Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:28][C:29]([F:38])([F:37])[C:30]1([C:34](O)=[O:35])[CH2:33][CH2:32][CH2:31]1>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:34]([C:30]3([C:29]([F:38])([F:37])[F:28])[CH2:33][CH2:32][CH2:31]3)=[O:35])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Reactant: O=C(O)C1(C(F)(F)F)CCC1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC(=O)C3(C(F)(F)F)CCC3)ccc2F)N=C1N

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F2) and 1-trifluoromethyl-cyclobutanecarboxylic acid followed by deprotection of the intermediate yielded the title compound as a white solid. MS (ESI): m/z=429.3 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)[CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:28]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.B(Br)(Br)Br>C(Cl)Cl>[CH:28]1([C:34]([N:9]2[CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[C:6]3[C:11](=[CH:12][C:3]([OH:2])=[CH:4][CH:5]=3)[CH2:10]2)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: COc1ccc(C2CNCc3cc(OC)ccc32)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CCCCC1)N1Cc2cc(O)ccc2C(c2ccc(O)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 7-methoxy-4-(4-methoxy-phenyl)-1,2,3,4-tetrahydroisoquinoline (0.103 g, 0.382 mmol, 1.0 eq., see Preparation 64) and triethylamine (0.107 ml, 0.764 mmol, 2.0 eq.) in CH2Cl2 (2 ml) was added to a vial containing cyclohexanecarbonyl chloride (0.084 g, 0.573 mmol, 1.5 eq.). The reaction mixture was stirred overnight at RT. To this mixture was added BBr3 as a 1.0M solution in CH2Cl2 (1.15 ml, 1.15 mmol, 3.0 eq.). The reaction mixture was stirred overnight at rt, then cooled to −78° C. and quenched with MeOH (1.5 ml). The reaction mixture was evaporated under a stream of nitrogen and purified by reverse phase HPLC (gradient elution 98:2 H20:0.1% TFA, then 2:98 MeCN:H2O). The exact yield was not determined.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[C:4]([F:15])[CH:3]=1.[Na+].[CH3:17][S:18]([O-:20])=[O:19].[OH-].[Na+]>CS(C)=O>[F:15][C:4]1[CH:3]=[C:2]([S:18]([CH3:17])(=[O:20])=[O:19])[CH:7]=[CH:6][C:5]=1[C:8]1[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2F)nc1
Reactant: CS(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(-c2ccc(O)cn2)c(F)c1
Temperature: 120 °C
Yield: 68.3 %

Procedure:
A mixture of 6-(4-bromo-2-fluorophenyl)-3-pyridinol (0.245 g, 0.91 mmol), methanesulfinic acid sodium salt (0.47 g, 80%, 3.66 mmol), Cul (0.70 g, 3.66 mmol) and NaOH (44 mg, 1.10 mmol) in DMSO (20 mL) was degassed with N2 three times and heated at 120° C. overnight. After the mixture was cooled to ambient temperature, 1N HCl was added to adjust the aqueous pH to about 8. The mixture was extracted with EtOAc. The combined organic extract was washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a light brown viscous oil. The crude product was purified by chromatography on a silica gel column eluted with 2:4:0.1 EtOAc/CH2Cl2/MeOH to give 0.166 g (68%) of 6-[2-fluoro-4-(methylsulfonyl)phenyl]-3-pyridinol as a white solid. 1H NMR (400 MHz, CD3OD): δ 8.26 (d, 1H, J=2.7 Hz), 8.15-8.05 (m, 1H), 7.90-7.75 (m, 2H), 7.74 (dd, 1H, Ja=8.6 Hz, Jb=2.1 Hz), 7.32 (dd, 1H, Ja=8.6 Hz, Jb=2.8 Hz), 3.18 (s, 3H); LRMS (ESI), m/z 268 (M+H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)([O-:18])=[O:17]>O1CCCC1>[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][CH2:9][C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13])=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(=O)CC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)CC(=O)CCc1ccc([N+](=O)[O-])cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
To a reaction vessel (heat and vacuum dried and equipped with a magnetic spin bar) was added tetrahydrofuran and lithium diisopropylamide (2M heptane/ethylbenzene/tetrahydrofuran; 69.4 mL, 138.9 mmol). The solution cooled to −78° C. Pentane-2,4-dione (7.13 mL, 69.4 mmol) was added dropwise and the solution stirred 30 minutes at −78° C. 4-nitrobenzyl bromide (15.0 g, 69.4 mmol) was added in one portion. The solution was removed from the dry-ice/acetone bath, allowed to warm to room temperature and stirred 16 hours. The solution was cooled to approximately 0° C. and the reaction quenched with 1M HCl. Tetrahydrofuran was removed under reduced pressure. The crude material was taken up into dichloromethane and washed with 1M HCl and brine. The aqueous layers were again washed with dichloromethane. The combined dichloromethane layers were dried (Na2SO4) and removed under reduced pressure. Gradient flash column chromatography (FCC) was performed using 5% to 15% ethyl acetate/hexanes to afford title compound (8.5 g, 52%; yellow solid). 1H NMR (CDCl3): 8.14 (d, J=9.0 Hz, 2 H), ˜d, J=8.4 Hz, 2 H), 5.45 (s, 1 H), 3.06 (t, J=7.5 Hz, 2 H), 2.64 (t, J=7.8 Hz, 2 H), 2.04 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:11])[CH:9]=[C:4]([CH3:3])[O:11][C:10]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)c1ccccc1
Solvent: CC(=O)O
Product: Cc1cc(=O)c(-c2ccc(Cl)c(Cl)c2)c(-c2ccccc2)o1
Temperature: 140 °C
Yield: 50.7 %

Procedure:
To a solution of 3,4-dichlorophenylacetophenone (5.3 g; 20 mmoles) in glacial acetic acid (90 ml), polyphosphoric acid (64 g) was added and the resulting solution heated at 140° C. or 24 hours. After cooling, the reaction mixture was poured into ice-water, extracted with ethyl acetate (3×75 ml), the organic solution dried (Na2SO4) and the solvent removed under reduced pressure. The obtained residue was purified by column chromatography with silica gel and n-hexane-ethyl acetate 3:2 as eluent. 3-(3,4-dichlorophenyl)-2-phenyl-6-methylpyran-4-one (1.68 g) was obtained, m.p. 104° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=O)=O.C(=O)([O-])[O-].[K+].[K+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.[Br:63][C:64]1[CH:69]=[CH:68][C:67](I)=[CH:66][C:65]=1[O:71][CH3:72]>O1CCOCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:63][C:64]1[CH:69]=[CH:68][C:67]([C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:66][C:65]=1[O:71][CH3:72]
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCCC1
Reactant: COc1cc(I)ccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(c2ccc(Br)c(OC)c2)CCCC1
Temperature: 80 °C

Procedure:
To a solution of the product from Step 1, ethyl 2-{[(trifluoromethyl)sulfonyl]oxy}cyclohex-1-ene-1-carboxylate (6.65 g, 22.0 mmol) in dioxane (125 mL) was added potassium carbonate (4.56 g, 33.0 mmol), PPh3 (0.346 g, 1.32 mmol), bis(pinacolato)diboron (6.15 g, 24.20 mmol), and PdCl2(PPh3)2 (0.463 g, 0.66 mmol). The mixture was then heated to 80° C. overnight. This solution was then cooled to r.t. and added to a mixture of 1-bromo-4-iodo-2-methoxybenzene (6.86 g, 21.92 mmol), PdCl2(dppf) (0.481 g, 0.657 mmol), potassium carbonate (9.09 g, 65.7 mmol). This mixture was then heated to 80° C. overnight. The mixture was then cooled to r.t., diluted with EtOAc (300 mL) and washed with brine and aqueous KHSO4. The organic layer was then dried over Na2SO4 and the solvent was removed in vacuo. The crude material was then purified on silica (100% DCM) to give impure product which was repurified on silica (gradient elution, 5-20% EtOAc/hexanes) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:25][C:26](=[O:28])[CH3:27])=[N:6][C:7]=1[C@@H:8]([NH:18]S(C(C)(C)C)=O)[CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1.[ClH:29]>CO.O1CCOCC1>[ClH:29].[NH2:18][CH:8]([C:7]1[N:6]=[C:5]([NH:25][C:26](=[O:28])[CH3:27])[CH:4]=[CH:3][C:2]=1[Br:1])[CH2:9][C:10]1[CH:11]=[C:12]([F:17])[CH:13]=[C:14]([F:16])[CH:15]=1
Reactant: CC(=O)Nc1ccc(Br)c([C@H](Cc2cc(F)cc(F)c2)NS(=O)C(C)(C)C)n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(Br)c(C(N)Cc2cc(F)cc(F)c2)n1

Procedure:
(S)—N-(5-Bromo-6-(2-(3,5-difluorophenyl)-1-(1,1-dimethylethylsulfinamido)ethyl)pyridin-2-yl)acetamide (1E, crude material from last step) was treated with a mixture of 2 ml of 1.25 M HCl in MeOH (methanol)/1 ml of 4 M HCl in dioxane for 1 hour. The solvent was removed in vacuo. The crude material was used without further purification. MS (m/z) 369.9 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]2[CH2:13][O:14][C:15](=O)[C@H:11]2[N:10]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[S].[SH2:31].Cl>[Zn].O.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C@H:12]2[CH2:13][S:31][C:15](=[O:14])[C@H:11]2[N:10]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Reactant: S
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1SC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 90 °C
Reaction time: 4.5 h

Procedure:
After heating to 90° C. a mixture of 38.68 g of (+)-cis-1,3-dibenzylhexahydrofuro[3,4-d]imidazole-2,4-dione, 6.04 g of sodium acetate, 2.49 g of sulfur and 47.56 g of polyethylene glycol (the average molecular weight: 600), it was stirred for 4.5 hours at the temperature while blowing 4.50 g of hydrogen sulfide at a rate of 10 ml/minute. Then blowing of hydrogen sulfide was stopped and the resultant mixture was stirred for 5 hours at the temperature. After cooling the reaction mixture to room temperature, 173.61 g of toluene and 99.70 g of water were added to the mixture, and 8.25 g of zinc powder was further added to the mixture while stirring at room temperature. After dropping 54.90 g of 35% hydrochloric acid at the same temperature, the resultant mixture was stirred at 45° C. for 8 hours. The mixture was separated by removing water layer to give an oil layer, which was concentrated to give a product. Recrystallization from 2-propanol and water gave a crystal of (+)-cis-1,3-dibenzylhexahydrothieno[3,4-d]imidazole-2,4-dione. The yield was 36.96 g (yield percentage: 91%). Melting point was 126° C. [α]D20 was 90° C.=1.0; chloroform).
Reaction SMILES: [NH2:1][S:2]([CH:5]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=1[Br:21])[CH2:6][C:7](OC)=[O:8])(=[O:4])=[O:3].C[O-].[Na+]>CO>[Br:21][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:11]=1[CH:5]1[S:2](=[O:4])(=[O:3])[NH:1][C:7](=[O:8])[CH2:6]1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)CC(c1ccc(C(=O)OC)cc1Br)S(N)(=O)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(C2CC(=O)NS2(=O)=O)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.5 %

Procedure:
Methyl 4-[1-(aminosulfonyl)-3-methoxy-3-oxopropyl]-3-bromobenzoate (187 mg, 0.492 mmol) in methanol (16 mL) was treated with sodium methoxide (281 μL, 4.92 mmol) at 0° C. The solution stirred at room temperature for 3 h and 30 minutes. The reaction mixture was purified by preparative LCMS to afford product as a white solid (66 mg, 38%). 1H NMR (400 MHz, CD3OD): δ 8.31 (d, J=1.8 Hz, 1H), 8.07 (dd, J=8.2, 1.8 Hz, 1H), 7.67 (d, J=8.2 Hz, 1H), 5.71 (dd, J=8.7, 6.7 Hz, 1H), 3.94 (s, 3H), 3.52 (dd, J=17.5, 8.6 Hz, 1H), 3.27 (m, 1H). LCMS found for C11H10BrNO5SNa (M+Na)30: m/z=370, 372.
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]([NH:12][NH:13][C:14](=O)[CH2:15][C@@H:16]2[CH2:20][CH2:19][N:18]([C:21]([CH:23]3[CH2:25][CH2:24]3)=[O:22])[CH2:17]2)=[O:11])=[C:4]([F:27])[CH:3]=1.C([O-])([O-])=O.[K+].[K+]>O>[Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N:9]2[C:14]([CH2:15][C@@H:16]3[CH2:20][CH2:19][N:18]([C:21]([CH:23]4[CH2:25][CH2:24]4)=[O:22])[CH2:17]3)=[N:13][NH:12][C:10]2=[O:11])=[C:4]([F:27])[CH:3]=1
Reactant: O=C(C[C@@H]1CCN(C(=O)C2CC2)C1)NNC(=O)Nc1cc(Cl)c(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2cc(Cl)c(Br)cc2F)C1
Temperature: 115 °C

Procedure:
N-(4-bromo-5-chloro-2-fluorophenyl)-2-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetyl}hydrazinecarboxamide (2.426 mmol) and K2CO3 (8.49 mmol) were added to a round-bottom flask and suspended in water (105 mL). The mixture was heated at reflux (115° C.) for 21 h. Analysis by LCMS indicated formation of desired product (and other major by-products). The reaction was cooled to room temperature and the pH was adjusted to ˜6 with 1N aq HCl and poured into a separatory funnel containing ethyl acetate. The aqueous layer was extracted with ethyl acetate (3×) and the combined organic layers were dried over Na2SO4, filtered, and concentrated to an oil. The residue was purified by silica gel chromatography (0-30% isopropanol/ethyl acetate). The desired fractions were combined and concentrated to afford the title product as an off-white solid (401 mg, 38%). MS(ES)+ m/e 443.0, 445.0 [M+H]+.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH:14]([CH:16]=[CH2:17])[C@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[C].[Pd].C(O)C>[C:22]([O:21][C:19]([NH:18][C@H:13]1[CH:14]([CH2:16][CH3:17])[CH2:15][NH:11][CH2:12]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: C=CC1CN(C(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCC1CNC[C@H]1NC(=O)OC(C)(C)C

Procedure:
A 10% palladium carbon catalyst (15 mg) was added to a solution of (3S)-1-benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-vinylpyrrolidine [an isomer mixture of (4S)-form:(4R)-form (1:4)] (230 mg, 0.66 mmol) in ethanol (8 mL), followed by stirring in a hydrogen atmosphere under an ordinary pressure at room temperature for 12 hours. After filtration, the filtrate was concentrated under reduced pressure, to thereby yield the title compound (an isomer mixture of (4S)-form and (4R)-form (1:4)) as a colorless oily substance (148 mg, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[CH:15]1([C:18]([N:20]2[CH2:24][CH2:23][C@@H:22]([CH2:25][C:26]([NH:28][NH2:29])=[O:27])[CH2:21]2)=[O:19])[CH2:17][CH2:16]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:29][NH:28][C:26](=[O:27])[CH2:25][C@@H:22]2[CH2:23][CH2:24][N:20]([C:18]([CH:15]3[CH2:17][CH2:16]3)=[O:19])[CH2:21]2)=[O:10])=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: O=C=Nc1ccc(Br)cc1C(F)(F)F
Reactant: NNC(=O)C[C@@H]1CCN(C(=O)C2CC2)C1
Solvent: ClCCl
Product: O=C(C[C@@H]1CCN(C(=O)C2CC2)C1)NNC(=O)Nc1ccc(Br)cc1C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a round-bottom flask was added 4-bromo-1-isocyanato-2-(trifluoromethyl)benzene (0.4 mL, 2.55 mmol) and dichloromethane (10 mL) under nitrogen. The mixture was cooled to −78° C. and a solution of 2-[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetohydrazide (520 mg, 2.461 mmol) in dichloromethane (15 mL) was then added to the cooled solution and immediately allowed to warm to room temperature. After 1 h, analysis by LCMS indicated desired product formation. The resulting precipitate was collected and dried under vacuum filtration to yield the title product as a white solid (130 mg, 88%). MS(ES)+ m/e 476.9, 478.9 M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:11]1([CH:17]([C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=2)[CH2:18][NH2:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:20]1[CH:21]=[N:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: NCC(c1ccccc1)c1ccc(C(F)(F)F)nc1
Product: O=C(NCC(c1ccccc1)c1ccc(C(F)(F)F)nc1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and 2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine. LCMS (MH+): m/z=405.2, tR (minutes, Method D)=0.79
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:31]2[CH:36]=[CH:35][C:34](Br)=[CH:33][CH:32]=2)[S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])(=[O:21])=[O:20])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:39][C:40]1[CH:45]=[CH:44][C:43](OB(O)O)=[CH:42][CH:41]=1.O>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].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>[C:1]([O:5][C:6](=[O:38])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:31]2[CH:36]=[CH:35][C:34]([C:43]3[CH:44]=[CH:45][C:40]([F:39])=[CH:41][CH:42]=3)=[CH:33][CH:32]=2)[S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])(=[O:21])=[O:20])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN(c2ccc(Br)cc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cs1
Reactant: OB(O)Oc1ccc(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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN(c2ccc(-c3ccc(F)cc3)cc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cs1
Yield: 89.5 %

Procedure:
2-{[4-(2-{(4-Bromophenyl)[(2-nitrophenyl)sulfonyl]amino}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (1.2 g) synthesized in Example 256-1 and 4-fluorophenylboric acid (0.31 g) were dissolved in dioxane (10 mL) and 2 mol/L sodium carbonate (5 mL), tetrakis(triphenylphosphine)palladium (0.11 g) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:1 to 2:1) to give the title compound (1.1 g) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].N1CCCC1.O>C1(C)C=CC=CC=1>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][C:22]2([NH:9][C:7](=[O:8])[C:6]3[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[O:11]2)[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NC(=O)c1cc(Br)ccc1O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)c1cc(Br)ccc1O2
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
A mixture of 5-bromo salicylamide (2.5 g, 11.6 mmol), N—BOC-4-piperidone (2.30 g, 11.6 mmol) and pyrrolidine (0.96 ml, 11.6 mmol) in toluene (40 ml) was heated to reflux under N2 atmosphere. After 3 h, the mixture was cooled down to RT, poured into water and extracted with AcOEt. The organic phase was washed with a 2 M solution of NaOH (150 ml) and then with 2 M HCl (150 ml), dried over Na2SO4, filtered and the solvent was evaporated under vacuum. The crude mixture was purified by column chromatography using DCM/MeOH 90/10 as eluent, to give 1.82 g of 6-bromo-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-1′-carboxylic acid tert-butyl ester as a white solid (40%). Reaction with methyl acrylate according to the procedure for preparation of Intermediate 1, Step B, gave (E)-3-{1′-tert-butoxycarbonyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (1.3 g, 71%) as a yellow solid.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:22])[C:14]3[CH:19]=[CH:18][N:17]=[C:16](Cl)[C:15]=3[Cl:21])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].C(OCC)(=O)C>CS(C)=O>[C:1]12([CH2:11][NH:12][C:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[C:15]=3[Cl:21])=[O:22])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1ccnc(Cl)c1Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCNc1nccc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1Cl
Yield: 72.9 %

Procedure:
N-(1-Adamantylmethyl)-2,3-dichloroisonicotinamide (0.4 g) and tert-butyl 3-aminopropylcarbamate (0.4 g) in DMSO (4 ml) were heated in a sealed tube at 160 C for 5 hrs. Ethyl acetate was added and the solution was washed with NaHCO3 solution, water, KHSO4 solution and water. The solution was dried and the solvent was evaporated. The resulting oil was subjected to flash chromatography, using ethyl acetate/hexane as eluant, to give the title compound as a colourless oil (0.41 g).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][CH2:28][CH2:29][CH3:30])=[O:26])=[C:20]([Cl:31])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.O>CN(C)C=O>[Cl:31][C:20]1[CH:19]=[C:18]([O:17][C:8]2[C:7]3[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([O:4][CH2:3][CH2:2][CH2:1][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)[CH:6]=3)[N:11]=[CH:10][N:9]=2)[CH:23]=[CH:22][C:21]=1[NH:24][C:25]([NH:27][CH2:28][CH2:29][CH3:30])=[O:26]
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OCCC)cc23)cc1Cl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OCCCN4CCOCC4)cc23)cc1Cl
Temperature: 120 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
A starting compound (N-(4-{[6-(3-propoxy)-7-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)-N′-propylurea, 54 mg), potassium carbonate (138 mg), and morpholine (0.017 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at 120° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with ethyl acetate to give 42 mg (yield 77%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@:11]2([C:19](OC)=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH2:1]([N:8]1[CH2:12][C@:11]2([CH2:19][OH:20])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@]12CN(Cc3ccccc3)C[C@H]1c1ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC[C@]12CN(Cc3ccccc3)C[C@H]1c1ccccc12
Reaction time: 8 h
Yield: 96.7 %

Procedure:
A solution of 4 g of compound obtained in Step C in 50 ml of tetrahydrofuran is added dropwise to a suspension of 1.03 g of LiAlH4 in 15 ml of tetrahydrofuran. The mixture is left overnight at ambient temperature. After hydrolysis and filtering off the salts, evaporation to dryness is carried out to obtain 3.5 g of expected product.