Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:10]=[C:11]([C:25](=[O:27])[CH3:26])[CH:12]=[N:13][C:14]=2[NH:15][C:16]2[CH:17]=[N:18][C:19]([O:23][CH3:24])=[C:20]([F:22])[CH:21]=2)[CH:3]=1.[CH3:28][Mg]Br>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:10]=[C:11]([C:25]([OH:27])([CH3:28])[CH3:26])[CH:12]=[N:13][C:14]=2[NH:15][C:16]2[CH:17]=[N:18][C:19]([O:23][CH3:24])=[C:20]([F:22])[CH:21]=2)[CH:3]=1
Reactant: COc1ncc(Nc2ncc(C(C)=O)cc2-c2cc(N)nc(C)n2)cc1F
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1ncc(Nc2ncc(C(C)(C)O)cc2-c2cc(N)nc(C)n2)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.9 %

Procedure:
A suspension of 1-(5-(6-amino-2-methylpyrimidin-4-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanone (88 mg, 0.24 mmol) in 2 mL of THF at 0° C. was treated with methylmagnesium bromide (0.55 mL of 3.0 M solution in diethyl ether, 1.67 mmol). It was stirred at 0° C. for 15 min, and quenched with 5 mL of sat. NH4Cl. The mixture was extracted with 2×15 mL of EtOAc. The organic extracts were dried and concentrated. The crude material was purified on a silica gel column and eluted with 20-70% EtOAc in DCM to give 2-(5-(6-amino-2-methylpyrimidin-4-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)propan-2-ol (58 mg, 63% yield) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.23 (s, 1H), 8.35 (m, 1H), 8.32 (d, J=2.2 Hz, 1H), 8.17 (m, 2H), 7.02 (br, 2H), 6.03 (s, 1H), 5.18 (s, 1H), 3.92 (s, 3H), 2.47 (s, 3H), 1.48 (s, 6H). m/z (ESI, positive ion) 385.2 (M+H)+.
Reaction SMILES: COCC1CCCCN1C1N=CN=C(NC2C=C(CS(N)(=O)=O)C=CC=2)N=1.Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]2[CH:37]=[C:38]([CH2:42][S:43]([NH2:46])(=[O:45])=[O:44])[CH:39]=[CH:40][CH:41]=2)[N:30]=1.[N:47]1([CH2:52][C@H:53]2[CH2:57][CH2:56][CH2:55][NH:54]2)[CH2:51][CH2:50][CH2:49][CH2:48]1>>[N:47]1([CH2:52][C@H:53]2[CH2:57][CH2:56][CH2:55][N:54]2[C:29]2[N:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]3[CH:37]=[C:38]([CH2:42][S:43]([NH2:46])(=[O:45])=[O:44])[CH:39]=[CH:40][CH:41]=3)[N:30]=2)[CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: C1CN[C@@H](CN2CCCC2)C1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Agent: COCC1CCCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCC[C@@H]3CN3CCCC3)n2)c1

Procedure:
B31 was prepared following the procedure reported for B4 using A1 and (R)-2-((pyrrolidin-1-yl)methyl)pyrrolidine. It was obtained as a white crystalline solid; yield: 65 mg (17%). MS (ES) C19H27N7O2S requires: 417. found: 418 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([F:15])[CH:14]=1)[C:8](OC)=[O:9])[CH3:3].[AlH4-].[Li+].C1COCC1.[OH-].[Na+]>CCOCC.CO>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH2:8][OH:9])[CH:12]=[C:13]([F:15])[CH:14]=1)[CH3:1]
Reactant: COC(=O)c1cc(F)cc(CN(C)C)c1
Agent: [AlH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)Cc1cc(F)cc(CO)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of methyl 3-[(dimethylamino)methyl]-5-fluorobenzoate (0.14 g, 0.66 mmol, Example 33, Step 3) in Ether (4 mL) at 0° C. in an ice bath was added dropwise 1.0M lithium tetrahydroaluminate in THF (1.32 mL, 1.32 mmol). The reaction was allowed to warm to room temperature and stirred for 1.5 hours. The reaction mixture was re-cooled in an ice bath and methanol, followed by 1N NaOH, were added to quench the reaction. The product was extracted from the reaction mixture with three portions of ethyl acetate. The combined extracts were dried over sodium sulfate, decanted and concentrated, to afford product which was used without further purification (0.100 g, 82%). 1H NMR (300 MHz, CD3OD): δ 7.13-6.94 (m, 3H), 4.59 (s, 2H), 3.47 (s, 2H), 2.24 (s, 6H); 19F NMR (282 MHz, CD3OD): δ−116.41 (t, 1F); LCMS (M+H)+: 184.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>C(O)CCC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:3][CH:4]=1
Reactant: C1CCNC1
Reactant: Brc1ccc(Br)nc1
Solvent: CCCCO
Product: Brc1ccc(N2CCCC2)nc1
Temperature: 75 °C
Yield: 97.6 %

Procedure:
A solution of 2,5-dibromopyridine (1.60 g, 6.76 mmol) and pyrrolidine (5.64 mL, 67.6 mol) in 1-butanol (10.0 mL) was allowed to stir in a sealed reaction vessel while heating at 75° C. for 16 h. The reaction solvent was evaporated to produce an oily solid which was purified by column chromatography to give 5-bromo-2-(pyrrolidin-1-yl)pyridine (1.50 g, 6.60 mmol, 98%) as a white solid. LCMS (FA): m/z=229.1 (M+H).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])[N:22]=[CH:21][N:20]=2)=[O:17])[CH2:10]1)=O)(C)(C)C>ClCCl>[ClH:1].[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:23]1[N:22]=[CH:21][N:20]=[C:19]([NH:18][C:16]([NH:15][CH:11]2[CH2:12][CH2:13][CH2:14][NH:9][CH2:10]2)=[O:17])[CH:24]=1
Reactant: COc1ccccc1-c1cc(NC(=O)NC2CCCN(C(=O)OC(C)(C)C)C2)ncn1
Agent: Cl
Solvent: ClCCl
Product: COc1ccccc1-c1cc(NC(=O)NC2CCCNC2)ncn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethereal HCl (2 ml) was added to a solution of 3-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-ureido}-piperidine-1-carboxylic acid tert-butyl ester (XLII) (0.20 g, 0.47 mmol) in dry dichloromethane (2 ml) and the mixture was stirred for 2 hours at room temperature. The reaction was monitored by TLC. After completion, the solvent was removed from the reaction mixture to provide 0.20 g of 1-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-3-piperidin-3-yl-urea hydrochloride (compound #23A).
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[F:25])=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3].[C:26]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH2:1]([C:4]1[C:13]([O:14][CH3:26])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[F:25])=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CCc1c(O)c(OC)cc2ncnc(Nc3ccc(Br)cc3F)c12
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: C=CCc1c(OC)c(OC)cc2ncnc(Nc3ccc(Br)cc3F)c12
Temperature: 90 °C
Reaction time: 4.5 h

Procedure:
To a solution of 5-allyl-4-(4-bromo-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-ol (0.34 g, 0.84 mmol) (from Example 19, Step D, supra) in acetone (100 mL) was added K2CO3 (0.35 g, 2.52 mmol) and methyl iodide (1.19 g, 8.41 mmol) (Aldrich). The reaction mixture was heated with stirring at 90° C. for 4.5 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:4:0.01) as eluent to give the desired (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-(4-bromo-2-fluoro-phenyl)-amine as a yellow solid. (Yield 0.33 g, 94%).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12]1)=O)C1C=CC=CC=1>[Pd].C(O)C>[C:21]([O:20][C:18](=[O:19])[NH:17][CH:13]1[CH2:14][CH2:15][CH2:16][NH:11][CH2:12]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NC1CCCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCCNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
A mixture of 3-t-butoxycarbonylaminopiperidine-1-carboxylic acid benzyl ester (10 g), 10% palladium on carbon (500 mg), and ethanol (100 mL) was stirred under hydrogen atmosphere at room temperature overnight. The catalyst was removed by filtration, and the filtrate was concentrated to dryness to give the title compound (6.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][C:12]([SH:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+].O>CC(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:15][C:12]([CH3:14])([CH3:13])[CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CC(C)(C)S
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)Sc1ccc(Br)cc1C=O
Temperature: 25 °C
Yield: 36 %

Procedure:
To a solution of 5-bromo-2-fluorobenzaldehyde (4.06 g) in 2-propanol (20.0 mL) was added 2-methyl-2-propanethiol (2.26 mL) and K2CO3 (3.04 g) and heated overnight. The reaction mixture was cooled to room temperature, poured into 50.0 mL water and extracted with dichloromethane. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was flash chromatographed (3% EtOAc/Haptanes) to obtain 1.97 g (36%) of 5-bromo-2-(tert-butylthio)benzaldehyde as a clear oil. 1H NMR (500 MHz, CDCl3) 8 ppm 1.30 (s, 9 H) 7.51 (d, J=8.05 Hz, 1 H) 7.70 (dd, J=8.29, 2.20 Hz, 1 H) 8.12 (d, J=2.20 Hz, 1 H) 10.70 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](Cl)=[O:8].[CH3:10][O:11][C:12]1[N:17]=[CH:16][C:15]([C:18](=[N:20]O)[NH2:19])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[O:8][N:19]=[C:18]([C:15]2[CH:16]=[N:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[N:20]=1
Reactant: COc1ccc(C(N)=NO)cn1
Reactant: O=C(Cl)c1sccc1Cl
Product: COc1ccc(-c2noc(-c3sccc3Cl)n2)cn1

Procedure:
The title compound was prepared as in Example 16 from 3-chloro-thiophene-2-carbonyl chloride (0.150 g, 0.828 mmol) and 6-methoxy-pyridine-3-amidoxime (0.138 g, 0.828 mmol) as a white solid (166 mg, 63%).
Reaction SMILES: C([Li])CCC.CCCCCC.[C:12]([C:16]#[CH:17])([CH3:15])([CH3:14])[CH3:13].[CH:18]([CH:20]=[CH2:21])=[O:19].[Cl-].[NH4+].S(=O)(=O)(O)O>O1CCCC1>[CH3:13][C:12]([CH3:15])([CH3:14])[C:16]#[C:17][CH:18]([OH:19])[CH:20]=[CH2:21]
Reactant: C=CC=O
Reactant: C#CC(C)(C)C
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CC(O)C#CC(C)(C)C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 60.6 %

Procedure:
Butyllithium 1.6 M solution in hexane (106.2 ml, 0.17 mole) was added dropwise during 70 minutes to a mixture of t-butylacetylene (13.3 gr., 0.162 mole) and tetrahydrofuran (133.1 ml) at 0° C. A solution of freshly distilled acrolein (10 gr., 0.17 mole) in tetrahydrofuran (26.6 ml) was added to the reaction mixture at 0° C. during 45 minutes. The reaction mixture was stirred at 0° C. for 40 minutes. It was further stirred for 18 hours at room temperature. Saturated ammonium chloride solution (45 ml) was added. The reaction mixture was brought to pH 6 using 10% sulfuric acid (about 85 ml). Tetrahydrofuran was evaporated under reduced pressure. The residue was extracted by dichloromethane. The organic phase was washed with water and dried. The dichloromehane was removed to give the crude product (20.1 gr., 90% yield). Pure 6,6-dimethylhept-1-en-4-yn-3-ol was obtained by distillation. Boiling point was 83° C. at 24 mbar. 13.5 gr. were obtained (60.6% yield).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]([N:14]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:21]([OH:23])=O)=[O:13])([CH3:10])([CH3:9])[CH3:8].[CH3:34][O:35][C:36](=[O:46])[CH2:37][CH2:38][NH:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.CCN(C(C)C)C(C)C>ClCCl.CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:34][O:35][C:36](=[O:46])[CH2:37][CH2:38][N:39]([C:21](=[O:23])[C:20]1[CH:24]=[C:25]([Cl:27])[CH:26]=[C:18]([O:17][CH2:16][CH2:15][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:13])[C:28]2[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=2)[CH:19]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: COC(=O)CCNc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)CCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
2M Oxalyl chloride solution in dichloromethane (1.8 ml), and DMF (0.05 ml) were added to a suspension of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (1.18 g) in anhydrous dichloromethane (30 ml). The reaction was stirred at room temperature for 1 h then 3-phenylamino-propionic acid methyl ester (0.644 g), DMAP (0.036 g) and DIPEA (1.04 ml) were added. The reaction mixture was stirred at room temperature for 20 h and partitioned between ethyl acetate and 1M aqueous hydrochloric acid. The aqueous layer was removed and the organic phase washed with saturated aqueous sodium bicarbonate, water and dried with brine and over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with ethyl acetate:petroleum ether (4:1 v/v) and neat ethyl acetate, to give the title compound as a colourless gum (1.22 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:25])[CH:23]=[CH2:24]>ClCCl>[O:25]=[C:22]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1)[CH:23]=[CH2:24]
Reactant: CCOC(=O)Cc1ccc(CN)cc1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)NCc1ccc(CC(=O)OCC)cc1
Reaction time: 0.75 h

Procedure:
A solution of Ethyl 4-[aminomethyl]benzeneacetate (4.12 g) in anhydrous dichloromethane (60 ml) containing triethylamine (3.0 ml), was added over 20 min to a cold (-15°) stirred solution of acryloyl chloride (1.73 ml) in dry dichloromethane (50 ml) and stirring was continued for 0.75 h. After washing the dichloromethane solution with 8% aqueous sodium bicarbonate soln (2×50 ml) and drying (MgSO4), the organic solvent was removed by rotary evaporation to yield a a solid (approximately 6 g) which was triturated with cyclohexane to give the title compound as a solid (4.1 g) m.p. 93°-95°.
Reaction SMILES: O[CH:2]([C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][C:6]([OH:14])([CH2:7]3)[CH2:5]1)[CH2:11]2)[CH3:3].S(=O)(=O)(O)O>C1(C=CC(O)=CC=1)O.C1(C)C=CC=CC=1>[CH:2]([C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][C:6]([OH:14])([CH2:7]3)[CH2:5]1)[CH2:11]2)=[CH2:3]
Reactant: CC(O)C12CC3CC(CC(O)(C3)C1)C2
Agent: O=S(=O)(O)O
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: C=CC12CC3CC(CC(O)(C3)C1)C2
Yield: 55.1 %

Procedure:
To 3 g of 3-(1-hydroxyethyl)-1-adamantanol were added 60 ml of toluene, 0.4 g of 98% sulfuric acid, and 0.01 g of hydroquinone, and the resultant mixture was stirred for 5 hours with azeotropic distillation and dehydration. The reaction mixture was cooled, was washed with a saturated aqueous sodium bicarbonate and saturated sodium chloride aqueous solution, and was then concentrated. The residue was purified by column chromatography on a silica gel (SiO2 80 g, developing solution: hexane/ethyl acetate=10/1) to give 1.5 g of 3-vinyl-1-adamantanol.
Reaction SMILES: C(OC1C=CC(C=CC(OCC=C)=O)=CC=1[N+]([O-])=O)C=C.[CH2:22]([O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34])=[CH:28][C:27]=1[N+:39]([O-])=O)[CH:23]=[CH2:24]>>[CH2:22]([O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34])=[CH:28][C:27]=1[NH2:39])[CH:23]=[CH2:24]
Reactant: C=CCOC(=O)Cc1ccc(OCC=C)c([N+](=O)[O-])c1
Agent: C=CCOC(=O)C=Cc1ccc(OCC=C)c([N+](=O)[O-])c1
Product: C=CCOC(=O)Cc1ccc(OCC=C)c(N)c1

Procedure:
Allyl 4-allyloxy-3-nitrocinnamate was reduced by the method described in example 1 using allyl 4-allyloxy-3-nitrophenylacetate in place of allyl 3-nitrocinnamate, to give allyl 4-allyloxy-3-aminophenylacetate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][O:13][C:14]2[N:19]=[N:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=2)=[CH:10][O:9][N:8]=1.[NH2:23][CH2:24][CH:25]1[CH2:27][CH2:26]1>>[CH:25]1([CH2:24][NH:23][C:20]([C:17]2[N:18]=[N:19][C:14]([O:13][CH2:12][C:11]3[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:8][O:9][CH:10]=3)=[CH:15][CH:16]=2)=[O:22])[CH2:27][CH2:26]1
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccccn2)nn1
Reactant: NCC1CC1
Product: O=C(NCC1CC1)c1ccc(OCc2conc2-c2ccccn2)nn1
Yield: 61 %

Procedure:
As described for example 123 g, 6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (70 mg, 0.24 mmol) was converted, using aminomethylcyclopropane instead of isopropylamine, to the title compound (50 mg, 61%) which was obtained as an off white solid. MS: m/e=352.3 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([NH2:31])[CH:28]=[CH:29][CH:30]=4)[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:32]([N:39]=[C:40]=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl.CCOC(C)=O>[CH2:32]([NH:39][C:40]([NH:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][CH:19]2[CH2:20][CH2:21][CH2:22][CH:23]=[C:18]2[C:9]2[O:10][C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH:26]=1)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C=NCc1ccccc1
Reactant: Nc1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NCc1ccccc1)Nc1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
To a solution of (±)-3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}phenylamine (110 mg, 0.27 mmol) in methylene chloride (3 ml) was added benzylisocyanate (0.17 ml, 1.36 mmol) at 5° C., and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with EtOAc, washed with 1N hydrochloric acid, water, saturated sodium hydrogencarbonate solution, water and brine, dried over magnesium sulfate, and evaporated in vacuo. The resulting solid was collected and washed with EtOAc-hexane to give (±)-1-benzyl-3-{3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}phenyl}urea (100.7 mg, 69%).
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27](O)=[O:28])[CH:22]=3)[CH:17]=1)[CH2:12]2.[CH3:30][CH:31]1[CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:30][CH:31]1[CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]1[C:27]([C:23]1[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[CH2:12][C:4]2([C:5]4[C:6](=[N:7][CH:8]=[CH:9][CH:10]=4)[NH:11][C:3]2=[O:2])[CH2:19]3)[CH:22]=1)=[O:28]
Reactant: CC1Cc2ccccc2N1
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC1Cc2ccccc2N1C(=O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1

Procedure:
50 mg (0.12 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 16 μL (0.12 mmol) 2-methylindoline, 0.10 mL (0.72 mmol) TEA and 45 mg (0.14 mmol) TBTU in 1.8 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[C:10]([P:14](Cl)[C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])([CH3:12])[CH3:11].S(=O)(=O)(O)O>O1CCCC1.[Cu](Br)Br.C1(C)C=CC=CC=1>[C:10]([P:14]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: ClCc1ccccc1
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Agent: Br[Cu]Br
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)P(Cc1ccccc1)C(C)(C)C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
In a 200 ml four-necked flask thoroughly purged with nitrogen, a Grignard reagent solution previously prepared from 8.2 g (0.065 mol) of benzyl chloride and 2.1 g (0.085 mol) of metallic magnesium in 50 ml of tetrahydrofuran, and 0.055 g (0.0003 mol (corresponding to 0.6% by mol)) of copper(II) bromide were placed. To the contents of the flask, 9.0 g (0.05 mol) of di-tert-butylphosphinous chloride was dropwise added as it is without being dissolved in a solvent, over a period of 1 hour at a temperature in the vicinity of 40° C. After the dropwise addition was completed, stirring was conducted at a temperature of 40° C. to 45° C. for 3 hours. After the temperature of the reaction solution was returned to room temperature, 20 ml of toluene and 20 ml of a 5% sulfuric acid aqueous solution were added to the reaction solution to perform liquid separation. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, followed by further distillation. Then, fractions given by distillation at 145° C. to 150° C. under reduced pressure of 0.5 Torr were collected. As a result, 10.6 g (purity: 98.5%) of the aimed di-tert-butylbenzylphosphine was obtained as an oily substance. The yield was 88.3%.
Reaction SMILES: NC(N)=O.[CH3:5][O:6][CH2:7][CH2:8][N:9]([CH2:22][CH2:23][O:24][CH3:25])[S:10]([C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([NH2:20])[C:14]=1[OH:21])(=[O:12])=[O:11].[Cl:26][C:27]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=1[N:34]=[C:35]=[O:36]>>[Cl:19][C:18]1[CH:17]=[CH:16][C:15]([NH:20][C:35]([NH:34][C:28]2[CH:29]=[CH:30][CH:31]=[C:32]([Cl:33])[C:27]=2[Cl:26])=[O:36])=[C:14]([OH:21])[C:13]=1[S:10]([N:9]([CH2:8][CH2:7][O:6][CH3:5])[CH2:22][CH2:23][O:24][CH3:25])(=[O:11])=[O:12]
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: COCCN(CCOC)S(=O)(=O)c1c(Cl)ccc(N)c1O
Agent: NC(N)=O
Product: COCCN(CCOC)S(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cccc(Cl)c2Cl)c1O
Yield: 87 %

Procedure:
Following the general procedure for urea formation outlined in example 15, N,N-di-(2-methoxyethyl)-3-amino-6-chloro-2-hydroxybenzenesulfonamide (40 mg, 0.12 mmol) and 2,3-dichlorophenylisocyanate (22mg, 0.12 mmol) were coupled to form the desired urea (55 mg, 87%). 1H NMR (MeOD-d4): 8δ 8.27 (m, 1H), 8.03 (m, 1H), 7.23 (m, 2H), 7.03 (m, 1H), 3.61 (m, 4H), 3.45 (m, 4H), 3.23 (s, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH:6]1[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][CH2:7]1.C(N(C(C)C)CC)(C)C.[CH3:25][C:26]1([CH3:39])[C:30]2([CH2:34][S:35](Cl)(=[O:37])=[O:36])[C:31]([CH2:33][CH:27]1[CH2:28][CH2:29]2)=[O:32]>ClCCl>[O:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][CH2:7][CH:6]1[CH2:5][NH:4][CH2:3][CH2:2][NH:1][S:35]([CH2:34][C@:30]12[C:26]([CH3:25])([CH3:39])[CH:27]([CH2:28][CH2:29]1)[CH2:33][C:31]2=[O:32])(=[O:37])=[O:36]
Reactant: NCCNCC1COc2ccccc2O1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)Cl)C(=O)C2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C2CC[C@@]1(CS(=O)(=O)NCCNCC1COc3ccccc3O1)C(=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
To a solution of 2.1 g (10 mmole) of 2-{N-(2-aminoethyl)]aminomethyl-2,3-dihydrobenzodioxin and 1.3 g (10 mmole) of diisopropylethylamine in 100 ml of dichloromethane stored in an ice bath was added 2.5 g (10 mmole) (+)-10-camphorsulfonyl chloride. The mixture was allowed to stir overnight at room temperature. The reaction was next washed with saturated aqueous sodium bicarbonate, with saturated sodium chloride, dried over sodium sulfate, filtered and evaporated in vacuum. Column chromatography on 75 g of silica gel with chloroform as eluant, followed by crystallization from 100 ml of isopropanol with the addition of 5 ml of 4 N HCl/isopropyl alcohol and 300 ml of diethyl ether gave 1.2 g of the title compound as a monohydrochloride, m.p. 143°-146° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[F:24][C:25]([F:29])([F:28])[CH2:26][NH2:27]>>[F:24][C:25]([F:29])([F:28])[CH2:26][NH:27][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:20][N:19]=1)=[O:23]
Reactant: NCC(F)(F)F
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)NCC(F)(F)F)nc1
Yield: 88 %

Procedure:
As described for example 7, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (100 mg, 0.32 mmol) was converted, using 2,2,2-trifluoroethylamine instead of isopropylamine, to the title compound (111 mg, 88%), which was obtained as a white solid. MS: m/e=393.2 [M+H]+.