Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][CH2:5][CH2:6]Cl.C[O-].[Na+].[CH2:12]([SH:15])[CH:13]=[CH2:14]>O>[CH3:1][O:2][C:3](=[O:8])[CH2:4][CH2:5][CH2:6][S:15][CH2:12][CH:13]=[CH2:14]
Reactant: COC(=O)CCCCl
Reactant: C=CCS
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: C=CCSCCCC(=O)OC

Procedure:
Into a 1 liter flask equipped with cooling bath, thermometer, reflux condenser and addition funnel as well as electric stirrer is placed 68.2 grams of methyl-4-chlorobutyrate. The methyl-4-chlorobutyrate is cooled to 20° C. The mixture of sodium methoxide and allyl mercaptan is added to the addition funnel. Over a period of 0.5 hours while maintaining the pot temperature at 20°-30° C., the mixture of allyl mercaptan and sodium methoxide is added slowly to the methyl-4-chlorobutyrate with stirring. The reaction is exothermic and requires slight cooling. At the end of the addition of the mixture of allyl mercaptan and sodium methoxide, the reaction mass is stirred for 1 hour and the temperature of the reaction mass is permitted to rise to 38° C. 500 ml water are then added to the reaction mass and the reaction mass is transferred to a separatory funnel. The reaction mass is then extracted with three 50 ml portions of methylene dichloride and dried over anhydrous sodium sulfate and filtered. The reaction mass is then distilled on a micro Vigreux column yielding the following fractions:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]3[N:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][C:11]3=[N:12][C:13]=2[CH:14]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(O)C.O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]3[N:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][C:11]3=[N:12][C:13]=2[CH:14]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc3cc(NC(C)=O)ccc3c(=O)n2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1ccc2c(=O)n3nc(C(=O)O)ccc3nc2c1

Procedure:
A mixture of methyl 7-acetylamino-10-oxo-10H-pyridazino [6, 1-b]-quinazoline-2-carboxylate (0.38 g, 1.22 mmol, Example 4, Step B) and 0.5M sodium carbonate solution (6.0 mL, 3.0 mmol), Example 4, Step B) and 0.5M sodium carbonate solution (6.0 mL, 3.0 mmol) in 100 mL of THF:ethanol:water (1:1:2) was gently refluxed for 3 h. The resultant solution was filtered through a pad of Celite, concentrated, redissolved into water, acidified to a pH~ 1.5-2.0 with 10% hydrochloric acid and cooled. Solid formed, the mixture was filtered and washed with water, acetone and diethyl ether to give the titled compound as a dark yellow solid, mp 272°-275° C. dec
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[C@H:6]([CH:7]=[O:8])[C@:5]1([CH3:23])[C:9]1[CH:18]=[CH:17][C:16]2[C:15]([CH3:20])([CH3:19])[CH2:14][CH2:13][C:12]([CH3:22])([CH3:21])[C:11]=2[CH:10]=1.CC12C(C)(C)C(C(OC[C@H]3[C@H](COC)[C@@]3(C)C3C=CC4C(C)(C)CCC(C)(C)C=4C=3)=O)(CC1)OC2=O>>[CH3:1][O:2][CH2:3][C@H:4]1[C@H:6]([CH:7]=[O:8])[C@:5]1([CH3:23])[C:9]1[CH:18]=[CH:17][C:16]2[C:15]([CH3:20])([CH3:19])[CH2:14][CH2:13][C:12]([CH3:22])([CH3:21])[C:11]=2[CH:10]=1
Reactant: COC[C@@H]1[C@H](C=O)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: COC[C@H]1[C@H](COC(=O)C23CCC(C)(C(=O)O2)C3(C)C)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: COC[C@H]1[C@H](C=O)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 84 %

Procedure:
Following a procedure similar to that for the preparation of Intermediate 12a but using Intermediate 10a as the starting material afforded the title compound (23 mg, 84% yield) as a colorless oil:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:19][CH:20]=[CH:21][CH2:22][CH2:23]Br>>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:23][CH:22]=[CH:21][CH2:20][Br:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrC=CCCBr
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(O)ccc21
Product: CC(C)(C)OC(=O)N1CCCc2cc(OCC=CCBr)ccc21

Procedure:
In analogy to example 2.2, 6-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester and 1,4-dibromobutene were converted to yield 6-(4-Bromo-but-2-enyloxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester as colorless oil, MS: 381 (M, 1Br);
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=3)[S:17][C:10]=12.[ClH:25].FC1C=C(N[C:51]([NH:53][C:54](=[O:62])[CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[O:52])C=CC=1OC1C=CN=C2C=C(C(N3CCCC3)=O)SC=12>>[ClH:25].[ClH:25].[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:51]([NH:53][C:54](=[O:62])[CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)=[O:52])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=3)[S:17][C:10]=12
Reactant: O=C(Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccnc3cc(C(=O)N4CCCC4)sc23)c(F)c1
Reactant: Cn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Agent: Cl
Product: Cn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC(=O)Cc5ccccc5)cc4F)c3s2)c1
Yield: 54 %

Procedure:
Starting from the compound 177 (scheme 35) and following the procedure described above for the synthesis of compound 305a, title compound 305c was obtained in 54% yield as a white solid. 1H NMR (d-DMSO) δ (ppm): 11.08(s, 1H), 10.67(s, 1H), 8.66 (d, 1H, J=6.2 Hz), 8.26(s, 1H), 8.21(s, 1H), 7.93(s, 1H), 7.85(dd, 1H, J1=12.9 Hz, J2=2.5 Hz), 7.53(t, 1H, J=8.8 Hz), 7.65(s, 1H), 7.48-7.45(m, 1H), 7.35-7.30(m, 4H), 7.28-7.24(m, 1H), 6.94(d, 1H, J=6.1 Hz), 3.79(s, 3H), 3.75(s, 2H). MS (m/z): 502.1(M+H) (found).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])=[CH:20][CH:19]=1>CN1C(=O)CCC1>[Cl:16][C:12]1[CH:11]=[C:10]([C:4]2[N:3]=[C:2]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])=[CH:22][CH:23]=3)[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(CO)c1ccc(N)cc1
Reactant: CCc1cc(Cl)nc(-c2cccc(Cl)c2)n1
Solvent: CN1CCCC1=O
Product: CCc1cc(Nc2ccc(C(C)(C)CO)cc2)nc(-c2cccc(Cl)c2)n1
Yield: 59.6 %

Procedure:
Following General Procedure A1, 4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.075 g, 0.29 mmol) in NMP (3 mL) was reacted with 2-(4-aminophenyl)-2-methylpropan-1-ol (0.054 g, 0.33 mmol) to afford the title compound (0.066 g, 88%) as a light yellow solid. MW=381.91. 1H NMR (DMSO-d6, 500 MHz) δ 9.54 (s, 1H), 8.35-8.28 (m, 2H), 7.63 (d, J=8.6 Hz, 2H), 7.58-7.55 (m, 2H), 7.42-7.32 (m, 2H), 6.59 (s, 1H), 4.64 (t, J=5.4 Hz, 1H), 3.42 (d, J=5.4 Hz, 2H), 2.66 (q, J=7.6 Hz, 2H), 1.32-1.18 (m, 9H); APCI MS m/z 382 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8]([CH2:10][CH2:11][CH3:12])[NH:7][C:6](=[O:13])[CH:5]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8]([CH2:10][CH2:11][CH3:12])[N:7]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[C:6](=[O:13])[CH:5]=1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCc1nc(COC)cc(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCc1nc(COC)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
A mixture of 6-(methoxymethyl)-2-propylpyrimidin-4(3H)-one (17 g), 4′-(bromomethyl)biphenyl-2-carbonitrile (27 g) and potassium carbonate (25 g) in acetonitrile (300 mL) was stirred overnight at 50° C. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale yellow solid (15 g, 43%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[CH3:12].C([O:16][C@@H:17]1[C@@H:30]([O:31]C(=O)C)[C@H:29]([O:35]C(=O)C)[CH2:28][S:27][C@H:18]1[O:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24](Br)[CH:25]=1)(=O)C>>[O:19]([C:20]1[CH:21]=[N:22][CH:23]=[C:24]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:12])[CH:5]=2)[CH:25]=1)[C@@H:18]1[S:27][CH2:28][C@@H:29]([OH:35])[C@H:30]([OH:31])[C@H:17]1[OH:16]
Reactant: COc1ccc(B(O)O)cc1C
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Product: COc1ccc(-c2cncc(O[C@@H]3SC[C@@H](O)[C@H](O)[C@H]3O)c2)cc1C

Procedure:
By following a procedure analogous to Example 122 starting from 4-methoxy-3-methylphenylboronic acid and 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, 5-(4-methoxy-3-methylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=21%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:35][C:36]1[CH:45]=[CH:44][C:43]([F:46])=[C:42]2[C:37]=1[CH:38]=[C:39](OS(C(F)(F)F)(=O)=O)[N:40]=[CH:41]2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([C:39]4[N:40]=[CH:41][C:42]5[C:37]([CH:38]=4)=[C:36]([Br:35])[CH:45]=[CH:44][C:43]=5[F:46])[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Oc1cc2c(Br)ccc(F)c2cn1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4cc5c(Br)ccc(F)c5cn4)c3)cn2)CC1
Temperature: 100 °C

Procedure:
To a solution of 4-{4-[6-amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB3) (370 mg, 0.67 mmol), trifluoromethanesulfonic acid 5-bromo-8-fluoroisoquinolin-3-yl ester (250 mg, 0.67 mmol), and Pd(PPh3)4 (40 mg, 0.03 mmol) in 1,4-dioxane (8.0 mL) in a sealable microwave tube was added a solution of Cs2CO3 (440 mg, 1.3 mmol) in H2O (2 mL). The tube was sealed, evacuated and refilled with nitrogen (3×), and heated in the microwave reactor to 100° C. for 30 minutes. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with 5% 7M NH3 in MeOH and DCM. One obtained the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=1.24-1.35 (m, 4H), 1.49 (s, 9H), 1.93-2.06 (m, 2H), 2.19 (d, J=2.3 Hz, 1H), 2.86-2.96 (m, 1H), 6.55 (br. s., 2H), 7.17 (dd, J=9.4, 8.3 Hz, 1H), 7.68 (s, 1H), 7.80 (s, 1H), 7.95 (dd, J=8.3, 4.8 Hz, 1H), 8.00 (d, J=2.3 Hz, 1H), 8.31 (s, 1H), 8.32 (d, J=2.3 Hz, 1H), 9.57 (s, 1H). MS (ES+): m/z=566.87/567.69 [MH+]. HPLC: tR=3.08 min (ZQ2, polar—5 min).
Reaction SMILES: [Mg].[Si:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1Br)([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[B:17](OC)([O:20]C)[O:18]C.Cl>C1COCC1.C(OC)(C)(C)C>[O:9]([C:10]1[CH:15]=[CH:14][C:13]([B:17]([OH:20])[OH:18])=[CH:12][CH:11]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: COB(OC)OC
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1Br
Agent: Cl
Agent: [Mg]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Temperature: 25 °C

Procedure:
Magnesium turnings (0.53 g, 22 mmol) and 20 mL of THF were placed into a two-necked flask. Next, tert-butyldimethylsilyloxyphenyl bromide (5.64 g, 19.6 mmol) was added and the mixture was heated under reflux for 2 h before it was cooled to room temperature. The brown mixture was added to a solution of trimethyl borate (2.43 g, 24 mmol) in 5 mL of THF through a dropping funnel at −78° C. and allowed to warm to room temperature overnight. After hydrolysis with 90 mL of ca. 0.1 M hydrochloric acid followed by standard work-up with methyl tert-butyl ether, the brown residue was washed with 20 mL of cold hexane, and the resulting white product (3.86 g, 78%) was dried in vacuo. Mp: 175° C. (1H NMR (300 MHZ, CDCl3): δ0.25 (s, 6H); 1.01 (s, 9H); 6.95 (d, J=8.5 Hz, 2H); 8.11 (d, J 8.5 Hz, 2H). 13C NMR (75 MHZ, CDCl3): δ−4.3; 18.1; 25.7; 119.8; 137.5; 159.8. Reference: Bolm, C.; Derrien, N.; Seger, A. Synlett 1996, 387.
Reaction SMILES: [CH3:1][C:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][C:5]1([CH3:37])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26]C(=O)OC(C)(C)C)=[CH:25][C:19]=3[S:18](=[O:35])(=[O:34])[N:17]=2)[C:6]1=[O:36].[ClH:40]>O1CCOCC1>[Cl:40][NH:26][C:24]1[CH:23]=[CH:22][C:20]2[NH:21][C:16]([C:7]3[C:6](=[O:36])[C:5]([CH2:4][CH2:3][C:2]([CH3:1])([CH3:38])[CH3:39])([CH3:37])[C:14]4[C:9]([C:8]=3[OH:15])=[CH:10][CH:11]=[CH:12][CH:13]=4)=[N:17][S:18](=[O:35])(=[O:34])[C:19]=2[CH:25]=1
Reactant: CC(C)(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Reactant: Cl
Solvent: C1COCCO1
Product: CC(C)(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NCl)ccc3N2)=C(O)c2ccccc21
Yield: 93 %

Procedure:
A solution of Example 42E (1.91 g, 3.45 mmol) in 4 M hydrochloric acid in 1,4-dioxane (30 mL) was stirred at 25° C. for 1 hour. The solution was concentrated in vacuo and the residue was triturated in diethyl ether to give 1.58 g (93%) of a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 0.38 (td, J=12.87, 3.68 Hz, 1H) 0.78 (m, 10H) 1.59 (s, 3H) 2.08 (m, 1H) 2.23 (td, J=12.78, 4.60 Hz, 1H) 7.07 (m, 2H) 7.53 (m, 2H) 7.77 (m, 2H) 8.16 (d, J=7.72 Hz, 1H) 13.58 (s, 1H); MS (ESI+) m/z 454 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1>C(#N)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:6]2[CH:7]=[C:2]([Br:1])[N:3]=[CH:4][C:5]2=[O:8])=[CH:12][CH:13]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=c1cnc(Br)c[nH]1
Solvent: CC#N
Product: O=c1cnc(Br)cn1Cc1ccc(Cl)cc1
Yield: 86.7 %

Procedure:
According to Scheme 27 Step 1: The title compound was prepared from 5-bromopyrazin-2(1H)-one (1 eq, 2.86 mmol, 0.50 g) and 1-(bromomethyl)-4-chlorobenzene (1.5 eq, 4.29 mmol, 0.88 g) according to the procedure described for Example 1 Step 2. Reaction conditions: 3 hours at 70° C. in acetonitrile. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 25 g SiO2) using pure AcOEt as eluent to afford 1-(4-chlorobenzyl)-5-bromopyrazin-2(1H)-one (2.48 mmol, 0.74 g, 87%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[CH2:15][NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:25]([O:32][C:33]([NH:35][C@@H:36]([C:39](O)=[O:40])[CH2:37][OH:38])=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1C=CC2N(O)N=NC=2C=1.O.CCN(CC)CC.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[CH2:15][N:16]([C:37](=[O:38])[C@@H:36]([CH2:39][OH:40])[NH:35][C:33]([O:32][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:34])[CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(N[C@H](CO)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(F)c(CNCCc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(F)c(CN(CCc2ccccc2)C(=O)[C@@H](CO)NC(=O)OCc2ccccc2)c1
Yield: 41.1 %

Procedure:
According to the procedure of Preparation 4(c), except using tert-butyl 4-fluoro-3-[(phenethylamino)methyl]benzoate (5.00 g, 15.2 mmole), N-(benzyloxycarbonyl)-D-serine (3.83 g, 16 mmole), HOBt.H2O (2.16 g, 16 mmole), Et3N (2.24 mL, 16 mmole), EDC.HCl (3.07 g, 16 mmole), and 1:1 DMF/CH2Cl2 (75 mL), the title compound (3.44 g, 41%) was prepared as a thick oil following flash chromatography on silica gel (40% EtOAc/hexanes): 1H NMR (300 MHz, DMSO-d6) mixture of amide rotamers δ 7.31-8.18 (m, 2 H), 7.19-7.29 (m, 11 H), 4.86-5.11 (m, 4 H), 4.33-4.79 (m, 3 H), 3.49-3.80 (m, 4 H), 1.51 (s, 9 H).
Reaction SMILES: [CH:1]12[C:13](=O)[CH:10]([CH2:11][CH2:12]1)[CH2:9][C:8]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:2]2.[C:15]1([S:21]([NH2:24])(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[CH:1]12[C:13](=[N:24][S:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:23])=[O:22])[CH:10]([CH2:11][CH2:12]1)[CH2:9][C:8]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:2]2
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C1C2CCC1Cc1ccccc1C2
Solvent: Cc1ccccc1
Product: O=S(=O)(N=C1C2CCC1Cc1ccccc1C2)c1ccccc1

Procedure:
Tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-one (130 mg, 0.70 mmol) and benzenesulfonamide (110 mg, 0.70 mmol) were mixed in toluene (6 mL). Amberlyst-15 ion exchange resin (35 mg) was added, and the mixture was heated at reflux under Dean Stark conditions for 36 h. The mixture was concentrated and the crude sulfonylimine was used directly in the next step.
Reaction SMILES: Cl[Mg][CH2:3][C:4]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH2:5].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[C@@H:22]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15].[Cl-].[NH4+]>C1COCC1>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][C@@:23]([OH:27])([CH2:3][C:4](=[CH2:5])[CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:22]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: C=C(COc1ccccc1)C[Mg]Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)[C@@H]1c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C(COc1ccccc1)C[C@]1(O)CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-(chloromagnesio)-2-(phenoxymethyl)-1-propene in THF (0.91M, 3 ml) (Louw et. al., Tetrahedron, 48, 6087-6104, 1992, prepared from 2.74 mmol of 3-chloro-2-(phenoxymethyl)-1-propene) was slowly added to a solution of (2S)-1-tert-butoxycarbonyl-2-phenylpiperidin-3-one (Preparation 1) in THF (3 ml). The mixture was stirred at room temperature for 1 hours, then saturated aqueous ammonium chloride (20 ml) was added and the mixture was extracted with ethyl acetate (20 ml). The organic phase was washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane/ethyl acetate (100:0 increasing to 80:20) to give the title compound. 1H NMR (360MHz, CDCl3) δ7.48 (2H, d, J=6.9 Hz), 7.35-7.2 (6H, m), 6.9-6.88 (3H, m), 5.4 (1H, s), 5.15 (2H, d, J=13.7 Hz), 4.61 (2H, s), 4.11 (2H, m), 3.17 (1H, m), 2.66 and 2.59 (2H, AB d, J=14.0 Hz), 1.95 (2H, m), 1.79 (2H, m), and 1.36 (9H, s). m/z (ES+) 424 (M+1).
Reaction SMILES: NCCCOC1C=CC(C(N2CCC([N:18]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:19]3=[O:20])CC2)=O)=CC=1.C(=O)C1C=CC=CC=1.B.[Na]>CO>[NH:18]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][C:19]1=[O:20]
Reactant: NCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Agent: B
Agent: [Na]
Solvent: O=Cc1ccccc1
Solvent: CO
Product: O=C1CCc2ccccc2N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 201.7 %

Procedure:
A mixture of 1-{1-[4-(3-aminopropoxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (1.4 g), benzaldehyde (0.42 ml) and methanol (15 ml) is stirred at room temperature for 3 hours and cooled with ice. Thereto is added sodium boron hydride (0.21 g) and the mixture is stirred under ice cooling for 2 hours and then allowed to stand a room temperature overnight. The solvent is distilled off and water is added to the resulting residue and the mixture is extracted with ethyl acetate. The extract is washed successively with saturated sodium hydrogen carbonate, water and saline solution, dried with sodium sulfate and then the solvent is distilled off. The resulting residue is purified by silica gel column chromatography (solvent: methanol:dichloromethane=1:100) to give 1-{1-[4-benzylaminopropoxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (1.02 g).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:13][N:14]1[CH2:19][CH2:18][C:17]([C:21]2[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=2)([CH3:20])[CH2:16][CH2:15]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:11][C:9]1[C:8]([F:12])=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([C:17]3([CH3:20])[CH2:16][CH2:15][N:14]([CH3:13])[CH2:19][CH2:18]3)=[CH:22][CH:23]=2)[N:10]=1
Reactant: NC(=O)c1cc(F)c(Cl)nc1Cl
Reactant: CN1CCC(C)(c2ccc(N)cc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCC(C)(c2ccc(Nc3nc(Cl)c(F)cc3C(N)=O)cc2)CC1
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
To a solution of 2,6-dichloro-5-fluoronicotinamide (287 mg, 1.372 mmol) and 4-(1,4-dimethylpiperidin-4-yl)aniline (267 mg, 1.307 mmol) in THF (10 mL) was added lithium bis(trimethylsilyl)amide (4.57 mL, 4.57 mmol) at room temperature. After 30 min, the reaction was quenched by the addition of satd. NH4Cl. The mixture was extracted with methylene chloride twice, the combined organic layers were washed with water and brine, and then concentrated. The residue was purified by MPLC (ISCO, 6-10% ammonia/methanol/methylene chloride, 40 g silica gel column) to give 229 mg of product as yellow solid.
Reaction SMILES: [N:1]1([C:7]([C@@H:9]2[CH2:14][C@H:13]([N:15](S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH2:16][CH2:17][CH3:18])[CH2:12][N:11]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O.[OH-].[Li+].C(O)CS>CN(C=O)C.C(=O)(O)[O-].[Na+]>[N:1]1([C:7]([C@@H:9]2[CH2:14][C@H:13]([NH:15][CH2:16][CH2:17][CH3:18])[CH2:12][N:11]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCCN([C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: OCCS
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.5 %

Procedure:
tert-Butyl (3R,5S)-3-(morpholin-4-ylcarbonyl)-5-{[(2-nitrophenyl)sulfonyl](propyl)amino}piperidine-1-carboxylate (4.02 g) and lithium hydroxide monohydrate (1.56 g) were dissolved in DMF (20 ml), thioglycol acid (1.3 ml) was added at room temperature, and the mixture was stirred for 2 days at room temperature. The reaction mixture was diluted with aqueous sodium bicarbonate, 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. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:9-10:0) was concentrated under reduced pressure. The residue was diluted with 10% aqueous citric acid solution, and washed with ethyl acetate. The aqueous layer was neutralized with aqueous sodium bicarbonate and 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 (1.89 g).