Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([CH:12]1CC2O[CH:13]1C=C2)(OC)=[O:9].Cl>O>[C:2]1([NH:1][C:8](=[O:9])[CH:12]=[CH2:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)C1CC2C=CC1O2
Agent: Cl
Solvent: O
Product: C=CC(=O)Nc1ccccc1
Temperature: 140 °C
Reaction time: 15 h

Procedure:
7.2 parts 30% methanolic Na-methylate solution are added to 46.5 parts aniline. 77 parts 2-carbomethoxy-7-oxabicyclo(2,2,1)hept-5-ene are added drop-wise at 40° C. The reaction medium is then stirred for 15 hours at this temperature and neutralised with 4 parts concentrated hydrochloric acid. 50 parts water are added, and the organic phase separated off. The organic phase is reduced in a rotary evaporator at a bath temperature of 90° C. and under a vacuum of 20 Torr. The residue is heated in a vacuum of 20 Torr to 110° to 120° C. (bath temperature 140° C.). On conclusion of the furane separation, the sedimentation temperature increases and the product distills over. 27.5 parts N-phenylacrylamide with a boiling point of 135° C. at 0.4 Torr are obtained. The product recrystallised from the acetonitrile at -20° C. has a melting point of 114° to 115° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([SH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.[C:12]([C:14]1[CH:19]=[C:18]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:17]=[CH:16][N:15]=1)#[N:13]>N1C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:5]2[C:6](=[O:8])[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:17]=[CH:16][N:15]=3)[S:11][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)CCc1ccnc(C#N)c1
Reactant: O=C(O)c1ccc(F)cc1S
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CCc1ccnc(-c2nc(=O)c3ccc(F)cc3s2)c1
Yield: 55.5 %

Procedure:
4-Fluorothiosalicylic acid (1.9 g, 11.3 mmol) and tert-butyl 3-(2-cyano-4-pyridyl)propanoate (1.3 g, 5.6 mmol) were dissolved in pyridine (20 ml), and the mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (2:1, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (1.2 g, 54%) as white crystals.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[CH3:13][O:14][C:15]([CH:17]1[CH2:22][CH2:21][CH:20]([C:23](=[NH:26])[NH:24][OH:25])[CH2:19][CH2:18]1)=[O:16]>O1CCOCC1>[CH3:13][O:14][C:15]([CH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[NH:26][C:6](=[O:7])[O:25][N:24]=2)[CH2:19][CH2:18]1)=[O:16]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)C1CCC(C(=N)NO)CC1
Solvent: C1COCCO1
Product: COC(=O)C1CCC(c2noc(=O)[nH]2)CC1
Temperature: 100 °C
Yield: 66.6 %

Procedure:
A mixture of carbodiimidazole (624 mg, 3.85 mmol) and 4-(N-hydroxycarbamimidoyl)-cyclohexanecarboxylic acid methyl ester (770 mg, 3.85 mmol) in anhydrous 1,4 dioxane (15 mL) was heated in a sealed vial in an oil bath at 100° C. for 30 min. The reaction was concentrated, diluted with ethyl acetate (200 mL) washed with aqueous ammonium chloride (sat'd, 200 mL) and brine (200 mL), dried over sodium sulfate, and concentrated to give 4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-cyclohexanecarboxylic acid methyl ester (580 mg 67%) as a clear light yellow oil. LCMS calcd for C10H14N2O4 (m/e) 226, obsd 225 (M−H).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[Si:13]([O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([C:31]1[N:35]3[CH:36]=[CH:37][C:38]([CH2:40]O)=[CH:39][C:34]3=[N:33][N:32]=1)[CH:27]=[CH:26]2)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[C:42]1(=[O:52])[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44](=[O:51])[NH:43]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Si:13]([O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([C:31]1[N:35]3[CH:36]=[CH:37][C:38]([CH2:40][N:43]4[C:44](=[O:51])[C:45]5[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=5)[C:42]4=[O:52])=[CH:39][C:34]3=[N:33][N:32]=1)[CH:27]=[CH:26]2)([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(-c3nnc4cc(CO)ccn34)nc12
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(-c3nnc4cc(CN5C(=O)c6ccccc6C5=O)ccn34)nc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
DEAD (0.6524 mL, 4.143 mmol) was added to a solution of (3-(8-(tert-butyldimethylsilyloxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol (1.123 g, 2.762 mmol), isoindoline-1,3-dione (0.6096 g, 4.143 mmol) and triphenylphosphine (1.087 g, 4.143 mmol) in THF (20 mL) at 0° C. Following addition, the cold bath was removed and the reaction stirred at ambient temperature for 3 hours. The crude reaction was concentrated and the residue was purified by flash column chromatography (eluting with at 1:4 mixture of ethyl acetate/Hexanes) to afford the desired product mixed with triphenylphosphine oxide.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:27]=[CH:26][C:8]([CH2:9][C@@H:10]2[CH2:15][C@H:14]([C:16]3[O:20][NH:19][C:18](=[O:21])[CH:17]=3)[CH2:13][CH2:12][N:11]2C(OC)=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br>>[CH3:1][S:2]([C:5]1[CH:27]=[CH:26][C:8]([CH2:9][C@@H:10]2[CH2:15][C@H:14]([C:16]3[O:20][NH:19][C:18](=[O:21])[CH:17]=3)[CH2:13][CH2:12][NH:11]2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@H]1Cc1ccc(S(C)(=O)=O)cc1
Agent: Br
Product: CS(=O)(=O)c1ccc(C[C@@H]2C[C@H](c3cc(=O)[nH]o3)CCN2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
(2S,4R)-Methyl 2-(4-(methylsulfonyl)benzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (225 mg, 0.57 mmol) was dissolved in HBr (33% in acetic acid, 5 mL, 28.55 mmol) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2S,4R)-2-(4-(methylsulfonyl)benzyl)piperidin-4-yl)isoxazol-3(2H)-one (91 mg, 47.4%). 1H NMR (600 MHz, dmso) δ 1.05-1.14 (m, 1H), 1.30-1.38 (m, 1H), 1.72-1.79 (m, 2H), 2.39-2.56 (omitted signals), 2.62-2.80 (m, 4H), 2.94-3.00 (m, 1H), 3.16 (s, 3H), 5.68 (s, 1H), 7.46 (d, 2H), 7.80 (d, 2H). HRMS Calcd for [C16H20N2O4S+H]+: 337.1222. Found: 337.1198
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:31])[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[S:23][C:22]3[C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:20][C:19](Cl)=[N:18][C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)=[O:7].CC1(C)C(C)(C)OB([C:40]2[CH:41]=[CH:42][C:43]([NH2:46])=[N:44][CH:45]=2)O1>>[NH2:46][C:43]1[N:44]=[CH:45][C:40]([C:19]2[N:20]=[C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:22]3[S:23][C:15]([CH2:14][N:11]4[CH2:12][CH2:13][N:8]([C:6]([N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH3:31])=[O:7])[CH2:9][CH2:10]4)=[CH:16][C:17]=3[N:18]=2)=[CH:41][CH:42]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: COCCN(C)C(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: COCCN(C)C(=O)N1CCN(Cc2cc3nc(-c4ccc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazine-1-carboxylic acid (2-methoxy-ethyl)-methyl-amide (Example 27) was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine in General Procedure A. Purification on silica yielded 156. NMR (CDCl3): 2.57-2.59 (m, 4H, 2×CH2), 2.92 (s, 3H, CH3), 3.30-3.32 (m, 4H, 2×CH2), 3.36 (s, 3H, CH3), 3.38-3.41 (m, 4H, 2×CH2), 3.55-3.58 (m, 4H, 2×CH2), 3.85 (s, 2H, CH2), 3.89-3.91 (m, 4H, 2×CH2), 4.04-4.06 (m, 4H, 2×CH2), 4.67 (sbr, 2H, NH2), 6.58 (d, H, ArH, J=8.64 Hz), 7.29 (s, H, ArH), 8.48 (dd, H, ArH, J=2.2 Hz, 8.6 Hz), 9.17 (d, H, ArH, J=2.02 Hz). MS: (ESI+): MH+527.49
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:10](=[O:17])N(C1CCNCC1)[C:8]2=[O:24])([CH3:3])[CH3:2].CO.C=O.[C:29]([BH3-])#[N:30].[Na+]>C1COCC1.CC(O)=O>[CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:10](=[O:17])[CH:8]([CH:7]1[CH2:11][CH2:10][N:30]([CH3:29])[CH2:5][CH2:6]1)[C:8]2=[O:24])([CH3:2])[CH3:3]
Reactant: [BH3-]C#N
Reactant: CC(C)Oc1cc2c(cc1[N+](=O)[O-])C(=O)N(C1CCNCC1)C2=O
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)Oc1cc2c(cc1[N+](=O)[O-])C(=O)C(C1CCN(C)CC1)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the 5-isopropoxy-6-nitro-2-piperidin-4-yl-isoindole-1,3-dione generated in the previous step in THF (5 mL) and methanol (5 mL) are added formaldehyde (30 uL, 0.4 mmol) and 2 drops of AcOH sequentially. The reaction mixture is stirred at room temperature for 1 h, then sodium cyanoborohydride (50.4 mg, 0.8 mmol) is added in one portion and the resulting mixture is stirred for an additional 30 min. The reaction is quenched by the addition of saturated aqueous NH4Cl followed by concentration in vacuo to give an oily residue. This oil is partitioned between EtOAc and brine. The organic extract is dried over Na2SO4, filtered and concentrated. Silica gel chromatography (5% MeOH in DCM) affords 5-isopropoxy-2-(1-methyl-piperidin-4-yl)-6-nitro-indan-1,3-dione; MS m/z 347.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:16]Br)=[CH:11][C:10]=1[CH2:26][OH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31](=[O:44])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][C:40]([NH2:43])([CH3:42])[CH3:41])[CH:34]=1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:44])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][C:40]([NH:43][CH2:16][C@@H:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]([CH2:26][OH:27])[CH:11]=2)[O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])([CH3:41])[CH3:42])[CH:34]=1)[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(CO)c1
Reactant: CCOC(=O)Cc1cccc(CC(C)(C)N)c1
Product: CCOC(=O)Cc1cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c(CO)c2)c1

Procedure:
Prepared according to the procedure used for preparation 22 using [2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]methanol (Preparation 23) and [3-(2-amino-2-methyl-propyl)-phenyl]-acetic acid ethyl ester (Preparation 47) to give the title compound as a yellow oil. 1H NMR (400 MHz, CD3OD): δ=7.48-7.05 (11H, m), 7.04-6.96 (1H, d), 5.10 (2H, s), 4.80-4.74 (1H, m), 4.78-4.63 (2H, q), 4.16-4.05 (2H, q), 3.60 (2H, s), 2.89-2.63 (2H, m), 2.70-2.62 (2H, m), 1.24-1.20 (3H, t), 1.07-1.04 (6H, d), 0.81 (9H, s), 0.00 (3H, s), -0.18 (3H, s) ppm. LRMS (electrospray): m/z [M+H]+ 606, [M−H]− 604.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[C:21]([Cl:23])[CH:22]=1>>[Cl:16][C:17]1[CH:18]=[C:19]([C:2]2[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=2)[CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(I)cc1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: CCOC(=O)/C=C(\C)c1ccc(-c2cc(Cl)cc(Cl)c2)cc1

Procedure:
The colourless solid (E)-ethyl 3-(3′,5′-dichloro-biphenyl-4-yl)-but-2-enoate was prepared from (E)-ethyl 3-(4-iodophenyl)-but-2-enoate (example 91a) and 3,5-dichlorobenzene boronic acid by a procedure analogous to that described in example 52a.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([S:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][CH2:38][NH2:39])=[CH:31][CH:30]=2)[CH:22]=1)(=O)C.[OH:40][CH2:41][C:42]([CH3:47])([CH3:46])[C:43]([OH:45])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:40][CH2:41][C:42]([CH3:47])([CH3:46])[C:43]([NH:39][CH2:38][CH2:37][CH2:36][CH2:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][C:23]2[CH:22]=[C:21]([C@H:6]3[C@H:5]([OH:4])[C@@H:10]([OH:11])[C@H:9]([OH:15])[C@@H:8]([S:19][CH3:20])[O:7]3)[CH:26]=[CH:25][C:24]=2[CH3:27])=[CH:34][CH:33]=1)=[O:45]
Reactant: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(CCCCN)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(CO)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(CCCCNC(=O)C(C)(C)CO)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.4 %

Procedure:
To a solution of (2S,3S,4R,5S,6R)-2-(3-(4-(4-aminobutyl)benzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (19, 55 mg, 0.10 mmol), 3-hydroxy-2,2-dimethylpropanoic acid (18 mg, 0.15 mmol), HATU (57 mg, 0.15 mmol), and DIPEA (52 μL, 0.30 mmol) were combined in DMF (1 mL) and stirred for 4 hours at room temperature. The reaction quenched with saturated aqueous NaHCO3 and extracted twice with EtOAc. The combined organic layers were washed with brine, dried with MgSO4, filtered, and concentrated under vacuum. The residue was dissolved in MeOH and treated with a few drops of NaOMe (25 wt % in MeOH) for 1 hour. The reaction was concentrated under vacuum, and the residue was purified by prep HPLC (C18 30×100 mm column, 5-40% CH3CN/10 mM aqueous ammonium formate, 45 mL/min) to give the title compound 21 as a white solid (22 mg, 41% yield). 1H NMR (400 MHz, MeOH-d4) δ ppm 6.98-7.22 (m, 7 H), 4.39 (d, J=9.6 Hz, 1 H), 4.13 (d, J=9.1 Hz, 1 H), 3.90-3.99 (m, 2 H), 3.49 (s, 2 H), 3.35-3.46 (m, 3 H), 3.19 (t, J=6.9 Hz, 2 H), 2.58 (t, J=7.5 Hz, 2 H), 2.18-2.23 (m, 3 H), 2.14 (s, 3 H), 1.60 (s, 2 H), 1.46-1.57 (m, 2 H), 1.11 (s, 6 H). MS (ES+) [M+H]+=532.
Reaction SMILES: [F-].[Cs+].[CH3:3][O:4][CH2:5][O:6][C:7]1[C:8]([SH:13])=[N:9][CH:10]=[CH:11][CH:12]=1.CS(O[C@H:19]([CH3:38])[C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[CH:24][CH:23]=1)=[O:21])(=O)=O.Cl>CN(C=O)C.O>[CH3:37][O:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][O:28][C:25]2[CH:26]=[CH:27][C:22]([C:20](=[O:21])[C@@H:19]([S:13][C:8]3[C:7]([O:6][CH2:5][O:4][CH3:3])=[CH:12][CH:11]=[CH:10][N:9]=3)[CH3:38])=[CH:23][CH:24]=2)=[CH:31][CH:32]=1
Reactant: COCOc1cccnc1S
Reactant: COc1ccc(COc2ccc(C(=O)[C@@H](C)OS(C)(=O)=O)cc2)cc1
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1cccnc1S[C@@H](C)C(=O)c1ccc(OCc2ccc(OC)cc2)cc1

Procedure:
Dried cesium fluoride (5.31 g, 35.0 mmol) and 3-(methoxymethoxy)pyridine-2-thiol (6.0 g, 35.0 mmol) synthesized in Reference Example 15 were dissolved in DMF (120 mL), and under stirring with cooling with ice, (1R*)-2-{4-[(4-methoxybenzyl)oxy]phenyl}-1-methyl-2-oxoethyl methanesulfonate (11.58 g, 31.8 mmol) synthesized in the above (4) was added. The reaction solution was stirred for 20 hours with cooling with ice, then 2 N HCl (20 mL) and water (180 mL) were added, and further stirred for 20 minutes with cooling with ice. The formed solid was collected by filtration, washed with water, and dried under reduced pressure to obtain the entitled compound (13.3 g, containing 20% side product) as a milky white solid.
Reaction SMILES: [ClH:1].O1CCOCC1.[NH2:8][CH:9]([CH2:37][O:38]C(C)(C)C)[C:10]([NH:12][C:13]1[CH:18]=[C:17]([C:19]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=2)=[CH:20][C:21]#[N:22])[CH:16]=[CH:15][C:14]=1[O:35][CH3:36])=[O:11].CCOCC>C(Cl)Cl>[ClH:1].[NH2:8][CH:9]([CH2:37][OH:38])[C:10]([NH:12][C:13]1[CH:18]=[C:17]([C:19]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=2)=[CH:20][C:21]#[N:22])[CH:16]=[CH:15][C:14]=1[O:35][CH3:36])=[O:11]
Reactant: COc1ccc(C(=CC#N)c2cc(OC)c(OC)c(OC)c2)cc1NC(=O)C(N)COC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(C(=CC#N)c2cc(OC)c(OC)c(OC)c2)cc1NC(=O)C(N)CO
Temperature: 25 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
A solution of 4N HCl/dioxane (1 mL) was added to a stirred solution of 2-amino-N-{5-[2-cyano-1-(3,4,5-trimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-3-t-butoxy-propionamide (0.5 g, 1.1 mmol) in CH2Cl2 (10 mL). The resulting mixture was stirred at room temperature for 1 day. Ether (20 mL) was added and the mixture was stirred for 2 h. The slurry was filtered and washed with ether to afford mixture isomers of 2-amino-N-{5-[2-cyano-1-(3,4,5-trimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-3-hydroxy-propionamide hydrochloride (0.4 g, 78%) as white solid: mp 151-153° C.; 1H NMR (DMSO-d6) δ 9.89 (9.94) (s, 1H), 8.31 (b, 3H), 7.98-7.95 (m, 1H), 7.39-7.16 (m, 2H), 6.68 (6.65) (s, 2H), 6.12 (6.25) (s, 1H), 5.63 (b, 1H), 4.18 (b, 1H), 3.91 (d, J=8 Hz, 2H), 3.87-3.70 (m, 12H); 13C NMR (DMSO-d6) δ 166.20, 161.24 (160.99), 152.62, 151.52 (150.82), 139.43 (138.36), 133.54 (132.24), 129.80 (128.56), 126.60 (126.29), 126.16 (125.31), 122.99 (122.32),118.51 (118.47), 111.50 (111.16), 106.91 (106.26), 94.46 (93.64), 66.33, 60.33 (60.15), 56.15, 56.02, 54.43; Anal Calcd for C22H26N3O6Cl+0.2 H2O: C, 56.52; H, 5.69; N, 8.99; Cl, 7.58. Found: C, 56.29; H, 5.81; N, 8.63; Cl, 7.35.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[S:8].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)=O>C(O)C>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]2[N:6]([CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:16])[C:7](=[N:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:8][CH:18]=2)=[CH:22][CH:23]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: CN(C)CCCNC(=S)Nc1ccccc1
Solvent: CCO
Product: CN(C)CCCn1c(-c2ccc(Br)cc2)csc1=Nc1ccccc1
Yield: 59.1 %

Procedure:
A mixture of N-[3-(dimethylamino)propyl]-N′-phenylthiourea (800 mg) obtained in Reference Example 3 as described below and 2-bromo-4′-bromoacetophenone (1.09 g) in ethanol (30 ml) was heated with reflux under nitrogen atmosphere. Nine hours thereafter, the reaction mixture was concentrated under reduced pressure, and to the residue was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with a saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol (50:1)), and crystallized from isopropyl alcohol to give the title compound (830 mg)
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([O:28][CH2:29][CH2:30][N:31]([CH3:56])[C:32]([C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][S:42]([N:45]2[CH2:50][CH2:49][C:48]([NH2:54])([C:51]([NH2:53])=[O:52])[CH2:47][CH2:46]2)(=[O:44])=[O:43])=[C:36]([CH3:55])[CH:35]=1)=[O:33])[CH:26]=[CH2:27].[CH2:57]([O:61][C:62]1[CH:63]=[C:64]([CH:68]=[CH:69][C:70]=1[C:71]([F:74])([F:73])[F:72])[C:65](O)=[O:66])[CH2:58][CH:59]=[CH2:60].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH2:25]([O:28][CH2:29][CH2:30][N:31]([CH3:56])[C:32]([C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][S:42]([N:45]2[CH2:46][CH2:47][C:48]([NH:54][C:65](=[O:66])[C:64]3[CH:68]=[CH:69][C:70]([C:71]([F:73])([F:74])[F:72])=[C:62]([O:61][CH2:57][CH2:58][CH:59]=[CH2:60])[CH:63]=3)([C:51]([NH2:53])=[O:52])[CH2:49][CH2:50]2)(=[O:44])=[O:43])=[C:36]([CH3:55])[CH:35]=1)=[O:33])[CH:26]=[CH2:27]
Reactant: C=CCCOc1cc(C(=O)O)ccc1C(F)(F)F
Reactant: C=CCOCCN(C)C(=O)c1ccc(CCS(=O)(=O)N2CCC(N)(C(N)=O)CC2)c(C)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCCOc1cc(C(=O)NC2(C(N)=O)CCN(S(=O)(=O)CCc3ccc(C(=O)N(C)CCOCC=C)cc3C)CC2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
HATU (245 mg, 0.644 mmol) was added to a solution of 1-(2-{4-[(2-allyloxy-ethyl)-methyl-carbamoyl]-2-methyl-phenyl}-ethanesulfonyl)-4-amino-piperidine-4-carboxylic amide (250 mg), 3-but-3-enyloxy-4-trifluoromethyl-benzoic acid (155 mg, 0.596 mmol) and diisopropylethylamine (0.140 ml, 0.812 mmol) in DMF (5 ml), and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1-(2-{4-[(2-allyloxy-ethyl)-methyl-carbamoyl]-2-methyl-phenyl}-ethanesulfonyl)-4-(3-but-3-enyloxy-4-trifluoromethyl-benzoylamino)-piperidine-4-carboxylic amide as a crude compound (381 mg).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([Cl:20])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[C:26]([F:31])[CH:25]=1>C(O)(C)C>[ClH:20].[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:28][C:27]3[CH:29]=[CH:30][C:24]([Cl:23])=[CH:25][C:26]=3[F:31])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: Nc1ccc(Cl)cc1F
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCc1ccccc1
Yield: 70.3 %

Procedure:
A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (1.2 g, 3.6 mmol), (prepared as described for the starting material in Example 1), and 4-chloro-2-fluoroaniline (444 μl, 4 mmol) in isopropanol (40 ml) was heated at reflux for 1.5 hours. The mixture was allowed to cool, the precipitate was collected by filtration, washed with isopropanol then ether and dried under vacuum to give 7-benzyloxy-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (1.13 g, 71%).
Reaction SMILES: [C:1]1([S:7][C@@H:8]2[NH:11][C:10](=[O:12])[C@H:9]2[CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[N:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:50](Cl)(=[O:52])[CH3:51]>C1COCC1>[C:1]1([S:7][CH:8]2[N:11]([C:50](=[O:52])[CH3:51])[C:10](=[O:12])[CH:9]2[CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[N:18][C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(N=C(NCCC[C@@H]1C(=O)N[C@H]1Sc1ccccc1)NC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: CC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N1C(=O)C(CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)C1Sc1ccccc1
Reaction time: 0.5 h

Procedure:
To a -78° C. THF (7 mL) solution of compound 14 (450 mg, 0.82 mmol) was added 1N THF solution of sodium bis(trimethylsilyl)amide (0.8 mL) dropwise. The resultant solution was stirred for 10 min, followed by the addition of acetyl chloride (0.054 mL, 0.76 mmol). The resultant solution was warmed to room temperature and stirred for an additional 30 min and concentrated- The residue was partitioned between ethyl acetate and H2O. The organic phase was dried (MgSO4) and concentrated to afford 450 mg (93%, crude yield) of the title compound which was directly used in Step B.