Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NO.[CH:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Zn][CH2:14][CH3:15])C.[C:16](OC(=O)C)(=[O:18])[CH3:17]>CCCCCC.CCOCC.C1(C)C=CC=CC=1>[C:16]([O:10][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:14][CH3:15])(=[O:18])[CH3:17]
Reactant: CC[Zn]CC
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1ccccc1
Agent: NO
Solvent: CCCCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCC(OC(C)=O)c1ccccc1
Reaction time: 72 h
Yield: 86 %

Procedure:
To a vial containing aminoalcohol 1 (0.05 g, 0.17 mmol) prepared as in Example 1 was added a solution containing benzaldehyde (0.32 g, 3.0 mmol), toluene (3.0 mL), and 1 M diethylzinc in hexane (6.0 mL). After 3 days at room temperature, acetic anhydride (1.2 mL, 13 mmol) was added. After 2 additional days, the mixture was diluted in ether (50 mL) and the reaction was quenched by dropwise addition of half-saturated aqueous ammonium chloride (50 mL). The ether layer was separated and the aqueous layer was further extracted with ether (2×50 mL). The combined ether layers were dried over magnesium sulfate whereupon the solvent was removed at reduced pressure. The residue was purified by flash chromatography on 220-400 mesh silica with 90% hexane and 10% ethyl acetate as eluant. The product (+)-1-phenylpropyl acetate (0.46 g, 86%) was isolated as a colorless liquid by distillation of the solvent at reduced pressure. Anal. for C11H14O2. Calcd: C, 74.13; H, 7.92; found: C, 74.32; H, 7.82. 1H NMR (CDCl3/TMS): δ0.87 (t, 3 H, J=7), 1.79, (m, 1 H), 1.90 (m, 1 H), 2.06 (s, 3 H), 5.66 (t, 1 H, J=7), 7.1-7.7 (m, 5 H). 13C NMR (CDCl3/TMS): δ9.89, 21.23, 29.30, 77.66, 126.76, 128.81, 128.57, 140.58, 170.36. [α]D25=+103.4, c=2.15 g/100 mL chloroform. Chiral capillary gas chromatographic analysis at 120° C. on Cyclodex B stationary phase (J & W Scientific) indicated that the enantiomeric excess of the product was 98%.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[O:6][C:7]([F:10])([F:9])[O:8][C:4]=2[CH:3]=1.C([Li])CCC.S(=O)=O.[S:21](Cl)([Cl:24])(=[O:23])=[O:22]>CCOCC>[F:9][C:7]1([F:10])[O:6][C:5]2[CH:11]=[CH:12][C:2]([S:21]([Cl:24])(=[O:23])=[O:22])=[CH:3][C:4]=2[O:8]1
Reactant: FC1(F)Oc2ccc(Br)cc2O1
Reactant: O=S(=O)(Cl)Cl
Agent: O=S=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=S(=O)(Cl)c1ccc2c(c1)OC(F)(F)O2
Temperature: -30 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
A solution of 2.37 g (10 mmol) 5-bromo-2,2-difluoro-1,3-benzodioxole in 25 ml anhydrous ether, cooled to −30° C., and 4 ml (10 mmol) n butyllithium (2.5 M in hexanes) was added at −30° C., over 10 minutes. The mixture was stirred at −30° C. for 1 hour, then sulfur dioxide gas was passed through the mixture at −20° C. for 5 minutes. The mixture then was allowed to warm up to 20° C., and the precipitate was filtered and washed with 20 ml hexane. The solid was suspended in 20 ml hexanes, 1.35 g (10 mmol) sulfuryl chloride was added, the mixture was stirred at 20° C. for 48 hours. The mixture then was filtered and the filtrate was concentrated under reduced pressure to obtain 1.6 g (62%) title compound. The product was used in the next step without further purification. 1H-NMR (CDCl3): δ 7.27 (1H,d), 7.74 (1H,s), 7.88 (1H,d).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)[CH2:19][C:20]([OH:22])=[O:21].N1CCCCC1.Cl>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH:11]=[CH:19][C:20]([OH:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc(Br)ccc1OCc1ccccc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cc(Br)ccc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 2-benzyloxy-5-bromobenzaldehyde (0.10 mol), malonic acid (15.0 g), and piperidine (2.0 ml) in 150 ml of pyridine was first heated at 90° C. for 90 min and subsequently refluxed for 0.5 hrs. After cooling to room temperature, the reaction was poured on a mixture of ice (1 kg) and concentrated aqueous hydrochloric acid (250 ml). The solid material that precipitated after stirring for 2 hrs. was collected by suction and recrystallized from a minimum of boiling methanol.
Reaction SMILES: [C:1]1([C:7]2[NH:12][CH2:11][CH:10](COS(C3C=CC(C)=CC=3)(=O)=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][NH:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.[Cl:33][C:34]1C=CC=CC=1>>[ClH:33].[ClH:33].[C:1]1([C:7]2[N:12]([CH3:34])[CH2:11][CH:10]([N:26]([CH3:25])[CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CNC(c3ccccc3)=NO2)cc1
Reactant: CNC1CCCCC1
Product: CN1CC(N(C)C2CCCCC2)ON=C1c1ccccc1
Product: Cl

Procedure:
To 2.0 g. of 3-phenyl-6-tosyloxymethyl-5,6-dihydro-4H-1,2,4-oxadiazine 30 ml. of chlorobenzene and 3 ml. of methylcyclohexyl amine are added and the reaction mixture is refluxed for 6 hours. The mixture is then cooled down and the precipitated product is filtered off, dissolved in ethyl acetate and the solution is acidified with hydrochloric acid in ethanol. 1.1 g. of 3-phenyl-6-(N-methyl-N-cyclohexylamino)-methyl-5,6-dihydro-4H-1,2,4-oxadiazine dihydrochloride are obtained, which has the same properties as the product of Example 2.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[N:6][N:7]([CH:9]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH:10]2[C:18]#[N:19])[CH:8]=1)(=[O:3])[NH2:2].[CH2:28](Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CO>[C:1]([C:4]1[C:5]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)=[N:6][N:7]([CH:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH3:28])=[O:16])[CH2:11][CH:10]2[C:18]#[N:19])[CH:8]=1)(=[O:3])[NH2:2]
Reactant: ClCCCl
Reactant: N#CC1CC(C(=O)O)CCC1n1cc(C(N)=O)c(Nc2ccc(Cl)cc2)n1
Agent: On1nnc2ccccc21
Solvent: CO
Product: COC(=O)C1CCC(n2cc(C(N)=O)c(Nc3ccc(Cl)cc3)n2)C(C#N)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the crude acid (1S,3S,4S and 1R,3R,4R)-4-[4-carbamoyl-3-[(4-chlorophenyl)amino]-1H-pyrazol-1-yl]-3-cyanocyclohexane-1-carboxylic acid (Example #35-1 Step C, 500 mg, 1.3 mmol) in MeOH (5 mL) were sequentially added EDC (324 mg, 1.7 mmol) and HOBt (210 mg, 1.6 mmol). The resulting solution was stirred at ambient temperature overnight before it was concentrated in vacuo. The crude residue was partitioned between DCM (20 mL) and water (5 mL). The organic solution was washed with saturated aqueous NaHCO3 (2×5 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by MPLC on Silica gel (eluting with 2-4% MeOH/DCM) to afford the title compound. 1H NMR (400 MHz, CD3OD) δ 8.13 (s, 1H), 7.55 (d, J=8.8 Hz, 2H), 7.24 (d, J=9.2 Hz, 2H), 4.35-4.28 (m, 1H), 3.74 (s, 3H), 3.52-3.34 (m, 1H), 2.68-2.62 (m, 1H), 2.55-2.52 (m, 1H), 2.24-2.16 (m, 3H), 2.00-1.90 (m, 1H), 1.73-1.70 (m, 1H). MS ESI: [M+H]+ m/z 401.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][C:31]=1[CH3:32])[NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21]CC3C=CC=CC=3)=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][N:10]=1)(=[O:3])[CH3:2]>[Pd].CO.CN(C=O)C.ClC(Cl)Cl>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][C:31]=1[CH3:32])[NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][N:10]=1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.6 %

Procedure:
A mixture of 4-(3-acetoxy-4-methylanilino)-7-benzyloxy-6-methoxyquinazoline (2.68 g, 5.75 mmol) and 10% palladium-on-charcoal catalyst (0.27 g) in methanol (50 ml), DMF (12 ml) and trichloromethane (50 ml) was stirred at ambient temperature under hydrogen at 1.5 atmospheres pressure for 30 minutes. The catalyst was removed by filtration through diatomaceous earth and the solvent removed from filtrate by evaporation. The residue was triturated with ether, collected by filtration and dried under vacuum at 50° C. to give 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline (2.1 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[C:15]([CH3:25])[N:14]=3)=[O:9])=[CH:4][CH:3]=1.[C:28](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[N:14][C:15]([CH3:25])=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH3:28])[CH:11]=2)=[O:9])=[CH:26][CH:27]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1nc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2cc1C#CCO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1nc2c(cc1C#CCO)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
To a mixture of the N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-7-methyl[1,8]naphthyridine-3-carboxamide (0.081 g, 0.212 mmol) and potassium carbonate (0.117 g, 0.848 mmol) in 5 mL DMF is added methyl iodide (0.036 g, 0.254 mmol). The mixture is stirred at room temperature for 30 min then diluted with water. The resulting precipitate is filtered and dried. The crude solid is triturated with EtOAc-hexanes to yield 0.072 g (86%) of the desired product as a pale yellow solid. Physical characteristics are as follows: m.p. 217-218° C.; 1H NMR (DMSO-d6) δ 10.13, 8.99, 8.46, 7.39, 5.47, 4.55, 4.40, 3.99, 2.75; IR (drift) 3395, 1661, 1604, 1561, 1544, 1503, 1413, 1357, 1261, 1032, 1017, 842, 811, 800, 601 cm−1; MS (EI) m/z (rel. intensity) 395 (M+, 8), 255 (29), 229 (17), 228 (99), 198 (41), 169 (14), 140 (54), 89 (15), 77 (14), 73 (22), 73 (17); HRMS (FAB) calcd for C21H18ClN3O3+H1 396.1115, found 396.1121.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:16])[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[NH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][OH:25])[CH2:19][CH2:18]1>>[NH2:14][C:9]1[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]2[O:4][C:3]([CH2:2][N:17]3[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][OH:25])[CH2:19][CH2:18]3)([CH3:16])[CH2:7][C:6]=2[C:8]=1[CH3:15]
Reactant: OCCC1CCNCC1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(CCO)CC1)O2
Yield: 88 %

Procedure:
Using 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine and 4-piperidineethanol, the procedure of Example 1, presented hereinafter, was otherwise repeated to provide the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3N)[CH2:12][CH2:11]2)=[N:2]1.[CH2:25]([N:27](CC)CC)[CH3:26].C(Cl)(=[O:34])C>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([NH:27][C:25](=[O:34])[CH3:26])=[CH:22][CH:23]=3)[CH2:12][CH2:11]2)=[N:2]1
Reactant: CCN(CC)CC
Reactant: Nc1ccccc1CCN1CCN(c2nsc3ccccc23)CC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1
Reaction time: 17 h
Yield: 61 %

Procedure:
A round bottomed flask was charged with 0.528 g (1.5 mmol) (0.2-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-phenylamine, 6.2 mL CH2Cl2, 0.26 mL (1.8 mmol) triethylamine, and 0.15 mL (2 mmol) acetyl chloride. After 17 h at rt, the reaction was quenched with 1M NaHCO3. The organic layer was separated, dried, and concentrated in vacuo to give a white foam. This white foam was triturated with ether to give 0.36 g (61% yield) of the desired material as a white solid. MS (APCI): 381 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=8 Hz, 1H), 7.9 (d, J=8 Hz, 1H), 7.47–7.24 (m, 4H), 7.18–7.14 (m, 3H), 3.59–3.56 (m, 4H), 2.84–2.63 (m, 8H), 2.15 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][C@@H:10]([C@@:14]2([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[NH:20][CH2:19][C:18](=[O:21])[N:17]([CH2:22][C:23]3[C:28]([F:29])=[CH:27][C:26]([F:30])=[CH:25][C:24]=3[F:31])[C:16]3[CH:32]=[CH:33][CH:34]=[CH:35][C:15]2=3)[C:11]([OH:13])=[O:12])[N:3]=1.C(N(CC)CC)C.Cl[CH2:50][C:51]([N:53]([CH3:55])[CH3:54])=[O:52]>CN(C=O)C.CC(=O)OCC>[CH3:54][N:53]([CH3:55])[C:51]([CH2:50][O:12][C:11](=[O:13])[C@@H:10]([O:9][C:4]1[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=1)[C@@:14]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[NH:20][CH2:19][C:18](=[O:21])[N:17]([CH2:22][C:23]2[C:28]([F:29])=[CH:27][C:26]([F:30])=[CH:25][C:24]=2[F:31])[C:16]2[CH:32]=[CH:33][CH:34]=[CH:35][C:15]1=2)=[O:52]
Reactant: Cc1cc(C)nc(O[C@H](C(=O)O)[C@@]2(c3ccccc3)NCC(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc32)n1
Reactant: CN(C)C(=O)CCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(O[C@H](C(=O)OCC(=O)N(C)C)[C@@]2(c3ccccc3)NCC(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc32)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.7 %

Procedure:
A solution of (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-2-oxo-5-phenyl-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]di-azepin-5-yl]-acetic acid (150 mg, 0.266 mmol, Example 107) in DMF (5 ml) is treated with triethylamine (162 mg, 1.60 mmol) and 2-chloro-dimethylacetamide (162 mg, 1.38 mmol). The mixture is stirred at rt for 18 h before it is diluted with EA, washed twice with water, dried over MgSO4 and evaporated. The crude product is purified by chromatography on prep. tlc plates (DCM with 10% methanol) and crystallisation from diethyl ether/hexane to give (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-2-oxo-5-phenyl-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid dimethylcarbamoylmethyl ester (151 mg) as a white powder. LC-MS1: tR=1.10 min, [M+1]+=648.15.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[F:13][C:14]([F:22])([F:21])[CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17].C(N(C(C)C)C(C)C)C.[F:32][C:33]1[CH:34]=[C:35]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[CH:36]=[CH:37][C:38]=1[CH2:39][N:40]1[CH2:45][CH2:44][NH:43][C@H:42]([CH3:46])[CH2:41]1>CN(C)C1C=CN=CC=1.O.ClCCl>[F:32][C:33]1[CH:34]=[C:35]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[CH:36]=[CH:37][C:38]=1[CH2:39][N:40]1[CH2:45][CH2:44][N:43]([C:2]([O:20][CH:15]([C:16]([F:19])([F:18])[F:17])[C:14]([F:22])([F:21])[F:13])=[O:4])[C@H:42]([CH3:46])[CH2:41]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: C[C@@H]1CN(Cc2ccc(N3CCOCC3)cc2F)CCN1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(N3CCOCC3)cc2F)CCN1C(=O)OC(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 134.6 %

Procedure:
A 100 mL round-bottom flask was charged with triphosgene (142 mg, 0.480 mmol, 0.70 equiv), dichloromethane (15 mL), 1,1,1,3,3,3-hexafluoropropan-2-ol (229 mg, 1.36 mmol, 2.00 equiv) and N-ethyl-N-isopropylpropan-2-amine (352 mg, 2.72 mmol, 4.00 equiv) were added at 0° C. The mixture was stirred for 2 h at room temperature. 4-(3-Fluoro-4-[[(3R)-3-methylpiperazin-1-yl]methyl]phenyl)morpholine (200 mg, 0.68 mmol, 1.00 equiv) and 4-dimethylaminopyridine (83.0 mg, 0.680 mmol, 1.00 equiv) were added. The resulting solution was stirred overnight at room temperature, diluted with H2O (10 mL), extracted with dichloromethane (3×10 mL). The organic layers were combined and washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product (500 mg) was purified by preparative HPLC using the following gradient conditions: 20% CH3CN/80% Phase A increasing to 80% CH3CN over 10 min, then to 100% CH3CN over 0.1 min, holding at 100% CH3CN for 1.9 min, then reducing to 20% CH3CN over 0.1 min, and holding at 20% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: Xbridge Prep C18, 19*150 mm 5 um; Mobile phase: Phase A: aqueous NH4HCO3 (0.05%); Phase B: CH3CN; Detector, UV220 & 254 nm. Purification resulted in 315 mg (95% yield) of 1,1,1,3,3,3-hexafluoropropan-2-yl(2R)-4-[[2-fluoro-4-(morpholin-4-yl)phenyl]methyl]-2-methylpiperazine-1-carboxylate as yellow oil. 1H NMR 300 MHz (CDCl3) δ 7.19-7.26 (m, 1H), 6.63-6.67 (m, 1H), 6.53-6.58 (m, 1H), 5.70-5.82 (m, 1H), 4.25 (br, 1H), 3.85 (t, J=4.8 Hz, 5H), 3.49 (s, 2H), 3.20-3.29 (m, 1H), 3.15 (t, J=4.8 Hz, 4H), 2.81 (d, J=10.8 Hz, 1H), 2.65 (d, J=11.4 Hz, 1H), 2.21-2.26 (m, 1H), 2.05-2.13 (m, 1H), 1.30 (d, J=6.6 Hz, 3H). LCMS: (ESI, m/z): 488 [M+H]+.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[CH3:9][NH2:10]>CO>[CH3:8][O:7][C:1](=[O:6])[CH:2]=[C:3]([NH:10][CH3:9])[CH3:5]
Reactant: CN
Reactant: COC(=O)CC(C)=O
Solvent: CO
Product: CNC(C)=CC(=O)OC
Reaction time: 1 h

Procedure:
To a solution of methyl acetoacetate (29.4 g, 253 mmol) in MeOH (30 mL) was added methylamine (33 wt % in EtOH; 48 mL, 385 mmol) dropwise at room temperature. The reaction was stirred for 1 hour, and then concentrated and dried to give the title compound as a white crystalline solid.
Reaction SMILES: [O:1]=[C:2]1[N:11]2[N:12]=[C:13]([C:15](Cl)=[O:16])[CH:14]=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.C([OH:22])CCC.N1C=[CH:27][CH:26]=[CH:25][CH:24]=1>>[O:1]=[C:2]1[N:11]2[N:12]=[C:13]([C:15]([O:16][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])[CH:14]=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1
Reactant: CCCCO
Reactant: c1ccncc1
Reactant: O=C(Cl)c1cc2c3ccccc3[nH]c(=O)n2n1
Product: CCCCOC(=O)c1cc2c3ccccc3[nH]c(=O)n2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4.6 g (0.019 mole) of 5,6-dihydro-5-oxopyrazolo[1,5-c]quinazoline-2-carbonyl chloride in 200 ml of pyridine under nitrogen is added, slowly in a dropwise fashion, a solution of 1.98 g (0.019 mole) of n-butanol. After stirring overnight at room temperature, the reaction mixture is filtered and the filtrate concentrated to a small volume and diluted with cold water. The title compound is filtered off and dried, m.p. 198°-200°.
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:3]1[C:2]([I:1])=[CH:7][N:6]=[C:5]([C:8]([F:11])([F:9])[F:10])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C(F)(F)F)ncc1I
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: FC(F)(F)c1cc(CBr)c(I)cn1

Procedure:
A mixture of 5-iodo-4-methyl-2-(trifluoromethyl)pyridine (39.1 mg, 0.136 mmol), N-bromosuccinimide (29.1 mg, 0.163 mmol), and benzoyl peroxide (3.3 mg, 0.0136 mmol) in CCl4 (1 mL) was heated at reflux under N2 overnight. Water was added and the mixture was extracted with CH2Cl2 (3×20 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 1-5% EtOAc in hexanes gradient) to afford 4-(bromomethyl)-5-iodo-2-(trifluoromethyl)pyridine. Rf=0.41 (10% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 9.03 (s, 1H); 7.76 (s, 1H); 4.51 (s, 3H).
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]([CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:36][CH2:37][NH:38][CH2:39][CH:40]([CH3:42])[CH3:41].C(O)(=O)C>ClCCl>[F:29][C:26]1[CH:27]=[CH:28][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:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[C:5]3[C:3](=[O:2])[N:34]4[C@@H:35]([CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:36][CH2:37][N:38]([CH2:39][CH:40]([CH3:41])[CH3:42])[C@@H:32]4[CH2:31][N:6]3[CH:7]=2)=[O:30])=[CH:24][CH:25]=1
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Reactant: CC(C)CNCC[C@@H](N)CC(C)C
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)C[C@H]1CCN(CC(C)C)[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4)c(=O)c(OCc4ccccc4)c3C(=O)N12
Yield: 24.7 %

Procedure:
The title compound was made in two steps using a similar process to that described in example Z-2. 16 (25 mg, 0.055 mmol) and free based [(3S)-3-amino-5-methylhexyl](2-methylpropyl)amine (21 mg, 0.11 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4S,12aS)—N-[(4-fluorophenyl)methyl]-1,4-bis(2-methylpropyl)-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 (8 mg, 25%) 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-1,4-bis(2-methylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (5 mg, 78%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 0.74 (d, J=6.4 Hz, 3H), 0.84 (d, J=6.4 Hz, 3H), 0.97-1.00 (m, 6H), 1.37-1.66 (m, 5H), 1.75-1.82 (m, 1H), 2.05-2.09 (m, 2H), 2.21-2.26 (m, 1H), 2.72-2.79 (m, 1H), 2.87-2.93 (m, 1H), 4.16-4.26 (m, 2H), 4.38 (m, 1H), 4.55-4.66 (m, 2H), 4.93-4.99 (m, 1H), 6.97-7.02 (m, 2H), 7.31-7.34 (m, 2H), 8.27 (s, 1H), 10.49 (m, 1H), 12.61 (s, 1H); ES+ MS: 499 (M+1).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([OH:22])=O)=[N:18][CH:19]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:23])[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.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>[NH2:23][C@H:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[N:18][C:17]([C:20]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:22])=[CH:16][CH:15]=3)[CH:9]=2)[N:4]([C:1](=[O:3])[CH3:2])[C@@H:5]([CH3:24])[CH2:6]1
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)nc3)cc2[C@H](N)C[C@@H]1C
Reactant: C1COCCN1
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: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCOCC4)nc3)cc2[C@H](N)C[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
5-((2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)picolinic acid (for a preparation, see Intermediate 55) (510 mg, 1.567 mmol), morpholine (0.149 mL, 1.72 mmol), HATU (656 mg, 1.724 mmol) and DIPEA (0.821 mL, 4.70 mmol) were combined in DMF (5 mL) and the mixture stirred at room temperature overnight. Morpholine (0.149 mL, 1.72 mmol) was added and the reaction stirred at room temperature for a further 3 h. The mixture was concentrated in vacuo before being dissolved in DCM and loaded onto an aminopropyl SPE column (50 g). The column was eluted with 10% MeOH in DCM and the appropriate fractions were combined and concentrated in vacuo to give a residue. This residue was purified by chromatography (50 g column, 2M methanolic ammonia/DCM gradient) to give 1-((2S,4R)-4-amino-2-methyl-6-(6-(morpholine-4-carbonyl)pyridin-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone (470 mg, 1.19 mmol, 76% yield) as a beige solid. LCMS: (Formate, 2 min), Rt=0.48 mins, MH+=395.