Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:11][C@:10]([CH3:16])([C:12]([F:15])([F:14])[F:13])[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32]Br)=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][N:11]2[C:4]3=[N:3][C:2]([Cl:1])=[CH:7][C:6](=[O:8])[N:5]3[CH2:9][C@@:10]2([CH3:16])[C:12]([F:13])([F:14])[F:15])=[CH:29][CH:30]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(Cl)cc2=O)N1
Reactant: BrCCc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(Cl)cc2=O)N1CCc1ccc(OCc2ccccc2)cc1
Temperature: 120 °C

Procedure:
A mixture of 40 mL of DMF, 2 g (7.89 mmol) of (S)-7-chloro-2-methyl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one, 3.44 g (11.84 mmol) of 1-benzyloxy-4-(2-bromoethyl)benzene and 5.14 g (15.78 mmol) of cesium carbonate is heated in a Biotage microwave reactor at 120° C. for 20 minutes. The reaction medium is evaporated to dryness. After purification by chromatography on silica gel (eluent A/B: heptane/EtOAc, gradient A/B: t 0 min 20% B, t 25 min 50% B, t 35 min 50% B), 2.8 g of (S)-1-[2-(4-benzyloxyphenyl)ethyl]-7-chloro-2-methyl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one were obtained, corresponding to the following characteristics:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.O=[CH:7][CH2:8][CH2:9][C:10]1[S:14][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:12][C:11]=1[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[S:31][C:32]2[C:37]([N:38]=1)=[CH:36][CH:35]=[CH:34][N:33]=2)=[O:22].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[C:15]1([C:13]2[S:14][C:10]([CH2:9][CH2:8][CH2:7][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:11]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[S:31][C:32]4[C:37]([N:38]=3)=[CH:36][CH:35]=[CH:34][N:33]=4)=[O:22])[N:12]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C1CCNC1
Reactant: O=CCCc1sc(-c2ccccc2)nc1C(=O)Nc1ccccc1-c1nc2cccnc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: O=C(Nc1ccccc1-c1nc2cccnc2s1)c1nc(-c2ccccc2)sc1CCCN1CCCC1
Reaction time: 1 h
Yield: 31.2 %

Procedure:
Pyrrolidine (88 μL, 1.06 mmol) was added to a solution of 5-(3-oxopropyl)-2-phenyl-N-(2-(thiazolo[5,4-b]pyridin-2-yl)phenyl)thiazole-4-carboxamide (250 mg, 0.53 mmol) and AcOH (127 mg, 2.1 mmol) in dichloroethane (DCE) (10 mL). The reaction mixture was stirred for 1 h. Sodium triacetoxyborohydride (449 mg, 2.1 mmol) was added and stirring continued for 16 h. The reaction mixture was poured into sat aq NaHCO3 and extracted with DCM. The combined organics were washed with brine, dried (MgSO4), and concentrated. The crude product was purified by MPLC eluting with CH2Cl2/MeOH+1% TEA(0-10% gradient) to give the title compound (87 mg, 31% yield). MS Calcd for C29H27N5OS2: 525.17. Found (M+H)+ m/z=526.
Reaction SMILES: [OH-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][N:16]([CH:19]([CH3:27])[CH2:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24])[CH2:15][CH2:14]1.Cl>C(O)C>[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:14][CH2:15][N:16]([CH:19]([CH3:27])[CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:17][CH2:18]1
Reactant: COC(=O)CCCC(C)N1CCN(c2ccc3ccccc3n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(CCCC(=O)O)N1CCN(c2ccc3ccccc3n2)CC1
Yield: 89.3 %

Procedure:
To 10 ml of 1N sodium hydroxide:ethanol=1:1 solution, 850 mg of methyl 5-(4-quinolin-2-ylpiperazin-1-yl)hexanoate as synthesized in above Step 7-14-B was added and heated under reflux for an hour. Cooling the system, 2N hydrochloric acid was added to make the pH7, and the precipitate was recovered by filtration and dried to provide 728 mg (89%) of 5-(4-quinoline-2-ylpiperazin-1-yl)hexanoic acid.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2B(O)O)=[CH:4][CH:3]=1.[CH2:23]([O:25][C:26](=[O:40])[C:27]1[C:32]([NH2:33])=[CH:31][CH:30]=[C:29]([C:34]2[CH2:38][CH2:37][CH2:36][C:35]=2Br)[CH:28]=1)[CH3:24]>>[CH2:23]([O:25][C:26](=[O:40])[C:27]1[C:32]([NH2:33])=[CH:31][CH:30]=[C:29]([C:34]2[CH2:38][CH2:37][CH2:36][C:35]=2[C:9]2[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][C:5]2[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=2)[CH:28]=1)[CH3:24]
Reactant: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccc(F)cc1
Reactant: CCOC(=O)c1cc(C2=C(Br)CCC2)ccc1N
Product: CCOC(=O)c1cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccc(F)cc3)CCC2)ccc1N

Procedure:
Prepared by general procedure C(iii) but using 2-(4-fluorobenzyloxy)-5-trifluoromethylphenylboronic acid instead of 2-(benzyloxy)-5-chlorophenylboronic acid and 3-(2-bromocyclopent-1-enyl)-6-aminobenzoic acid ethyl ester instead of 3-(2-bromo-cyclopent-1-enyl)-6-methylbenzoic acid ethyl ester.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH:15](OCC)=[O:16]>C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([CH:15]=[O:16])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CCNCc1cccs1
Reactant: CCOC=O
Solvent: Cc1ccccc1
Product: CCOC(=O)CCN(C=O)Cc1cccs1
Yield: 99.9 %

Procedure:
Ethyl 3-[(thiophen-2-ylmethyl)amino]propionate (13.8 g) prepared in the step 1 and 47.8 g of ethyl formate were dissolved in 100 mL of toluene and heated to reflux overnight. After the reaction solution was cooled, the solvent was evaporated therefrom in vacuo to give 15.6 g of the objective compound as light yellow liquid.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[C:4]([O:10][C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)=[CH:3][CH:2]=1>C(O)C(N)(CO)CO.Cl>[N+:7]([C:5]1[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=1[OH:10])([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccccc1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: Cl
Agent: NC(CO)(CO)CO
Product: O=[N+]([O-])c1ccccc1O

Procedure:
Cells were harvested in 100 μl of 0,25 M Tris-HCl (pH 8); 80 μl were assayed for CAT activity by liquid scintillation counting using the same procedure as in in vitro translation assays, as described in the Technical Bulletin #084 from Promega, whereas 20 μl was used for assaying the β-galactosidase activity, with a colorimetric assay in which o-nitrophenyl β-D-galacto-side (ONPG) is cleaved to produce o-nitrophenol, as described in a standard protocol (Miller J. H. (1972) Experiments in Molecular Genetics, Cold Spring Harbor Laboratory Press, New-York, pp 352-355).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([C:21]2[NH:22][C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:15]=1>CN(C1C=CN=CC=1)C.ClCCl>[Br:13][C:14]1[CH:19]=[CH:18][C:17]2[O:20][C:1](=[O:2])[N:22]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[CH:29]=[C:21]3[C:16]=2[CH:15]=1
Reactant: Oc1ccc(Br)cc1-c1cc2ccccc2[nH]1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=c1oc2ccc(Br)cc2c2cc3ccccc3n12
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
Carbonyldiimidazole (490 mg, 2 mmol) and DMAP (50 mg) were added to a solution of 4-bromo-2-(1H-indol-2-yl)phenol (576 mg, 2 mmol) in 20 mL of dichloromethane and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane, washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (hexane/EtOAc 20:1) provided 2-bromo-6H-benzo[5,6][1,3]oxazino[3,4-a]indol-6-one as light yellow powder (500 mg, 79.6%). 1H-NMR (CDCl3, 400 MHz) δ 8.49 (d, J=8.4 Hz, 1H), 7.96 (s, 1H), 7.70 (d, J=7.2 Hz, 1H), 7.41˜7.53 (m, 3H), 7.22 (d, J=8.8 Hz, 1H), 7.07 (s, 1H). MS (M+H)+: 314/316.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].Br[C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=1>>[Cl:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Cl
Reactant: Cc1cc(C)nc(Br)c1
Product: Cc1cc(C)nc(-c2cc(C)c(Cl)c(C)c2)c1

Procedure:
The title compound is prepared from 2-chloro-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 2-bromo-4,6-dimethyl-pyridine following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 7): tR=0.89 min; Mass spectrum (ESI+): m/z=246/248 (Cl) [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[O:8])[CH2:3][CH2:2]1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26].O>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:10]1[N:11]=[C:12]([NH:14][C:25]([C:21]2[O:20][CH:24]=[CH:23][CH:22]=2)=[O:26])[S:13][C:9]=1[C:7]([CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:8]
Reactant: Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Reactant: O=C(Cl)c1ccco1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1)c1ccco1
Temperature: 50 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
Compound 454 (556 mg, 2.00 mmol) and DMAP (24.4 mg, 0.200 mmol) were suspended in pyridine (8 mL), and 2-furoyl chloride (0.394 mL, 4.00 mmol) was added thereto, followed by stirring at 50° C. for 2 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=19:1), followed by recrystallizing from ethanol to afford the entitled Compound 511 (491 mg, 66%) as a white solid.
Reaction SMILES: [S:1]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)[C@@H:2]1[S:10][CH2:9][C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]>CO.[Pd]>[S:1]([C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1)[C@@H:2]1[S:10][CH2:9][C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: O=[N+]([O-])c1ccc(S[C@@H]2SC[C@@H](O)[C@H](O)[C@H]2O)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(S[C@@H]2SC[C@@H](O)[C@H](O)[C@H]2O)cc1
Reaction time: 24 h
Yield: 45.7 %

Procedure:
170 mg of 10% palladium-on-charcoal are added to a solution of 1.7 g (5.61.10-3 mol) of 4-nitrophenyl 1,5-dithio-β-D-xylopyranoside in 150 ml of methanol. The reaction medium is kept under hydrogen pressure (3.5.105Pa) at room temperature for 3 days. Repeat amounts of 170 mg of 10% palladium-on-charcoal are added after stirring for 3 hours, 4 hours, 12 hours and 24 hours. The mixture obtained is filtered, the solvent is evaporated off under reduced pressure and the residue obtained is purified by flash chromatography using a CHCl3 /CH3OH mixture (9/1 v/v) as the eluent, and is then recrystallized from water to give 0.7 g (yield: 46%) of the expected product.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C@@H:25]1[C@H:31]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:30]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@H:29]([CH3:48])[O:28][C@H:26]1[OH:27])(=[O:3])[CH3:2].[Cl:49][C:50]([Cl:54])([Cl:53])[C:51]#[N:52].C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[Cl:49][C:50]([Cl:54])([Cl:53])[C:51]([O:27][C@@H:26]1[O:28][C@@H:29]([CH3:48])[C@H:30]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@@H:31]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@H:25]1[O:24][C@@H:6]1[O:7][C@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:5]1[NH:4][C:1](=[O:3])[CH3:2])=[NH:52]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CC(=O)N[C@H]1[C@H](O[C@@H]2[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](C)O[C@H]2O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)N[C@H]1[C@H](O[C@H]2[C@H](OC(=N)C(Cl)(Cl)Cl)O[C@@H](C)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
The hemiacetal 320 (541 mg, 0.80 mmol) was dissolved in CH2Cl2 (20 mL), placed under argon and cooled to 0° C. Trichloroacetonitrile (0.810 mL, 8 mmol), then DBU (10 μL, 80 μmol) were added. The mixture was stirred at 0° C. for 1 h. The mixture was concentrated and toluene was co-evaporated from the residue. The residue was eluted from a column of silica gel with 1:1 cyclohexane-EtOAc and 0.2% of Et3N to give 307 (560 mg, 86%) as a colourless foam; [α]D+20 (c 1, CHCl3). 1H NMR: δ 8.56 (s, 1H, NH), 7.50-7.20 (m, 10H, Ph), 6.29 (d, 1H, J1,2=1.3 Hz, H-1A), 5.50 (d, 1H, J2,NH=8.3 Hz, NHD), 5.17 (pt, 1H, J2,3=J3,4=9.5 Hz, H-3D), 5.09 (dd, 1H, J4,5=9.5 Hz, H-4D), 4.85-4.60 (m, 4H, CH2Ph), 4.68 (d, 1H, J1,2=8.0 Hz, H-1D), 4.22-4.10 (m, 2H, J5,6=5.0, J6a,6b=12.2 Hz, H-6aD, 6bD), 4.00 (m, 1H, H-2D), 3.99 (dd, 1H, J2,3=3.5 Hz, H-2A), 3.90 (dq, 1H, J4,5=9.6, J5,6=6.2 Hz, H-5A), 3.89 (dd, 1H, J3,4=9.5 Hz, H-3A), 3.62 (m, 1H, H-5D), 3.50 (dd, 1H, H-4A), 2.02, 2.00, 1.98 (3s, 9H, OAc), 1.65 (s, 3H, NHAc), 1.32 (d, 3H, H-6A); 13C NMR: δ 171.2, 171.0, 170.4, 169.6 (C═O), 160.5 (C═NH), 138.2-128.0 (Ph), 103.3 (C-1D), 97.3 (C-1A), 91.4 (CCl3), 80.3 (C-4A), 79.9 (C-3A), 77.5 (C-2A), 76.0, 73.8 (2C, CH2Ph), 73.1 (C-3D), 72.2 (C-5D), 71.1 (C-5A), 68.8 (C-4D), 62.5 (C-6D), 54.8 (C-2D), 23.3 (NHAc), 21.4, 21.1, 21.0 (3C, OAc), 18.4 (C-6A). Anal. Calcd for C36H43Cl3N2O13: C, 52.85; H, 5.30; N, 3.42. Found: C, 52.85; H, 5.22; N, 3.47.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][CH:5]1[CH2:8][C:7](=[O:9])[C:6]1(Cl)Cl>CC(O)=O.[Zn]>[CH3:1][O:2][C:3](=[O:12])[CH2:4][CH:5]1[CH2:8][C:7](=[O:9])[CH2:6]1
Reactant: COC(=O)CC1CC(=O)C1(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: COC(=O)CC1CC(=O)C1
Temperature: 100 °C
Reaction time: 15 h
Yield: 36.2 %

Procedure:
To a solution of (2,2-dichloro-3-oxo-cyclobutyl)-acetic acid methyl ester (2.93 g, 13.8 mmol) in AcOH (100 ml), zinc powder (4.51 g, 69.0 mmol) is added. The mixture is stirred at 100° C. for 15 hours. The mixture is filtrated and washed with AcOH. The filtrate is concentrated under reduced pressure, and the residue is dissolved in AcOEt, and washed with saturated aqueous NaHCO3 and brine. The organic layer is dried over MgSO4, and concentrated under reduced pressure to give (3-oxo-cyclobutyl)-acetic acid methyl ester (710 mg, 36%); 1H NMR (400 MHz, chloroform-d) δ ppm 2.64-2.66 (m, 2H), 2.78-2.86 (m, 3H), 3.22-3.32 (m, 2H), 3.70 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]([CH:13]=O)[C@@H:9]([CH3:12])[CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([NH2:27])[CH:21]=[CH:20]2.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].O>ClCCCl>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]([CH2:13][NH:27][C:22]1[CH:21]=[CH:20][C:19]2[C:24](=[CH:25][CH:26]=[C:17]([Br:16])[CH:18]=2)[CH:23]=1)[C@@H:9]([CH3:12])[CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc2cc(Br)ccc2c1
Reactant: CC[C@H](C)[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CC[C@H](C)[C@@H](CNc1ccc2cc(Br)ccc2c1)NC(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 84.5 %

Procedure:
((1S,2S)-1-Formyl-2-methyl-butyl)-carbamic acid tert-butyl ester (1.62 g, 7.5 mmol), and 6-bromo-naphthalen-2-ylamine (1.11 g, 5.0 mmol) were combined in DCE (10 mL). After stirring 5 min, NaBH(OAc)3 (2.33 g, 11 mmol) was added. The whole mixture was then stirred at r.t. for 18 h. The reaction mixture was transferred to a separatory funnel containing water (50 mL). The aqueous layer was extracted with DCM (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered and concentrated. The residue was purified via column chromatography on silica gel (10% ethyl acetate in hexanes) to afford {(1S,2S)-1-[(6-bromo-naphthalen-2-ylamino)-methyl]-2-methyl-butyl}-carbamic acid tert-butyl ester (1.78 g, 85% yield) as an off-white solid. LC/MS (ESI) m/e 423.2 [(M+H)+, calcd for C21H29BrN2O2 421.4].
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH2:23]1[O:31][C:30]2[CH:29]=[CH:28][C:27]([CH2:32][O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]Cl)=[CH:26][C:25]=2[O:24]1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][O:33][CH2:32][C:27]3[CH:28]=[CH:29][C:30]4[O:31][CH2:23][O:24][C:25]=4[CH:26]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: ClCCCCCOCc1ccc2c(c1)OCO2
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCOCc2ccc3c(c2)OCO3)CC1
Yield: 39.8 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (0.72 g) as starting compound and 5-((3,4-methylenedioxyphenyl)methoxy)pentyl chloride (0.5 g) were reacted and treated in the same manner as in Example 168 to give 0.4 g of 4-amino-5-chloro-N-((1-(5-((3,4-methylenedioxyphenyl)methoxy)pentyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.Cl.[NH:12]1[CH2:15][CH2:14][CH2:13]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[N:12]1([C:6]([C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=2)=[O:8])[CH2:15][CH2:14][CH2:13]1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(Cl)nc1)N1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.7 %

Procedure:
Commercially available 6-chloronicotinic acid (160 mg, 1.01 mmol) was dissolved in dichloromethane (5 mL), and azetidine hydrochloride (130 mg, 1.39 mmol), HATU (420 mg, 1.10 mmol) and N,N-diisopropylethylamine (0.50 mL, 2.87 mmol) were added, followed by stirring at room temperature overnight under nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=40%-50%) to afford the desired compound (210 mg, yield ˜100%) as a colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([N+:28]([O-])=O)[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:23])[C:12]([O:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1.[NH4+].[Cl-]>C1COCC1.CO.[Zn]>[F:1][C:2]1[CH:27]=[C:26]([NH2:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:23])[C:12]([O:14][CH2:15][CH2:16][N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(N)cc3F)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a solution of 4-(2-fluoro-4-nitrophenoxy)-5-methyl-6-(2-morpholinoethoxy)pyrrolo[2,1-f][1,2,4]triazine (54 mg, 0.13 mmol) in a mixture of 0.8 mL of THF and 1.2 mL of MeOH were added NH4Cl (70 mg, 1.3 mmol) and Zn powder (85 mg, 1.3 mmol). The suspension was allowed to stir at room temperature for 2 h. Both HPLC analysis and LC-MS analysis indicated the completion of the reaction and the solid was thus filtered off. After concentration of the filtrate, the residue was taken into 10% MeOH in CH2Cl2. The solution was then filtered again and the filtrate was concentrated in vaco to provide the title compound (50 mg, 92%). MS(ESI+) m/z 388.4 (M+H)+.
Reaction SMILES: [O-]CC.[Mg+2].[O-]CC.[C:8]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:9][C:10]([O:12]CC)=O.[F:19][C:20]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:21]=1C(Cl)=O>C(OCC)C>[F:19][C:20]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:21]=1[C:10]([CH2:9][C:8]([O:16][CH2:17][CH3:18])=[O:15])=[O:12]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(Cl)c1cc(F)c(F)cc1F
Agent: CC[O-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CCOC(=O)CC(=O)c1cc(F)c(F)cc1F

Procedure:
On the other hand, a suspension of magnesium ethoxide and 3.1 g of diethyl malonate in 30 ml of anhydrous diethyl ether was refluxed for 1 hour. To the cooled suspension was added dropwise 15 ml of an anhydrous diethyl ether solution of 2,4,5-trifluorobenzoyl chloride obtained above with stirring. The resulting mixture was stirred at room temperature for 1 hour. After acidification with diluted hydrochloric acid, the mixture was extracted with 150 ml of ethyl acetate (50 ml×3). The extract was dried over sodium sulfate, and the solvent was removed by distillation. The resulting residue was dissolved in 50 ml of dioxane and a catalytic amount of p-toluenesulfonic acid was added thereto. The mixture was refluxed for 24 hours and, after cooling, the reaction mixture was neutralized with an aqueous sodium bicarbonate solution and extracted with 200 ml of chloroform. The extract was dried over sodium sulfate, and the solvent was removed. The residue was subjected to silica gel column chromatography and 2.1 g of ethyl 2,4,5-trifluorobenzoylacetate was yielded from benzene eluate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:10]=1[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-:20].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.O>CN(C=O)C>[Br:20][C:15]1[C:14]([O:18][CH3:19])=[C:10]([C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12]
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1C(=O)O
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(Br)ccc(NC(=O)OC(C)(C)C)c1C(=O)O
Reaction time: 18 h

Procedure:
A mixture of Example 151A (730 mg, 2.7 mmol) and tetrabutylammonium tribromide (1.3 g, 2.7 mmol) in DMF (15 mL) was treated dropwise with water (15 mL), stirred for 18 hours, and partitioned between water (250 mL) and ethyl acetate (250 mL). The organic phase was concentrated, diluted with dichloromethane (250 mL), washed with water (7×250 mL) and brine, dried (Na2SO4), filtered, concentrated and purified on silica gel with dichloromethane to provide the desired product. MS (ESI(+)) m/e 363, 365 (M+NH4)+, 368, 370 (M+Na)+; (ESI(−)) m/e 344, 346 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 13.50 (br s, 1H), 8.92 (s, 1H), 7.65 (d, 1H), 7.36 (d, 1H), 3.79 (s, 3H), 1.44 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.Cl.Cl.[CH3:18][N:19]([CH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([NH2:28])[CH2:24][CH2:23]1)[CH3:20]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:28][C@H:25]1[CH2:26][CH2:27][C@H:22]([CH2:21][N:19]([CH3:20])[CH3:18])[CH2:23][CH2:24]1
Reactant: CN(C)C[C@H]1CC[C@H](N)CC1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Agent: Cl
Product: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (256 mg, 0.90 mmol) was reacted with trans-4-((dimethylamino)methyl)cyclohexanamine dihydrochloride (320 mg, 1.40 mmol) to afford the desired product (149 mg, 70%) as a light orange solid. ESI MS m/z 404 [C20H26BrN3O+H]+