Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C@H:4]([CH:6]=[CH:7][C@H:8]([C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:17](=[CH:18][C:19](=O)[CH2:20][CH2:21]2)[CH:16]=[CH:15]3)[CH2:12][CH2:11]1)[CH3:9])[CH3:5])[CH3:3].Cl.[NH2:31][OH:32]>N1C=CC=CC=1>[CH3:1][CH:2]([C@H:4]([CH:6]=[CH:7][C@H:8]([C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:17](=[CH:18][C:19](=[N:31][OH:32])[CH2:20][CH2:21]2)[CH:16]=[CH:15]3)[CH2:12][CH2:11]1)[CH3:9])[CH3:5])[CH3:3]
Reactant: CC(C)[C@@H](C)C=C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)[C@@H](C)C=C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=NO)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 50 %

Procedure:
100 mg of 4,6,22-ergosta-trien-3-one (0.25 mmol) is solubilized in 10 ml of pyridine in a 50 ml flask, then 100 mg of hydroxylamine hydrochloride is added. Stirring is maintained for 24 hours at ambient temperature, and the solvent is evaporated off under reduced pressure. Water then ethyl acetate are added in order to carry out an extraction. Then the organic phase is washed with an acidified aqueous solution (HCl 1%). The ethyl acetate is evaporated off under reduced pressure. A white powder is obtained with a yield greater than 50%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH3:54][O:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[S:62](Cl)(=[O:64])=[O:63]>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:62]([C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=1[O:55][CH3:54])(=[O:64])=[O:63])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: COc1ccccc1S(=O)(=O)Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1ccccc1OC)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (40 mg) was treated with 2-methoxy-benzenesulfonyl chloride according to General Procedure E to give (S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(2-methoxy-benzenesulfonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-propionic acid methyl ester. This (26 mg) was hydrolyzed according to General Procedure B to give the title compound (23 mg). LCMS (m/z): 906.
Reaction SMILES: [CH2:1]([O:10][C:11](=[O:24])[C@H:12]([C@@H:21]([CH3:23])[OH:22])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[CH2:25]([O:32][C:33]([N:35]([CH3:49])[C@H:36]([C:46](O)=[O:47])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:10][C:11](=[O:24])[C@H:12]([C@@H:21]([CH3:23])[O:22][C:46](=[O:47])[C@H:36]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[N:35]([C:33]([O:32][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:34])[CH3:49])[NH:13][C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(=O)c1ccccc1
Reactant: COc1ccc(C[C@@H](C(=O)O)N(C)C(=O)OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C[C@@H](C(=O)O[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(=O)c2ccccc2)N(C)C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 98.8 %

Procedure:
To a solution of D3 (33.72 g, 100 mmol) in DCM at 0° C., DMAP (3.66 g, 30 mmol), and E1 (34.33 g, 100 mmol) were added. After stirring 10 min at 0° C., DCC (22.7 g, 110 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. Then the mixture was filtered and the filtrate concentrated to dryness. The residue was chased with ACN (100 ml), filtered again and the filtrate was concentrated. The residue was dissolved in EtOAc (200 ml) and partitioned successively between aq KHSO4 (100 ml, 10%), aq NaHCO3 (100 ml, sat.) and brine (100 ml), The organic phase was dried (Na2SO4), filtered and concentrated. The residue was purified by flash LC (silica gel, grad EtOAc-Hex 1:4 to 1:2) to yield D2 (65.5 g, 98%). [α]D22 −39.56 (c 1.06 CHCl3); Rf=0.55 (EtOAc:Hex 1:1).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:11]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(Cl)([Cl:25])=O>>[CH2:1]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:11][Cl:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCOc1ccc(CO)cc1OCCCCCC
Product: CCCCCCOc1ccc(CCl)cc1OCCCCCC
Temperature: 25 °C

Procedure:
Thionyl chloride (140 ml.) and 3,4-dihexoxybenzyl alcohol (14.0 g.) are combined and stirred at room temperature for one-half hour, at which time gas evolution ceases. The mixture is refluxed for one-half hour and then distilled to remove thionyl chloride (about 100 ml.). The residue is poured into ice-water (250 g. of each) and the aqueous solution extracted with chloroform (3× 100 ml.). The chloroform extracts are combined, washed successively with saturated sodium bicarbonate solution (2× 100 ml.) and water (3× 100 ml.). It is then dried (Na2SO4) and concentrated to give 3,4-dihexoxybenzyl chloride as a brown oil (11.7 g.).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][OH:25].CN([CH:29]=[O:30])C>C1COCC1>[F:16][C:17]1[C:18]([CH2:23][CH2:24][OH:25])=[CH:19][CH:20]=[CH:21][C:22]=1[CH:29]=[O:30]
Reactant: OCCc1ccccc1F
Reactant: CN(C)C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cccc(CCO)c1F
Temperature: -70 °C
Reaction time: 6 h

Procedure:
2,2,6,6-Tetramethylpiperidine (10.8 mL) was added to a solution of butyllithium (1.6M in hexanes, 40.1 mL) in THF (40 mL) at −70° C. A solution of 2-(2-fluorophenyl)ethanol (3 g) in THF (40 mL) was added dropwise and the resulting mixture stirred for 6 h at −70° C. DMF (8.29 mL) was then added and the mixture stirred for 1 h at −70° C. The mixture was then allowed to warm to RT and stirred for 70 h. The reaction was quenched with HCl solution (2M, 50 mL), diluted with ethyl acetate (100 mL) and the layers separated. The aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic solutions were washed with HCl solution (2M, 50 mL), brine (20 mL), dried over magnesium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with 4:1 to 2:1 isohexane:ethyl acetate gradient. The fractions containing product were combined and evaporated to give the subtitled compound as a yellow oil. Yield 1.2 g.
Reaction SMILES: Br[CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)=[O:4].[NH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16]>CO>[Cl:11][C:7]1[CH:6]=[C:5]([C@@:3]2([OH:4])[O:16][CH2:15][C:14]([CH3:18])([CH3:17])[NH:13][C@@H:2]2[CH3:12])[CH:10]=[CH:9][CH:8]=1
Reactant: CC(Br)C(=O)c1cccc(Cl)c1
Reactant: CC(C)(N)CO
Solvent: CO
Product: C[C@H]1NC(C)(C)CO[C@]1(O)c1cccc(Cl)c1
Reaction time: 18 h
Yield: 73.3 %

Procedure:
To a solution of 2-bromo-3′-chloropropiophenone (19.3g, 0.08 mol) in MeOH (100 mL) was added dropwise a solution of 2-amino-2-methyl-1-propanol (27.8 g, 0.31 mol) in methanol (200 mL) at ambient temperature. The mixture was stirred for 18 h and concentrated in vacuo. The residue was partitioned between water and diethyl ether. The combined organic phase was extracted with 10% aqueous hydrogen chloride. The combined aqueous acid extracts were chilled in an ice bath and made basic with 40% aqueous sodium hydroxide. The mixture was extracted with diethyl ether, the combined diethyl ether extracts were washed with water and saturated sodium chloride solution, dried (K2CO3) and concentrated in vacuo to give 15.0 g (75%) of (+/−)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol as an off-white solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[N:12][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=3)=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[N-:26]=[N+:27]=[N-:28].[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>CN(C)C=O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[N:12][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:26]=[N+:27]=[N-:28])=[CH:20][CH:19]=3)=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)N1CCN(c2ccc(CCc3ccc(CCl)cc3)nc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(CCc3ccc(CN=[N+]=[N-])cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
To a solution of 1-acetyl-4-(6-{2-[4-(chloromethyl)phenyl]ethyl}pyridin-3-yl)piperazine (234.8 mg, 0.656 mmol) in anhydrous N,N-dimethylformamide (5 ml) was added sodium azide (426.5 mg, 6.561 mmol), and the mixture was stirred at room temperature for 16 hrs. Aqueous sodium carbonate solution and ethyl acetate were added to the reaction mixture. The mixture was stirred, stood still and partitioned. The organic layer was dried over anhydrous magnesium sulfate, and concentrated to dryness to give 1-acetyl-4-(6-{2-[4-(azidomethyl)phenyl]ethyl}pyridin-3-yl)piperazine (226.8 mg, yield 94.9%) as a slightly yellow solid.
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](OC(C)(C)C)(=[O:25])[C:18](OC(C)(C)C)=[O:19].CC(C)([O-])C.[K+]>C1COCC1>[OH:25][C:17]1[C:18](=[O:19])[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][C:9]=1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CCNc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1=C(O)C(=O)N(c2ccccc2)C1
Yield: 52.1 %

Procedure:
To a solution of the title compound of Example B (29.37 g, 0.133 mol) and di-tert-butyl oxalate (26.90 g, 0.133 mol) in dry THF (350 ml) was added potassium tert-butoxide (29.84 g, 0.266 mol) and the resulting solution was heated under reflux for 24 h. The mixture was then cooled and the solvent removed in vacuo. The resulting solid was suspended in CH2Cl2 and 1N aqueous HCl was added. The resulting suspension was filtered and the organic filtrate was dried over MgSO4 and concentrated in vacuo. The residue was then chromatographed on silica gel eluting with 1/1/98 HOAc/EtOH/CH2Cl2 to give the title compound (19.06 g, 52%) as a solid. Anal calcd for C15H17NO4 : C, 65.44; H, 6.22; N, 5.09. Found: C, 65.05; H, 6.33; N, 4.86. MS M+1 calcd for C15H17NO4 276, found 276.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([N:20]3[CH2:29][C:28]4[C:23](=[N:24][C:25](SC)=[N:26][CH:27]=4)[N:22]([CH3:32])[C:21]3=[O:33])[C:17]([Cl:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:47][NH2:48]>>[C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([N:20]3[CH2:29][C:28]4[C:23](=[N:24][C:25]([NH:48][CH3:47])=[N:26][CH:27]=4)[N:22]([CH3:32])[C:21]3=[O:33])[C:17]([Cl:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc2c(n1)N(C)C(=O)N(c1cc(NC(=O)Nc3cnn(C(C)(C)C)c3)c(F)cc1Cl)C2
Reactant: CN
Agent: O=C(OO)c1cccc(Cl)c1
Product: CNc1ncc2c(n1)N(C)C(=O)N(c1cc(NC(=O)Nc3cnn(C(C)(C)C)c3)c(F)cc1Cl)C2
Yield: 73 %

Procedure:
Using a procedure analogous to Example A2, the sulfide was oxidized with mCPBA to the sulfone and then treated with methylamine to provide 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea (0.448 mmol, 73% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.76 (s, 1H), 8.72 (brs, 1H), 8.32 (d, J=8.5 Hz, 1H), 7.96 (brs, 1H), 7.82 (s, 1H), 7.60 (d, J=11 Hz, 1H), 7.41 (s, 1H), 7.04 m, 1H), 6.34 s, 1H), 4.56 (d, J=14 Hz, 1H), 4.41 (d, J=14 Hz, 1H), 3.25 (brs, 3H), 2.78 (d, J=5 Hz, 3H), 1.47 (m, 9H); MS (ESI) m/z: 502.2 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].O.[OH-].[Li+]>C1COCC1.O>[C:15]([O:14][C:5]1[CH:6]=[CH:7][C:8]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:9][C:4]=1[C:3]([OH:19])=[O:2])([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.6 %

Procedure:
To 2-tert-Butoxy-5-methanesulfonyl-benzoic acid methyl ester (1.58 g) in THF (25 mL) was added a solution lithium hydroxide monohydrate (0.35 g) in water (25 mL), and the reaction mixture was stirred at room temperature for 4 hours. After such time, the THF was removed in vacuo and to the remaining aqueous solution was added 8 mL of 1N HCl solution, leading to precipitation of the compound. The precipitate was filtered off and washed several times with water to yield the title compound (1.00 g) as a white solid. MS (m/e): 289.9 (M+NH4+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[C:10]=2[OH:17])[CH:5]=[CH:6][C:7]=1[Cl:8].C([O-])(=O)C.[Na+].[Br:23]Br>C(O)(=O)C>[Br:23][C:13]1[CH:12]=[C:11]([CH:15]=[O:16])[C:10]([OH:17])=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:14]=1
Reactant: BrBr
Reactant: O=Cc1cccc(-c2ccc(Cl)c(Cl)c2)c1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=Cc1cc(Br)cc(-c2ccc(Cl)c(Cl)c2)c1O
Reaction time: 8 h

Procedure:
To a solution of 3′,4′-dichloro-2-hydroxy-[1,1′-biphenyl]-3-carbaldehyde (400 mg, 1.5 mmol) and sodium acetate (185 mg, 1.5 mmol) in acetic acid (20 mL), bromine (100 uL, 1.5 mmol) was added slowly. The resulted solution was stirred overnight. The reaction mixture was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (20 mL), washed with 5% aqueous sodium thiosulfate, the organic layer dried (MgSO4), filtered and concentrated under reduced pressure to give 5-bromo-3′,4′-dichloro-2-hydroxy-[1,1′-biphenyl]-3-carbaldehyde.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:35]1([CH2:41][C:42]2[CH:43]=[C:44]([CH:58]=[CH:59][CH:60]=2)[O:45][CH2:46]/[CH:47]=[CH:48]\[CH2:49][NH:50][C:51](=[O:57])[CH2:52][S:53][CH2:54][CH2:55][NH2:56])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>ClCCl>[N:35]1([CH2:41][C:42]2[CH:43]=[C:44]([CH:58]=[CH:59][CH:60]=2)[O:45][CH2:46]/[CH:47]=[CH:48]\[CH2:49][NH:50][C:51](=[O:57])[CH2:52][S:53][CH2:54][CH2:55][NH:56][C:1](=[O:9])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: NCCSCC(=O)NC/C=C\COc1cccc(CN2CCCCC2)c1
Reactant: O=C(O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(CSCCNC(=O)c1ccccc1)NC/C=C\COc1cccc(CN2CCCCC2)c1
Reaction time: 0.5 h
Yield: 23.4 %

Procedure:
There was dissolved 0.97 g (0.008 mol) of benzoic acid in 60 ml of dichloromethane and added 1.22 g (0.008 mol) of HOBt and 1.65 g (0.0095 mol) of DCC under cooling with ice, and the mixture was stirred for 30 minutes under cooling with ice. Thereto was added 3.0 g (0.008 mol) of N-[4-[3-(piperidinomethyl) phenoxy]-cis-2-butenyl]-2-(2-aminoethylthio)acetamide and the mixture was stirred for 18 hours at room temperature. The precipitate was filtrated off, and the filtrate was washed with 5% aqueous solution of sodium hydroxide and with water and dried over Glauber's salt. Then the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=5:1) to give 0.9 g of the titled compound as oily matter.
Reaction SMILES: [N+](C1C=CC(O[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH:21]=2)[C:17]([O:19][CH3:20])=[O:18])=[O:10])=CC=1)([O-])=O.C(#N)C.Cl.[NH:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH2:35][C:36]2[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=2)[C:39]#[N:40])[CH2:30][CH2:29]1>CCOC(C)=O>[C:39]([C:38]1[CH:37]=[C:36]([CH2:35][CH2:34][CH:31]2[CH2:32][CH2:33][N:28]([C:9]([O:11][C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:21]=3)[C:17]([O:19][CH3:20])=[O:18])=[O:10])[CH2:29][CH2:30]2)[CH:43]=[CH:42][CH:41]=1)#[N:40]
Reactant: COC(=O)c1cncc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: N#Cc1cccc(CCC2CCNCC2)c1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cncc(OC(=O)N2CCC(CCc3cccc(C#N)c3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
Methyl 5-{[(4-nitrophenoxy)carbonyl]oxy}nicotinate (723 mg) was added to an acetonitrile (10 ml) solution of 3-[2-(4-piperidyl)ethyl]benzonitrile hydrochloride (475 mg) and TEA (0.58 ml), followed by stirring overnight at room temperature. The reaction liquid was diluted with EtOAc, followed by washing with an aqueous saturated sodium hydrogencarbonate solution and drying over anhydrous magnesium sulfate. The solvent was evaporated, the resulting residue was subjected to basic silica gel column chromatography (eluent: hexane:EtOAc=1:1 (v/v)) and the side-product, nitrophenol was removed. Then, this was purified by silica gel column chromatography (eluent: hexane:EtOAc=3:2 (v/v)) to obtain methyl 5-[({4-[2-(3-cyanophenyl)ethyl]-1-piperidyl}carbonyl)oxy]nicotinate (284 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.O.[NH2:27][NH2:28]>CCO>[NH2:13][C:12]1[C:11]2[C:10](=[CH:9][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:17][CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:5]=3)=[CH:15][CH:14]=2)[NH:28][N:27]=1
Reactant: N#Cc1ccc(-c2cc(NCCc3ccccc3)nc(N)n2)cc1F
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nc1nc(NCCc2ccccc2)cc(-c2ccc3c(N)n[nH]c3c2)n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution of 4-{2-amino-6-[(2-phenylethyl)amino]-4-pyrimidinyl}-2-fluorobenzonitrile (800 mg, 2.4 mmol) in EtOH (20 mL) was added hydrazine monohydrate (7 mL), and the resulting suspension was stirred overnight at 95° C. The clear reaction mixture was concentrated, and the resulting residue was purified by RPHPLC (CH3CN/H2O w/0.1% THF) to afford the title compound (500 mg, 42%) as a light yellow powder. LC-MS (ES) m/z=346 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 2.85 (t, J=7.2 Hz, 2H), 3.53 (m, 2H), 5.37 (s, 2H), 6.02 (s, 2H), 6.28 (s, 1H), 6.94 (s, 1H), 7.18-7.23 (m, 1H), 7.28-7.33 (m, 4H), 7.42 (d, J=8.4 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.85 (s, 1H), 11.5 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7]/[C:8](/[NH:17]C(=O)OC(C)(C)C)=[N:9]\C(=O)OC(C)(C)C)[CH:4]=[N:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([NH2:17])=[NH:9])[CH:4]=[N:3]1
Reactant: Cn1cc(N/C(=N\C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(NC(=N)N)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 251.5 %

Procedure:
To a solution of di-tert-butyl {(E)-[(1-methyl-1H-pyrazol-4-yl)amino]methylylidene}biscarbamate (17.5 g, 50 mmol) in DCM (50 mL) was added TFA (50 mL) at 0° C. The reaction was allowed to warm to rt and stirred for 20 hrs. The reaction mixture was concentrated to dryness to afford the crude title compound (17.5 g, quant) as a yellow oil. 1H NMR (400 MHz, Methanol-d4) δ ppm 7.81-7.82 (d, 1H), 7.74 (s, 1H), 7.47 (s, 1H), 3.89 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH:34]5[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[CH2:46][C:47]([F:50])([F:49])[F:48])(=O)=O.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH:34]5[CH2:39][CH2:38][N:37]([CH2:46][C:47]([F:50])([F:49])[F:48])[CH2:36][CH2:35]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OC1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OC1CCN(CC(F)(F)F)CC1
Yield: 11 %

Procedure:
The title compound was prepared as described in Example 103C, using 1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-yloxy]phenyl}urea (0.213 g, 0.4 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.139 g, 0.6 mmol), and N,N-diisopropylethylamine (0.5 mL) in CH2Cl2 (10 mL) at room temperature for 4 hours, which was purified by silica gel chromatography with EtOAc/hexane as eluants and preparative HPLC (C18 column and 60-90% MeCN/H2O with 0.05% AcOH) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-{6-methoxy-7-[1-(2,2,2-trifluoroethyl)piperidin-4-yloxy]quinazolin-4-yloxy}phenyl)urea as a solid (0.027 g, 11%). 1H NMR (300 MHz, CDCl3) δ 9.42 (s, 1H), 8.61 (s, 1H), 7.66 (t, 1H), 7.59 (m, 1H), 7.55 (s, 1H), 7.40 (t, 1H), 7.31 (m, 2H), 7.02 (d, 1H), 5.83 (s, 1H), 4.60 (m, 1H), 4.04 (s, 3H), 3.04 (q, 2H), 3.00 (m, 2H), 2.67 (m, 2H), 2.15 (m, 2H), 2.02 (m, 2H), 1.33 (s, 9H); LC-MS (ESI) m/z 615 (M+H)+.