][CH:32]=[C:15]([NH:14][S:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)(=[O:12])=[O:13])[CH:16]=2)=[CH:22][CH:23]=1)[CH3:34]
Reactant: O=C(O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3ccc4ccccc4c3)c2)cc1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3ccc4ccccc4c3)c2)cc1

Procedure:
4-[3-(Naphthalene-2-sulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=445.1 (M−H), was prepared in analogy to example 1, steps A to D. Step C was performed using naphthalene-2-sulfonyl chloride and yielded 4-[3-(naphthalene-2-sulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:26])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1.C(N(CC)C(C)C)(C)C.Br[CH2:37][CH:38]1[CH2:40][CH2:39]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[CH:38]1([CH2:37][NH:26][C:5]2[CH:6]=[CH:7][C:8]([C:9]3[O:10][C:11]([C:14]4[C:15]([C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=5)=[N:16][O:17][C:18]=4[CH3:19])=[N:12][N:13]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:40][CH2:39]1
Reactant: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: BrCC1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(NCC2CC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Temperature: 25 °C
Reaction time: 24 h
Yield: 14.8 %

Procedure:
To a suspension of 3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine (200 mg, 0.57 mmol) in THF was added N,N-diisopropyl ethyl amine (128 μL, 0.75 mmol) and bromomethyl-cyclopropane (61 μL, 0.63 mmol) and the reaction mixture was stirred for 24 h at ambient temperature. After addition of potassium bis(trimethylsilyl)amide (0.91 M in THF, 0.82 mL, 0.75 mmol) was added stirring was continued for 15 min and further bromomethyl-cyclopropane (78 μL, 0.80 mmol) was added. After stirring for 18 h at ambient temperature further bromomethyl-cyclopropane (0.12 mL, 1.2 mmol) was added and stirring continued for 24 h at this temperature. The reaction mixture was extracted with aqueous sodium carbonate (saturated, 20 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers dried over sodium sulfate. Concentration and then purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=40:40:20 to 0:80:20) afforded the title compound (34 mg, 15%) as a light brown solid. MS: m/e=403.4 [M+H]+.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][O:5][C:6]([C:8]12[CH2:13][CH:12]1[CH2:11][CH2:10][C:9]2=[O:14])=[O:7]>CS(C)=O>[CH3:4][O:5][C:6]([CH:8]1[CH:12]([CH2:13][C:1]#[N:2])[CH2:11][CH2:10][C:9]1=[O:14])=[O:7]
Reactant: [C-]#N
Reactant: COC(=O)C12CC1CCC2=O
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C1C(=O)CCC1CC#N
Temperature: 25 °C
Yield: 60.3 %

Procedure:
In argon atmosphere, sodium cyanide (200 mg, 4 mmol) and 2-oxo-bicyclo [3.1.0] hexane-1-carboxylic acid methyl ester (462 mg, 3 mmol) were added to dimethyl sulfoxide (2ml). The mixture was stirred at the room temperature for one night and was treated in accordance with the process of Preparation 4 to obtain 328 mg of 5-cyanomethyl-2-oxo-cyclopentanecarboxylic acid methyl ester. Yield: 60%.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:31]=[CH:30][C:8]([NH:9]/[C:10](=[C:17]2\[C:18](=[O:29])[NH:19][C:20]3[C:25]\2=[CH:24][CH:23]=[C:22]([C:26]([OH:28])=[O:27])[CH:21]=3)/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH3:3].NC1C=CC=CC=1.[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42]O>>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH:9]/[C:10](=[C:17]2\[C:18](=[O:29])[NH:19][C:20]3[C:25]\2=[CH:24][CH:23]=[C:22]([C:26]([O:28][CH2:42][CH2:41][N:40]([CH3:44])[CH3:39])=[O:27])[CH:21]=3)/[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:30][CH:31]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)O)ccc32)c2ccccc2)cc1
Reactant: CN(C)CCO
Solvent: Nc1ccccc1
Product: CN(C)CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN(C)C)cc1)c1ccccc1

Procedure:
Prepared from 3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone and 2-dimethylaminoethanol aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=5:2) C29H32N4O3
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH:4]1[CH2:15][N:14]2[C:6]([C:7]3[NH:8][C:9]([CH:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[N:10][C:11]=3[N:12]([CH2:17][CH2:18][CH3:19])[C:13]2=[O:16])=[N:5]1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])O.[Na+]>O>[ClH:2].[ClH:1].[CH:20]1([C:9]2[NH:8][C:7]3[C:6]4=[N:5][CH:4]([CH2:3][NH:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH2:15][N:14]4[C:13](=[O:16])[N:12]([CH2:17][CH2:18][CH3:19])[C:11]=3[N:10]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Nc1ccccc1
Reactant: CCCN1C(=O)N2CC(CCl)N=C2c2[nH]c(C3CCCC3)nc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCN1C(=O)N2CC(CNc3ccccc3)N=C2c2[nH]c(C3CCCC3)nc21
Temperature: 70 °C
Yield: 16.1 %

Procedure:
To Compound 26 (12 mg, 0.04 mmol) obtained in Example 26 were added water (3 mL), aniline (20 mg, 0.24 mmol, 6.0 equivalents) and sodium hydrogen carbonate (62 mg, 0.74 mmol, 18.5 equivalents), and the mixture was stirred with heating at 70° C. for 2 hours. To the reaction solution was added water, the mixture was extracted with ethyl acetate, and the extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform:methanol=95:5), to the product was added a 4 mol/L solution of hydrogen chloride in ethyl acetate, and then the mixture was concentrated. The residue was crystallized from acetone and methanol to obtain the title compound (3 mg, 19%) as a light yellow solid.
Reaction SMILES: C(O[C:4](=[O:25])[NH:5][S:6]([C:9]1[CH:24]=[CH:23][C:12]2[CH2:13][CH2:14][N:15]([C:18](=[O:22])[N:19]([CH3:21])[CH3:20])[CH2:16][CH2:17][C:11]=2[CH:10]=1)(=[O:8])=[O:7])C.[CH:26]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCOCC1>[CH:26]1([NH:31][C:4]([NH:5][S:6]([C:9]2[CH:24]=[CH:23][C:12]3[CH2:13][CH2:14][N:15]([C:18](=[O:22])[N:19]([CH3:21])[CH3:20])[CH2:16][CH2:17][C:11]=3[CH:10]=2)(=[O:8])=[O:7])=[O:25])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CCOC(=O)NS(=O)(=O)c1ccc2c(c1)CCN(C(=O)N(C)C)CC2
Reactant: NC1CCCC1
Solvent: C1COCCO1
Product: CN(C)C(=O)N1CCc2ccc(S(=O)(=O)NC(=O)NC3CCCC3)cc2CC1

Procedure:
A solution of 8.0 g. of [(3-dimethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)sulfonyl]carbamic acid ethyl ester and 2.4 ml. of cyclopentylamine in 43 ml. of dioxane is heated under reflux for 1 hour and the solution subsequently evaporated in vacuo. Chromatography of the evaporation residue on 400 g. of silica gel with a mixture of 5 parts by volume of methanol and 95 parts by volume of chloroform yields the 1-cyclopentyl-3-[(3-dimethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)sulfonyl]urea, m.p. 179°-180° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]=[O:8])[C:5](=[O:9])[CH2:4][N:3]1[CH2:10][C:11]#[CH:12].[C-:13]#[N:14].[Na+].S(=O)(O)[O-].[Na+]>CCOCC.O>[C:13]([CH:7]([N:6]1[C:5](=[O:9])[CH2:4][N:3]([CH2:10][C:11]#[CH:12])[C:2]1=[O:1])[OH:8])#[N:14]
Reactant: C#CCN1CC(=O)N(C=O)C1=O
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: C#CCN1CC(=O)N(C(O)C#N)C1=O
Reaction time: 2 h

Procedure:
To a solution of 2,4-dioxo-1-propargyl-3-imidazolidine-carbaldehyde (1.8 mmol) in 25 ml of ether is added 25 ml of water followed by sodium cyanide (3.04 mmol). The mixture is stirred vigorously while a solution of sodium bisulfite (2.45 mmol) in 15 ml of water is added over about 5 minutes. The reaction mixture is stirred for two hours. The organic phase is separated, washed with water, dried over calcium sulfate and solvent evaporated to give cyano(2,4-dioxo-1-propargyl-3-imidazolidinyl)methanol.
Reaction SMILES: [NH2:1][C:2]1([C:6]2[S:7][C:8]([C:11]3[CH:12]=[C:13]([NH:18][C:19]4[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=4)[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:9][N:10]=2)[CH2:5][O:4][CH2:3]1.[S:29](N)([NH2:32])(=[O:31])=[O:30]>O1CCOCC1.C(OCC)(=O)C>[CH3:17][C:15]1[CH:16]=[C:11]([C:8]2[S:7][C:6]([C:2]3([NH:1][S:29](=[O:31])(=[O:30])[NH2:32])[CH2:3][O:4][CH2:5]3)=[N:10][CH:9]=2)[CH:12]=[C:13]([NH:18][C:19]2[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=2)[CH:14]=1
Reactant: NS(N)(=O)=O
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(N)COC3)s2)c1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(NS(N)(=O)=O)COC3)s2)c1
Temperature: 100 °C
Yield: 55.7 %

Procedure:
To a solution of N-{3-[2-(3-aminooxetan-3-yl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (Example 59, 25 mg, 0.061 mmol) in dioxane (600 uL), sulfamide (70 mg, 0.725 mmol) was added. The reaction mixture was stirred at 100° C. The resulting mixture was stirred at 100° C. for 4 days. The mixture was diluted with ethyl acetate, washed with saturated aqueous NaHCO3, followed by brine, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica (10-100% ethyl acetate in hexanes) and lyophilized to afford N-{3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]oxetan-3-yl}sulfuric diamide (16.3 mg, 0.034 mmol, 54.6% yield) as a pale yellow solid. MS ESI: [M H]+ m/z 487.0. 1H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 2H), 8.85 (m, 1H), 8.30 (s, 1H), 8.04 (s, 1H), 7.95 (s, 1H), 7.51 (s, 1H), 7.28 (m, 1H), 7.17 (s, 1H), 6.98 (s, 2H), 5.02 (m, 2H), 4.84 (m, 2H), 2.32 (s, 3H). rhSYK activity=+++