Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:20]([C:22]3[CH:23]=[C:24]([CH:35]=[CH:36][CH:37]=3)[O:25][CH2:26][CH2:27][NH:28][S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])=O)[CH2:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1.C(O)(C)C.O>C(OC(=O)C)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:1]([NH:8][CH:20]([C:16]1([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)[CH2:19][CH2:18][CH2:17]1)[C:22]1[CH:23]=[C:24]([CH:35]=[CH:36][CH:37]=1)[O:25][CH2:26][CH2:27][NH:28][S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCCS(=O)(=O)NCCOc1cccc(C(=O)C2(c3ccc(Cl)cc3)CCC2)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: O
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)NCCOc1cccc(C(NCc2ccccc2)C2(c3ccc(Cl)cc3)CCC2)c1
Temperature: 35 °C
Reaction time: 6 h
Yield: 9.8 %

Procedure:
Titanium (IV) isopropoxide (235 mg, 0.83 mmol) was added under nitrogen at room temperature to a mixture of benzylamine (147 mg, 1.37 mmol) and propane-1-sulfonic acid (2-{3-[1-(4-chloro-phenyl)-cyclobutanecarbonyl]-phenoxy}-ethyl)-amide (120 mg, 0.27 mmol), followed by 1 ml of isopropanol. The mixture was stirred at 35° C. for 6 h, then over night at room temperature followed by addition of NaCNBH4 (43 mg, 0.69 mmol) and heating to reflux for further 6 hours. The suspension was treated with water and diluted with ethylacetate and filtered. The organic layer was separated, washed with water, dried (sodium sulfate) and the solvent evaporated. Purification on SiO2 afforded 14 mg of desired product which was further purified by transformation into the hydrochloride. (white solid, 2.7 mg)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1([C:26](Cl)=[O:27])[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2>>[C:2]1([NH:1][C:26]([C:13]2([CH2:12][CH2:11][CH2:10][CH2:9][Br:8])[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:27])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(Nc1ccccc1)C1(CCCCBr)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1c from aniline and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[O:16]C)[C:12](=[O:18])[C:11]([CH3:20])([CH3:19])[CH2:10]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl-].[Al+3].[Cl-].[Cl-].C1(C)C=CC=CC=1>O>[CH2:1]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[OH:16])[C:12](=[O:18])[C:11]([CH3:19])([CH3:20])[CH2:10]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cc2c(cc1OC)C(=O)C(C)(C)C2
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCc1cc2c(cc1O)C(=O)C(C)(C)C2

Procedure:
1.93 g (7 mmol) of 5-hexyl-6-methoxy-2,2-dimethylindan-1-one, 2.84 g (21 mmol) of aluminium chloride and 40 ml of toluene are heated for 15 minutes at reflux. The mixture is poured into water and extracted with ether. The organic phase is dried (Na2SO4) and the solvent evaporated off. The residue is purified by flash chromatography (dichloromethane, 2.8 g; 90%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:22])([CH3:21])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=[O:12].Br[CH2:29][CH2:30][CH2:31][C:32]([CH3:38])([CH3:37])[C:33]([O:35][CH3:36])=[O:34]>CN(C)C=O>[CH3:3][C:4]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:22])([CH3:21])[C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:29][CH2:30][CH2:31][C:32]([CH3:38])([CH3:37])[C:33]([O:35][CH3:36])=[O:34])=[CH:18][CH:19]=1)=[O:12]
Reactant: COC(=O)C(C)(C)CCCBr
Reactant: Cc1ccc(C)c(OCCCC(C)(C)C(=O)Nc2ccc(O)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)CCCOc1ccc(NC(=O)C(C)(C)CCCOc2cc(C)ccc2C)cc1
Reaction time: 8 h
Yield: 48 %

Procedure:
Sodium hydride, 50% dispersion in mineral oil, 2.2 g, is added to 15.3 g of 5-(2,5-dimethylphenoxy)-N-(4-hydroxyphenyl)-2,2-dimethylpentanamide in 200 ml of N,N-dimethylformamide (DMF). Then 10 g of methyl 5-bromo-2,2-dimethylpentanoate (Journal of Medicinal Chemistry, Vol. 26, pp 1020-1027 (1983)) is added to the previous mixture. The mixture is stirred overnight and then stirred three hours on a steam bath, the DMF is removed on a rotary evaporator and water is added to the residue. The product is taken up in diethyl ether, extracted with base, washed with water and concentrated on a steam bath. Isopropyl ether is added to afford 10.4 g of 5-[4-[[5-(2,5-dimethylphenoxy)-2,2-dimethyl-1-oxopentyl]amino]phenoxy]-2,2-dimethylpentanoic acid, methyl ester after recrystallization from isopropyl ether (2X); mp 62°-63° C.
Reaction SMILES: [F:1][C:2]([F:9])([C:5]([F:8])([F:7])[F:6])[CH2:3][OH:4].CC(C)([O-])C.[K+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[C:18]=1[O:24][CH3:25]>C(OCC)(=O)C>[CH3:25][O:24][C:18]1[C:19]([CH3:23])=[N:20][CH:21]=[CH:22][C:17]=1[O:4][CH2:3][C:2]([F:9])([F:1])[C:5]([F:8])([F:7])[F:6]
Reactant: COc1c(Cl)ccnc1C
Reactant: OCC(F)(F)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1c(OCC(F)(F)C(F)(F)F)ccnc1C

Procedure:
To 2,2,3,3,3-pentafluoropropanol (21 ml) were added in small portions, potassium tert-butoxide (23.6 g) and then 4-chloro-3-methoxy-2-methyl-pyridine (7.5 g). After being refluxed for 40 hours, the reaction mixture was cooled, to which ethyl acetate was added and the insoluble substance was filtered off. The filtrate was concentrated and purified by column chromatography, to give 3-methoxy-2-methyl-4-(2,2,3,3,3-pentafluoropropoxy)pyridine (1.7 g) as a light yellow oil while 4.1 g of the starting material was recovered at the same time.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:45][CH3:46])=[C:6]([C:8]([CH3:44])([CH3:43])[CH2:9][C:10]([OH:42])([C:38]([F:41])([F:40])[F:39])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([C:29]([N:31]([CH3:37])[C@@H:32]([C:34](O)=[O:35])[CH3:33])=[O:30])[CH:26]=[CH:27][CH:28]=2)[CH:7]=1.[NH3:47]>>[NH2:47][C:34](=[O:35])[C@H:32]([N:31]([CH3:37])[C:29](=[O:30])[C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([N:17]2[C:18]3[C:14](=[C:13]([NH:12][CH2:11][C:10]([OH:42])([C:38]([F:41])([F:40])[F:39])[CH2:9][C:8]([C:6]4[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:45][CH3:46])([CH3:44])[CH3:43])[CH:21]=[C:20]([CH3:22])[CH:19]=3)[CH:15]=[N:16]2)[CH:24]=1)[CH3:33]
Reactant: N
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)N(C)[C@H](C)C(=O)O)c1)C(F)(F)F
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)N(C)[C@H](C)C(N)=O)c1)C(F)(F)F

Procedure:
Prepared similarly to Example 14 from N-{[3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)phenyl]carbonyl}-N-methyl-D-alanine and ammonia.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([OH:20])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[CH:4][CH:3]=1.Br[CH2:22][CH2:23][CH2:24][CH2:25]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>O>[OH:20][C@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:3][CH:4]=1)[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11]
Reactant: Nc1ccc(C[C@@H](O)C(=O)OCc2ccccc2)cc1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Product: O=C(OCc1ccccc1)[C@H](O)Cc1ccc(N2CCCC2)cc1

Procedure:
The suspended solution of benzyl (R)-3-(4-aminophenyl)-2-hydroxypropionate(1.53 g), 1,4-dibromobutane (0.61 ml),potassium carbonate (2.07 g) and sodium iodide (0.37 g) indimethylformamide (5 ml) were stirred at room temperature for 71 hours. To the solution was added water (50 ml) and extracted withether (50 ml, 25 ml×2). After the ether layer was washed withsaturated brine, it was dried over anhydrous sodium sulfate. Thesolvent was evaporated in vacuo, the resultant crude product waspurified by silica gel column chromatography, and eluted withmixture of hexane and ethyl acetate (4:1, v/v). The fractionscontaining the desired product were combined and evaporated invacuo to obtain benzyl (R)-2-hydroxy-3-(4-pyrrolidinophenyl)propionate (1.35 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[N:12][CH:13]=2)=[C:6]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:5]=[C:4]([NH2:22])[CH:3]=1.[CH3:23][O-:24].[Na+]>CO.O>[CH3:23][O:24][C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[N:12][CH:13]=2)=[C:6]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:5]=[C:4]([NH2:22])[CH:3]=1
Reactant: Nc1cc(Cl)c(-c2cncnc2)c(C#Cc2ccccc2)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(N)nc(C#Cc2ccccc2)c1-c1cncnc1
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-chloro-6-(2-phenylethynyl)-5-pyrimidin-5-ylpyridin-2-amine C3c (400 mg, 1.3 mmol), sodium methoxide (a solution of 2.61 mmol in 0.29 ml MeOH) and MeOH (2 ml) is stirred for 20 minutes at 100° C. and 10 minutes at 110° C. The mixture is diluted with water and extracted with DCM. The combined organic layers are dried over Na2SO4, concentrated in vacuo and the product purified by NP chromatography. Yield: 228 mg (58%). HPLC-MS: M+H=303.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]2[N:9]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:10]=[C:11]3[C:16]=2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[NH:12]3)=[CH:4][CH:3]=1.[CH2:33](I)[CH:34]([CH3:36])[CH3:35].IC1CCCC1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]2[N:9]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][CH:22]=3)[N:10]=[C:11]3[C:16]=2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]3[CH2:33][CH:34]([CH3:36])[CH3:35])=[CH:31][CH:32]=1
Reactant: CC(C)CI
Reactant: Cn1c(=O)[nH]c2nn(Cc3ccc(C(F)(F)F)cc3)c(NCc3ccc(F)cc3)c2c1=O
Agent: IC1CCCC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(NCc3ccc(F)cc3)n(Cc3ccc(C(F)(F)F)cc3)nc21

Procedure:
The synthesis method is analogous to example 7 wherein 3-(4-fluorobenzylamino)-5-methyl-2-(4-(trifluoromethyl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione is used instead of 5-methyl-3-(phenylamino)-2-(4-(pyridin-2-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione, and isobutyl iodide is added instead of iodocyclopentane. MS (ESI) m/z 490.2 [M+H]+
Reaction SMILES: [C:1]([C:3]1[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)=[N:5][NH:6][CH:7]=1)#[CH:2].O.FC(F)(F)C(O)=[O:21].C(OCC)C>O1CCOCC1>[N+:14]([C:10]1[CH:9]=[C:8]([C:4]2[C:3]([C:1](=[O:21])[CH3:2])=[CH:7][NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: C#Cc1c[nH]nc1-c1cccc([N+](=O)[O-])c1
Reactant: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: O
Solvent: CCOCC
Product: CC(=O)c1c[nH]nc1-c1cccc([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
To a solution of 350 mg (1.6 mmol) of 4-ethynyl-3-(3-nitrophenyl)-1H-pyrazole in a mixture of 50 ml of dioxane and 0.5 ml (28 mmol) of water, 0.5 ml (6.5 mmol) of trifluoroacetic acid were added. The reaction was heated at 100° C. under stirring for 2 hours. The organic solvent was removed under reduced pressure and the residue partitioned between ethylacetate and aqueous sodium hydrogenocarbonate. The organic layer was then dried over sodium sulphate and evaporated to dryness, affording, after trituration with diethylether, 251 mg (68%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([N:17]=[C:18]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH:5]=[C:6]([C:8]#[C:9][C:10]2([OH:16])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[N:7]=1.[F:25][C:26]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[C:27]=1[CH:28]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[NH2:1][C:2]1[C:3]2[N:4]([N:17]=[C:18]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH:5]=[C:6]([C:8]#[C:9][C:10]2([OH:16])[CH2:11][CH2:12][N:13]([CH2:28][C:27]3[C:26]([F:25])=[CH:33][C:32]([F:34])=[CH:31][C:30]=3[F:35])[CH2:14][CH2:15]2)[N:7]=1
Reactant: O=Cc1c(F)cc(F)cc1F
Reactant: Nc1nc(C#CC2(O)CCNCC2)cn2nc(-c3ccco3)nc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1nc(C#CC2(O)CCN(Cc3c(F)cc(F)cc3F)CC2)cn2nc(-c3ccco3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.1 %

Procedure:
To a solution of 4-(8-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-6-ylethynyl)-piperidin-4-ol (22 mg,0.068 mmol) and 2,4,6-trifluoro-benzaldehyde (11 mg, 0.068 mmol) in CH2Cl2 (2 mL) was added sodium triacetoxyborohydride (32 mg, 0.15 mmol) and acetic acid (6 uL, 0.10 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through a pad of silica-gel, washed with ethyl acetate. The eluant was concentrated. The residue was isolated by reversed phased HPLC eluting with a water/acetonitrile gradient to yield 4-(8-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-6-ylethynyl)-1-(2,4,6-trifluoro-benzyl)-piperidin-4-ol (1 mg, 3%). 1H NMR (300 MHz, DMSO): δ 7.92 (br s, 1H), 7.70 (m, 3H), 7.41 (s, 2H), 7.14 (s, 1H), 6.72 (s, 1H), 4.43 (s, 2H), 3.80 (m, 4H), 2.12-1.96 (m, 4 H). MS: m/z: 469 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:27]1[CH:28]=[C:29]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[CH:30]=[CH:31][CH:32]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:28]=[C:29]([NH:33][C:34]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([S:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:35])[CH:30]=[CH:31][CH:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1cccc(NC(=O)Oc2ccccc2)c1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cccc(C(C)(C)C)c4)c3)c2cc1OC
Yield: 46.7 %

Procedure:
3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (94 mg, 0.3 mmol) and phenyl 3-tert-butylphenylcarbamate from Example 118A (114 mg, 0.42 mmol) were reacted as described in Example 115C to give 1-(3-tert-butylphenyl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (71 mg, 0.14 mmol, 48%). 1H NMR (300 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.70 (s, 2H), 7.84 (s, 1H), 7.53-7.39 (m, 3H), 7.35 (s, 2H), 7.28-7.17 (m, 3H), 7.02 (d, 1H), 3.99 (s, 6H), 1.27 (s, 9H); LC-MS (ESI) m/z 489 (M+H)+.
Reaction SMILES: [S:1]([CH2:8][C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:14]>>[C:2]1([S:1][CH2:8][C:9]([Cl:14])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CSc1ccccc1
Product: O=C(Cl)CSc1ccccc1
Yield: 98 %

Procedure:
To thiophenoxyacetic acid (8 g, 0.05 mol) was added SOCl2 (8 mL) and the reaction mixture was heated to reflux for 1 h. TLC showed disappearance of the starting material. The excess SOCl2 was removed in vacuo (hood|) and the product distilled to give 8.6 g (98%) of the title compound: bp 85°-86° C., 4-5 Torr (lit. 117°-119° C., 6 Torr (Mooradian, A.; Cavallito, C. J.; Bergman, A. J.; Lawson, E. J.; Suter, C. M. J. Am. Chem. Soc. 1949, 3372)); 1H NMR (CDCl3) δ7.48-7.34 (m, 5H), 4.06 (m, 2H); 13C NMR (CDCl3) δ169.75, 132.83, 131.44, 129.35, 128.22, 48.48; MS (EI, m/z) 186 (M+).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH2:13][C@H:12]([CH2:15]OS(C3C=CC(C)=CC=3)(=O)=O)[O:11][C:10]=2[CH:27]=1)(=[O:5])=[O:4].[CH2:30]([NH2:32])[CH3:31].Cl>C(#N)C>[F:1][C:2]([F:29])([F:28])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH2:13][C@H:12]([CH2:15][NH:32][CH2:30][CH3:31])[O:11][C:10]=2[CH:27]=1)(=[O:4])=[O:5]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(S(=O)(=O)C(F)(F)F)cc3O2)cc1
Reactant: CCN
Agent: Cl
Solvent: CC#N
Product: CCNC[C@H]1COc2ccc(S(=O)(=O)C(F)(F)F)cc2O1

Procedure:
Preparation according to Example 2 using [(2R)-7-(trifluoromethylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl-4-methylbenzenesulfonate (0.27 g, 0.68 mmol), ethanamine (1 ml, 70% in water) and ACN (2 ml). Yield: 0.170 g, 76%. The amine was converted to the hydrochloric acid salt and recrystallized from acetonitrile. M.p. 208° C. MS m/z (rel. intensity, 70 eV) 325 (M+, 1) 58 (bp), 56 (8), 79 (5), 59 (4). [α]=−40° (MeOH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@H:16]([CH3:17])[CH2:15][C@@H:14]([CH2:18][C:19](O)=[O:20])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C@H:16]([CH3:17])[CH2:15][C@@H:14]([CH2:18][C:19](=[O:20])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: C[C@@H]1C[C@@H](CC(=O)O)n2c(=O)c(=O)[nH]c3cc(Br)cc1c32
Reactant: Nc1ccccc1
Product: C[C@@H]1C[C@@H](CC(=O)Nc2ccccc2)n2c(=O)c(=O)[nH]c3cc(Br)cc1c32
Yield: 87.9 %

Procedure:
A procedure similar to that described in Example 5 was carried out with trans-9-bromo-5-carboxymethyl-7-methyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (90 mg, 0.255 mmol) and aniline (25 μL, 0.28 mmol) to give 96 mg of the title compound (88%): mp>300° C.; 1H NMR (270 MHz, DMSO-d6) δ12.09 (bs, 1H), 7.56 (d, 2H, J=7.3 Hz), 7.32 (d, 1H, J=2 Hz), 7.30 (t, 2H, J=7.3 Hz), 7.21 (d, 1H, J=2 Hz), 7.05 (t, 1H, J=7.3 Hz), 5.15~5.25 (m, 1H), 3.19 (ddq, 1H, J=12.5, 4.6, 6.6 Hz), 2.55~2.70 (m, 2H), 2.13 (ddd, 1H, J=14.2, 4.6, 2.3 Hz), 1.67 (ddd, 1H, J=14.2, 12.5, 4.9 Hz), 1.33 (d, 3H, J=6.3 Hz).
Reaction SMILES: [Mg].Br[CH2:3][CH:4]1[CH2:7][CH2:6][CH2:5]1.[C:8](OCC)(=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10]>C1COCC1>[CH2:12]([O:11][C:9](=[O:10])[C:8](=[O:14])[CH2:3][CH:4]1[CH2:7][CH2:6][CH2:5]1)[CH3:13]
Reactant: BrCC1CCC1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)CC1CCC1
Temperature: 60 °C
Yield: 35.7 %

Procedure:
To a suspension of 5 mg per mL Rieke® magnesium in THF (37.9 mmol, 40 mL) at room temperature is added bromomethyl cyclobutane (37.9 mmol, 4.25 mL) dropwise. After the addition, the reaction is heated to 60° C. for 1 h. The mixture is transferred via syringe to a −78° C. solution of diethyl oxalate (37.9 mmol, 5.14 g) in THF (20 mL). The reaction is allowed to warm to 0° C. and is quenched with 1N HCl. Diethyl ether is added (20 mL) and the layers are separated. The organic layer is dried (Na2SO4) and adsorbed onto silica and purified using a gradient to 0-10% EtOAc/Hexanes to yield the title compound (2.3 g, 37%). LC-MS: 171.0 (M+1).
Reaction SMILES: [C:1]([O:4][C@@H:5]([C@H:22]([O:53][C:54](=[O:56])[CH3:55])[C@H:23]([O:49][C:50](=[O:52])[CH3:51])[C@@H:24]([NH:30][C:31](=[O:48])[C@H:32]([CH2:44][CH:45]([CH3:47])[CH3:46])[NH:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[CH2:25][O:26][C:27](=[O:29])[CH3:28])[C:6]([O:8]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:7])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O>[C:1]([O:4][C@@H:5]([C@H:22]([O:53][C:54](=[O:56])[CH3:55])[C@H:23]([O:49][C:50](=[O:52])[CH3:51])[C@@H:24]([NH:30][C:31](=[O:48])[C@H:32]([CH2:44][CH:45]([CH3:47])[CH3:46])[NH:33][C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])[CH2:25][O:26][C:27](=[O:29])[CH3:28])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)C(=O)OC(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
Diphenylmethyl (2S,3R,4R,5S)-2,3,4,6-tetraacetoxy-5-(N-benzyloxycarbonyl-L-leucyl)aminohexanoate (270 mg) was dissolved in trifluoroacetic acid (5 ml) and the solution was stirred at room temperature for 1 hour. After concentration under reduced pressure, the residue was passed through silica gel column chromatography, followed by elution with ethyl acetate-methanol (10:1). The effective fractions were combined and concent rated under reduced pressure to afford the title compound (214 mg).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH2:31][CH:32]=O)[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11]CC1C=CC=CC=1)=[O:4].Cl.Cl.[NH2:36][C@@H:37]([CH3:45])[CH2:38][CH2:39][NH:40][CH2:41][CH2:42][O:43][CH3:44]>CO.ClCCl>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][NH:21][C:20]([C:8]2[C:9](=[O:19])[C:10]([OH:11])=[C:5]3[C:3](=[O:4])[N:36]4[C@@H:37]([CH3:45])[CH2:38][CH2:39][N:40]([CH2:41][CH2:42][O:43][CH3:44])[C@@H:32]4[CH2:31][N:6]3[CH:7]=2)=[O:30])=[CH:28][CH:27]=1
Reactant: COCCNCC[C@H](C)N
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COCCN1CC[C@H](C)N2C(=O)c3c(O)c(=O)c(C(=O)NCc4ccc(F)cc4)cn3C[C@@H]12
Yield: 57.7 %

Procedure:
In a manner similar to that described in example Z-36, from 16 (15 mg, 0.034 mmol) and [(3S)-3-Aminobutyl][2(methyloxy)ethyl]amine bis hydrochloride (19 mg, 0.087 mmol), (4S,12aS)-N-[(4-fluorophenyl)methyl]-4-methyl-1-[2-(methyloxy)ethyl]-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,8,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide was prepared as a white solid after silica gel chromatography (1-12% methanol/dichloromethane). This material was deprotected in a second step similar to that described in example Z-37 to give the title compound as a yellow solid (9 mg, 60%, 2 steps). 1H NMR (CDCl3) δ 12.56 (s, 1H), 10.51 (m, 1H), 8.29 (s, 1H), 7.32 (m, 2H), 6.98 (m, 2H), 5.08 (m, 1H), 4.65-4.59 (m, 2H), 4.53 (m, 1H), 4.21 (m, 1H), 3.61-3.40 (m, 2H), 3.34-3.13 (m, 8H), 3.08 (m, 1H), 2.04-2.84 (m, 2H), 2.68 (m, 1H), 2.07 (m, 1H), 1.50 (m, 1H), 1.35 (d, J=7.2 Hz, 3H), 1.14 (m, 1H); ES+MS: 459 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Cl:11][C:12]1[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]2[C:13]=1[C:14](=[O:23])[C:15](=[O:22])[NH:16]2>>[Cl:11][C:12]1[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]2[C:13]=1[C:14]([OH:23])([C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10])[C:15](=[O:22])[NH:16]2
Reactant: O=C1Nc2ccc(Cl)c(Cl)c2C1=O
Reactant: COc1ccc(C)cc1Br
Product: COc1ccc(C)cc1C1(O)C(=O)Nc2ccc(Cl)c(Cl)c21
Yield: 52.4 %

Procedure:
With 3.02 g of 2-bromo-1-methoxy-4-methyl benzene and 1.50 g of 4,5-dichloroisatin as starting materials, 1.23 g of the title compound (yellow solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].C(C1C[N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:10][N:9]1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH:3]([CH:2]1[CH2:1][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:10][N:9]1[C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])=[CH2:4]
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C=O)C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=CC1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
n-Butyl lithium (2.5M solution in hexane, 4.0 mL, 10 mmol) was added to a suspension of methyltriphenylphosphonium bromide (4.19 g, 11.7 mmol) in THF (100 mL) at −78° C. After 10 min., the reaction mixture was allowed to warm to rt. After 1 h, the reaction mixture was cooled to −78° C., and a solution of 1-benzyl 4-tert-butyl 2-formylpiperazine-1,4-dicarboxylate (3.07 g, 8.81 mmol) in THF (10 mL) was added dropwise. After 2 h, the reaction mixture was allowed to warm to rt and was quenched with NH4Cl (saturated, aqueous solution). The reaction mixture was diluted with water (100 mL) and was extracted with EtOAc (3×150 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chomatography (0 to 20% EtOAc in Hexane gradient) gave 2.33 g (76%) of the desired product as a thick oil. Rf=0.35 in 30% EtOAc/Hexane. LC-MS: RT=10.1 min., [M+H]+=369.1.