Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][C:15]1[N:19]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:18]([CH3:29])=[C:17]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH:16]=1>C(O)C.O1CCCC1.O.NN>[NH2:3][CH2:12][CH2:13][CH2:14][C:15]1[N:19]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:18]([CH3:29])=[C:17]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH:16]=1
Reactant: Cc1c(C(=O)OCc2ccccc2)cc(CCCN2C(=O)c3ccccc3C2=O)n1CCc1ccc(F)cc1
Agent: NN
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)OCc2ccccc2)cc(CCCN)n1CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 1.364 g portion of benzyl 5-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxylate was dissolved in a mixed solvent of 10 ml ethanol and 10 ml tetrahydrofuran, and 0.139 ml of hydrazine monohydrate was added, followed by stirring at room temperature for 24 hours. Then, 0.252 ml of hydrazine monohydrate was added, followed by stirring at 50° C. for 5 hours. Further, 0.252 ml of hydrazine monohydrate was added, followed by stirring at 50° C. for 20 hours. The reaction liquid was cooled to room temperature and then filtered through celite. The filtrate was concentrated under a reduced pressure, chloroform was added to the residue, and the resulting precipitate was removed by celite-filtration. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (Chromatorex (registered trademark), ethyl acetate) to obtain 850 mg of benzyl 5-(3-aminopropyl)-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxylate as a colorless oil.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[N:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[N:8]1[CH:13]=[CH:12][C:11]([NH:14][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:10][CH:9]=1
Reactant: Nc1ccncc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccncc1
Temperature: 20 °C
Reaction time: 6 h
Yield: 41.8 %

Procedure:
A solution of pivaloyl chloride (13.4 g, 111 mmol) in DCM (20 mL) was slowly added to a cooled (0° C.) solution of pyridin-4-amine (10 g, 106 mmol) and triethylamine (26.7 g, 265 mmol) in DCM (80 mL). After addition, the icebath was removed and the resulting mixture was stirred at 20° C. for 6 hours. The mixture was poured into water (100 mL) and extracted with DCM (3×100 mL). The combined organic extract was washed with saturated NaHCO3 solution (100 mL) and brine (100 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was re-crystallized from EtOAc/petroleum ether to give the desired product as white crystals (7.9 g, 40% yield). LCMS (ESI) m/z: 179.1 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[N:10]=[N:9]1>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[N:10]=[N:9]1
Reactant: CCOC(=O)c1cn(-c2ccccc2F)nn1
Solvent: O
Solvent: CCO
Product: O=C(O)c1cn(-c2ccccc2F)nn1
Temperature: 60 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
Ethyl 1-(2-fluorophenyl)-1H-1,2,3-triazole-4-carboxylate (110 mg) was dissolved in ethanol (3 ml)-water (2 ml)-1M aqueous sodium hydroxide solution (1 ml) and the mixture was stirred at 60° C. for 12 hr. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water, neutralized (pH:2) with 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (92 mg).
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:8]=[C:9]2[C:32](=[CH:33][CH:34]=1)[C:13]1=[N:14][O:15][C:16]([C:17]3[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)=[C:12]1[CH2:11][CH2:10]2)[C:3]([O:5][CH3:6])=[O:4].ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O.CC1(C)N([O])C(C)(C)CCC1>ClCCl>[O:1]=[C:2]([C:7]1[CH:8]=[C:9]2[C:32](=[CH:33][CH:34]=1)[C:13]1=[N:14][O:15][C:16]([C:17]3[C:21]([C:22]([F:23])([F:25])[F:24])=[C:20]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[O:19][N:18]=3)=[C:12]1[CH2:11][CH2:10]2)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(O)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: ClCCl
Product: COC(=O)C(=O)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.4 %

Procedure:
To methyl 2-hydroxy-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetate (Preparation 134A, 260 mg, 0.55 mmol) in dichloromethane (5 mL) was added 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (193 mg, 0.83 mmol). The reaction mixture was stirred for 5 min. at room temperature. The reaction mixture was cooled to 0° C. and TEMPO (12.95 mg, 0.083 mmol) was added. The reaction mixture was warmed up to room temperature and was stirred for 1 h. The layers were separated and the organic phase was washed with sat. aq. sodium bicarbonate (5 mL) followed by 1N hydrochloric acid (5 mL) and brine (5 mL). The organic layer was dried and concentrated to provide methyl 2-oxo-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetate (250 mg, 0.53 mmol, 97% yield): LC/MS M+1=470.02; 1H NMR (400 MHz, CDCl3) δ ppm 8.16-8.22 (1H, m), 8.01-8.08 (2H, m), 7.77 (2H, d, J=7.48 Hz), 7.53-7.68 (3H, m), 4.03 (3H, s), 3.15 (4H, s).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(Cl)(Cl)Cl.[C:31](=[O:34])([O-])[O-:32].[Na+].[Na+].[Cl-:37]>O>[C:31]([N:17]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:18]1[CH:19]=[CH:20][C:21]([C:22]([Cl:37])=[O:24])=[CH:25][CH:26]=1)([O:32][CH2:22][C:21]1[CH:25]=[CH:26][CH:18]=[CH:19][CH:20]=1)=[O:34]
Reactant: O=C([O-])[O-]
Reactant: [Cl-]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCN(C(=O)OCc1ccccc1)c1ccc(C(=O)Cl)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To 15 g. of 4-(n-hexadecylamino)benzoic acid in 200 ml. warm chloroform is added 15 g. sodium carbonate in 150 ml. water. To the vigorously stirred solution is added 10 g. carbobenzoyl chloride. After 2 hours stirring at 40° C., the layers are separated, washed three times with 1N hydrochloric acid, dried, and evaporated to an oil. The oil is dissolved in 300 ml. toluene, treated with 15 ml. of thionyl chloride, and the solution is refluxed for 5 hours. The solvents are evaporated and the residue is dissolved three times in toluene, evaporating each time to yield a viscous, orange oil.
Reaction SMILES: N[C@@H:2]([CH:6](C)C)[C@H:3](O)[CH3:4].[NH2:9][C@@H:10]([CH:19]([CH3:21])[CH3:20])[C@@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12].C([O-])([O-])=O.[Na+].[Na+].C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.CCCCCC>[CH3:20][CH:19]([CH3:21])[C@H:10]([N:9]1[CH2:4][CH2:3][CH2:2][CH2:6]1)[C@@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12]
Reactant: CC(C)[C@H](N)[C@@H](C)O
Reactant: CC(C)[C@H](N)[C@H](O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)[C@@H]([C@H](O)c1ccccc1)N1CCCC1
Yield: 86 %

Procedure:
Repeat Step (a) of EXAMPLE 1, but replace (2R,3S)-3-amino-4-methylpentan-2-ol with (1R,2S)-2-amino-3-methyl-1-phenylbutan-1-ol, and replace Na2CO3 (1.16 g, 11.0 mmol) with K2CO3 (1.52 g, 11.0 mmol). Column chromatography (Silica gel, eluent is n-Hexane:EtOAc=10:1) is used to purify the coarse product and a slightly-yellow liquid (1.00 g) is obtained. The yield is 86% and the other analysis includes:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19]([C:21]1([C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)[CH2:23][CH2:22]1)=[O:20])[CH3:17].C(=O)(O)[O-].[Na+]>COCCOC.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>[CH2:16]([O:18][C:19]([C:21]1([C:24]2[CH:29]=[CH:28][C:27]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]=[O:15])=[CH:4][CH:3]=3)=[CH:26][CH:25]=2)[CH2:22][CH2:23]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C=O)cc3)cc2)CC1
Temperature: 85 °C

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (0.5 g, 1.88 mmol) was mixed with 1-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester (0.72 g, 2.07 mmol) and sodium bicarbonate (0.553 g, 6.58 mmol) in DME (5 mL) and H2O (2.5 mL). The reaction was purged with N2 (g) then bis(triphenylphosphine)palladium(II) dichloride (0.066 g, 0.094 mmol) was added and the reaction was heated to 85° C. overnight. After cooling to room temperature the reaction was submitted to standard aqueous workup the purified by silica gel chromatograph (0-20% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:13]([CH3:14])=[C:12](O)[C:11]2[C:6](=[C:7]([F:20])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)[N:5]=1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>O1CCCC1>[CH3:3][C:4]1[C:13]([CH3:14])=[C:12]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:11]2[C:6](=[C:7]([F:20])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)[N:5]=1
Reactant: Cc1nc2c(F)cc(C(C)(C)C)cc2c(O)c1C
Reactant: CCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)c(C)nc2c(F)cc(C(C)(C)C)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In tetrahydrofuran (10 ml) was suspended 60% sodium hydride (60 mg). The compound 1 (200 mg) was added to the suspension under ice cooling, and the mixture was stirred for 30 min. Further, ethyl chloroformate (200 μl) was added thereto, and the mixture was stirred for 3 hr. The reaction solution thus obtained was poured into ice water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed under the reduced pressure. The crude product was purified by chromatography on silica gel (Wako Gel C-200, elution solvent: n-hexane-ethyl acetate (3:1)) to give 2,3-dimethyl-6-t-butyl-8-fluoro-4-ethoxycarbonyl-quinoline (compound 7, 220 mg).
Reaction SMILES: [C:1]1([S:7]([N-:10][C:11](=[O:16])[CH2:12][CH2:13][CH:14]=C)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:18].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[C:1]1([S:7]([N:10]2[CH:11]([OH:16])[CH2:12][CH2:13][C:14]2=[O:18])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CCCC(=O)[N-]S(=O)(=O)c1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1CCC(O)N1S(=O)(=O)c1ccccc1
Reaction time: 0.33 h
Yield: 40.5 %

Procedure:
50 mg of osmium tetraoxide is added to a solution of 5 g of N-benzenesulphonyl-4-pentenoylamide in 150 cm3 of dioxan and 50 cm3 of water. After about 20 minutes, 5.10 g of sodium metaperiodate is added, and after agitating for 1 hour, a further 5.10 g of sodium metaperiodate is added, with agitation for a further 2 hours at ambient temperature. The precipitate formed is filtered off, the filtrate is evaporated to dryness and the residue is dissolved in 50 cm3 of ethyl acetate, treated with activated charcoal, then evaporated to dryness. The residue is triturated in anhydrous ethyl ether, and 2.05 g of the expected product is obtained, which is re-crystallizxed from isopropanol m.p. 121° C.
Reaction SMILES: [C:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][CH:10](O)[CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][C:5]=1[OH:22])(=[O:3])[CH3:2].[O-][CH2:24]C.[Na+].[Na].C(O)C.C(OCC)(=O)[C:32]([O:34]CC)=[O:33]>C1C=CC=CC=1>[C:32]([CH:10]([CH2:11][O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:9][O:8][C:7]1[CH:6]=[C:5]2[C:4]([C:1](=[O:3])[CH:2]=[CH:24][O:22]2)=[CH:21][CH:20]=1)([OH:34])=[O:33]
Reactant: CC[O-]
Reactant: CC(=O)c1ccc(OCC(O)COc2ccccc2)cc1O
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na+]
Agent: [Na]
Solvent: c1ccccc1
Solvent: CCO
Product: O=C(O)C(COc1ccccc1)COc1ccc2c(=O)ccoc2c1

Procedure:
A solution of 1-(4-acetyl-3-hydroxyphenoxy)-2-hydroxy-3-phenoxy-propane (6.04 g) in diethyl oxalate (15 ml) was added to a suspension of sodium ethoxide, prepared from sodium (3.0 g) and ethanol (30 ml), in benzene (50 ml). The mixture was heated under reflux for 1.5 hours, then cooled and filtered. The residual yellow sodium salt was washed with ether, dried, and dissolved in a mixture of glacial acetic acid (80 ml) and concentrated hydrochloric acid (30 ml). This solution was heated under reflux for 1 hour, cooled, and poured with stirring into cold water (500 ml). The precipitated solid (6.0 g) was filtered off and crystallized from methanol to give 1-(2-carboxychromon-7-yloxy-3-phenoxypropane (4.3 g) as an off-white solid, m.p. 222°-223.5°.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:17]3[C:12]([C:13]([NH2:18])=[N:14][CH:15]=[N:16]3)=[C:11]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:35][N:36]([CH3:40])[C:37](Cl)=[O:38]>>[NH2:18][C:13]1[C:12]2=[C:11]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:10]=[C:9]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[CH2:2][NH:1][C:37](=[O:38])[N:36]([CH3:40])[CH3:35])[N:17]2[N:16]=[CH:15][N:14]=1
Reactant: CN(C)C(=O)Cl
Reactant: NCc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Product: CN(C)C(=O)NCc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Yield: 14 %

Procedure:
Using a procedure similar to that of Example 5 with 7-(3-aminomethyl-phenyl)-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and dimethylcarbamyl chloride as starting materials, 32 mg (14%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 4.3 (d, 2 H), 2.8 (s, 6 H); ES-MS m/z 517.3 [M+H]+, HPLC RT (min) 2.75.
Reaction SMILES: Br[CH2:2][C:3]([O:5]C(C)(C)C)=[O:4].[O:10]=[C:11]1[NH:20][CH:19]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][C:22]=2[S:29]([CH3:32])(=[O:31])=[O:30])[C:18]2[C:17](=[O:33])[CH2:16][CH2:15][CH2:14][C:13]=2[N:12]1[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)C(O)=O>CN(C)C=O.O>[C:25]([C:24]1[CH:27]=[CH:28][C:21]([CH:19]2[C:18]3[C:17](=[O:33])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[CH:35]=3)[C:11](=[O:10])[N:20]2[CH2:2][C:3]([OH:5])=[O:4])=[C:22]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:23]=1)#[N:26]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cc(C#N)ccc1C1C2=C(CCCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1CC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl bromoacetate (200 L, 1.35 mmol) is added to a mixture of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-3-(methylsulfonyl)benzonitrile (example 18, 440 mg, 0.90 mmol) and cesium carbonate (440 mg, 1.35 mmol) in N,N-dimethylformamide (5 mL), and the mixture is stirred at room temperature for 3 h. Another portion of tert-butyl bromoacetate (200 μL, 1.35 mmol) is added, and the mixture is stirred for 2 h. Water is added, and the mixture is extracted with ethyl acetate. The phases are separated and the organic layer is concentrated under reduced pressure. The residue is dissolved in acetonitrile (3 mL), and the mixture is treated with trifluoroacetic acid (10 mL, 123 mmol) and stirred at room temperature for 6 h. All volatiles are removed under reduced pressure, and the residue is directly used in the next step without further purification. Yield: 460 mg.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:15][C:14]([C:16](=[O:18])[CH3:17])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[CH3:19][CH:20]([CH2:23][CH3:24])[CH2:21][NH2:22]>>[CH3:19][CH:20]([CH2:23][CH3:24])[CH2:21][NH:22][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:15][C:14]([C:16](=[O:18])[CH3:17])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[N:7]=1
Reactant: CCC(C)CN
Reactant: CC(=O)c1ccc(-c2cnc3ccc(F)nn23)s1
Product: CCC(C)CNc1ccc2ncc(-c3ccc(C(C)=O)s3)n2n1

Procedure:
Prepared as in example 5.6.3 from 1-[5-(6-fluoro-imidazo[1,2-b]pyridazine-3-yl)-thiophen-2-yl]-ethanone (50 mg, 0.2 mmol) and racemic 2-methylbutylamine [96-15-1] (42 mg, 0.5 mmol). Purification by preparative RP-HPLC provided 1-{5-[6-(2-methyl-butylamino)-imidazo[1,2-b]pyridazin-3-yl]-thiophen-2-yl}-ethanone as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.88-1.01 (m, 5H) 1.19-1.30 (m, 1H) 1.50-1.61 (m, 4H) 1.89 (dq, J=13.29, 6.74 Hz, 1H) 2.54 (s, 2H) 3.26-3.33 (m, 1H) 3.40-3.49 (m, 1H) 4.57 (t, J=5.73 Hz, 1H) 6.43-6.47 (m, 1H) 7.21 (s, 1H) 7.56-7.58 (m, 1H) 7.61-7.67 (m, 2H) 7.90 (s, 1H). LRMS (ESI) m/z 329.1 [(M+H)]+, calc'd for C17H20N40S: 328.44.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][NH2:11])[CH:7]=[CH:8][CH:9]=1.[F:14][C:15]([F:20])([F:19])[CH:16]1[O:18][CH2:17]1>>[F:1][C:2]([F:12])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][NH:11][CH2:17][CH:16]([OH:18])[C:15]([F:20])([F:19])[F:14])[CH:7]=[CH:8][CH:9]=1
Reactant: FC(F)(F)C1CO1
Reactant: NCc1cccc(OC(F)(F)F)c1
Product: OC(CNCc1cccc(OC(F)(F)F)c1)C(F)(F)F
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 36.8 %

Procedure:
EX-632A) 3-Trifluoromethoxybenzenemethanamine (1.15 g, 6 mmol) and 1,1,1-trifluoro-2,3-epoxypropane (0.67 g, 6 mmol) were combined and stirred at 80° C. for 1.5 h. The mixture was cooled to room temperature, and the resulting solid was recrystallized from hot hexanes. The white solid was isolated by vacuum filtration and washed with cold hexanes to give 0.67 g (37%) of pure 3-[[[3-(trifluoromethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol. 1H NMR (CDCl3) δ 7.37 (t, 1H), 7.24 (d, 1H), 7.15 (m, 2H), 3.99 (m, 1H), 3.85 (d, 2H), 2.98 (dd, 1H), 2.88 (dd, 1H), 2.79 (s, 1H). 19F NMR (CDCl3) δ −58.19 (s, 3F), −78.88 (s, 3F). HRMS calcd. for C11H11F6NO2: 304.0772 [M+H]+, found: 304.0794.
Reaction SMILES: C[O:2][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][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[NH2:34][C@@H:35]([CH3:42])[CH2:36][CH2:37][NH:38][CH:39]([CH3:41])[CH3:40].C(O)(=O)C>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]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:5]3[C:3](=[O:2])[N:34]4[C@@H:35]([CH3:42])[CH2:36][CH2:37][N:38]([CH:39]([CH3:41])[CH3:40])[C@@H:32]4[CH2:31][N:6]3[CH:7]=2)=[O:30])=[CH:28][CH:27]=1
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Reactant: CC(C)NCC[C@H](C)N
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)N1CC[C@H](C)N2C(=O)c3c(OCc4ccccc4)c(=O)c(C(=O)NCc4ccc(F)cc4)cn3C[C@@H]12
Yield: 56.3 %

Procedure:
The title compound was made in two steps using a similar process to that described in example Z-2. 16 (27 mg, 0.060 mmol) and free based [(3S)-3-aminobutyl](1-methylethyl)amine (67 mg, 0.51 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4S,12aS)—N-[(4-fluorophenyl)methyl]-4-methyl-1-(1-methylethyl)-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (18 mg, 56%) as a film. This material was hydrogenated in a second step as described in example Z-2 to give (4S,12aS)—N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylethyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (15 mg, >1.00%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 1.02 (d, J=6.4 Hz, 3H), 1.07 (d, J=6.4 Hz, 3H), 1.32 (d, J=6.8 Hz, 3H), 1.54-1.58 (m, 1H), 1.94-2.03 (m, 1H), 2.71-2.76 (m, 1H), 2.82-2.88 (m, 1H), 3.13-3.16 (m, 1H), 4.16-4.19 (m, 1H), 4.30-4.33 (m, 1H), 4.48 (m, 1H), 4.55-4.65 (m, 2H), 4.97-5.00 (m, 1H), 6.97-7.01 (m, 2H), 7.30-7.34 (m, 2H), 8.28 (s, 1H), 10.51 (m, 1H), 12.55 (s, 1H); ES+ MS: 443 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:19]=[CH:18][C:10]([O:11][CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][NH:14]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33].O.ClCCl>ClCCl>[CH3:35][O:34][C:32](=[O:33])[CH2:31][CH2:30][N:14]1[CH2:15][CH2:16][CH2:17][C@@H:13]1[CH2:12][O:11][C:10]1[CH:18]=[CH:19][C:7]([O:6][C:5]2[CH:20]=[CH:21][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)CCBr
Reactant: Clc1ccc(Oc2ccc(OC[C@H]3CCCN3)cc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCN1CCC[C@@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 30 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of Example 18 (step 4) (0.8 g, 2.63 mmol) in dichloromethane (7.6 mL) was added triethylamine (0.78 mL, 5.60 mmol) and methyl 3-bromopropionate (0.32 mL, 2.93 mmol). The resulting solution was stirred at 30° C. overnight. The reaction mixture was poured into water/dichloromethane (50 mL/50 mL). The crude residue was extracted into dichloromethane. The organic portion was washed with water (50 mL), washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography using hexane/EtOAc (gradient system) to give the title compound (0.79 g, 77%).