Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:12]3[CH:13]=[C:14]([C:18]#[C:19][C:20]([OH:26])([CH3:25])[C:21](OC)=[O:22])[C:15]([F:17])=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][N:7]2[CH:27]=1)(=[O:3])[NH2:2].[CH:28]1([NH2:31])[CH2:30][CH2:29]1>CO>[CH:28]1([NH:31][C:21](=[O:22])[C:20]([OH:26])([CH3:25])[C:19]#[C:18][C:14]2[C:15]([F:17])=[CH:16][C:11]3[O:10][CH2:9][CH2:8][N:7]4[CH:27]=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=[C:6]4[C:12]=3[CH:13]=2)[CH2:30][CH2:29]1
Reactant: NC1CC1
Reactant: COC(=O)C(C)(O)C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2
Solvent: CO
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)C(=O)NC1CC1

Procedure:
A solution of methyl 4-(2-carbamoyl-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)-2-hydroxy-2-methylbut-3-ynoate (120 mg, 0.32 mmol, 1.00 equiv) and cyclopropanamine (1.83 g, 32.05 mmol, 99.72 equiv) in methanol (2 mL) was stirred for 12 h at 40° C. The resulting mixture was concentrated under vacuum and the residue was applied onto a silica gel column with dichloromethane/methanol (30:1) to give the titled compound, 23 mg (18%), as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH2:13][CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])C(OCC1C=CC=CC=1)=O>CO.[Pd]>[CH3:1][NH:2][CH2:13][CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17]
Reactant: CN(CCCS(C)(=O)=O)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CNCCCS(C)(=O)=O
Reaction time: 2 h

Procedure:
Ethereal HCl-(22.5 ml, 1 M solution) was added to a stirred solution of N-methyl-N-(3-mesylpropyl)-N-(benzyloxycarbonyl)amine (Method 14; 5 g) in methanol (100 ml). 10% Pd/C (1.25 g) was added and the mixture was stirred under an atmosphere of hydrogen for 2 hrs. The catalyst was removed by filtration and the filtrate evaporated to dryness. Trituration with ether gave the product as a white solid. NMR (DMSO−d6 +d4-acetic acid) 2.11 (m, 2H), 2.59 (s, 3H), 3.0 (s, 3H), 3.05 (t, 2H), 3.26 (t, 2H); m/z 152.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][O:7][CH2:8][C@@H:9]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]([NH2:25])=O)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>C(Cl)Cl>[F:32][C:29]([F:30])([F:31])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[CH2:6][O:7][CH2:8][C@@H:9]([N:16]1[CH2:17][CH2:18][N:19]([CH2:22][C:23]#[N:25])[CH2:20][CH2:21]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NC(=O)CN1CCN([C@H](COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: N#CCN1CCN([C@H](COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 74.1 %

Procedure:
In a round-bottomed flask fitted with a reflux condenser and a thermometer were introduced 3 g (6.13 mmoles) of (S)-2-{4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-piperazin-1-yl}-acetamide dissolved in 30 ml of CH2Cl2 (compound 144 prepared at example 1.4.1 above). The solution was cooled to −78° C. and DMSO (0.7 ml, 9.8 mmoles) and oxalyl chloride (0.6 ml, 7.4 mmoles) were added. After 15 minutes, triethylamine (2.5 ml, 18.4 mmoles) was added dropwise and the reaction mixture was stirred at −70° C. until complete disappearance of the starting material. The reaction was quenched with water and the pH was adjusted to 11 by addition of aqueous NaOH. The aqueous solution was extracted with CH2Cl2 and the combined organic layers were dried over MgSO4 and concentrated. The crude was purified by chromatography on silica gel (eluent: CH2Cl2/MeOH/NH3: 98/2/0.2 v/v/v) to yield (S)-{4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-piperazin-1-yl}-acetonitrile (compound 291, 2.14 g, 73%) as a pale yellow powder which was converted into the dichydrochloride salt by reaction with HCl in diethylether.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][O:29][CH:30]([O:36][CH3:37])[CH2:31][C:32](OC)=[O:33]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32](=[O:33])[CH2:31][CH:30]([O:36][CH3:37])[O:29][CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: COC(=O)CC(OC)OC
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: COC(CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)OC

Procedure:
The title compound, white solid (103 mg, 92%), MS (ISP) m/z=447.4 [(M+H)+], mp 218° C., was prepared in accordance with the general method of example 5 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and methyl 3,3-dimethoxy-propanoate.
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[CH3:27][C:28]1[N:29]2[CH:35]=[N:34][CH:33]=[C:30]2[S:31][CH:32]=1>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:34]3[CH:33]=[C:30]4[S:31][CH:32]=[C:28]([CH3:27])[N+:29]4=[CH:35]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Reactant: Cc1csc2cncn12
Product: Cc1csc2cn(CC3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)c[n+]12
Yield: 22.9 %

Procedure:
The same procedure as in Example 1 was repeated except that 187 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 212 mg of 3-methylimidazo[5,1-b]thiazole were used, thereby obtaining 42.4 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:32]>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)=[O:32])[CH:5]=[CH:4][C:3]=1[C:17]1[CH:22]=[N:21][C:20]([NH2:23])=[N:19][CH:18]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: O=C(c1ccccc1Br)N1CCOCC1
Product: Nc1ncc(-c2ccc(-c3ccccc3C(=O)N3CCOCC3)cc2F)cn1

Procedure:
The title compound was prepared using methods analogous to those described in Example 369 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and (2-bromophenyl)(morpholino)methanone. MS (ESI): mass calcd. for C21H19FN4O2, 378.15; m/z found, 379.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J=1.4, 2H), 7.54-7.41 (m, 5H), 7.36 (dd, J=8.0, 1.8, 1H), 7.32 (dd, J=11.5, 1.8, 1H), 5.20 (s, 2H), 3.74-3.58 (m, 3H), 3.49-3.30 (m, 2H), 3.15-3.01 (m, 1H), 2.94-2.77 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)[CH:5]=[CH:4][C:3]=1[CH2:13][C:14](N(OC)C)=[O:15].[CH3:20][Mg]Br.C1(C)C=CC=CC=1.C(OCC)C.[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:11][CH2:12]2)[CH:5]=[CH:4][C:3]=1[CH2:13][C:14](=[O:15])[CH3:20]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)Cc1ccc(OCC2CC2)cc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(=O)Cc1ccc(OCC2CC2)cc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution (50 mL) of 2-[2-bromo-4-(cyclopropylmethoxy)phenyl]-N-methoxy-N-methylacetamide (3.00 g) in THF was added dropwise methylmagnesium bromide (19.6 mL, 1.4 M, a mixed solution of toluene-diethyl ether (3/1)) under ice-cooling. The mixture was stirred at room temperature for 3 hr, poured into saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a colorless oil (1.29 g).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[N:13]([CH2:17][CH:18](O)[CH3:19])[C:14](=[O:16])[CH3:15]>C1C=CC=CC=1>[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[N:13]([CH2:17][CH:18]([Cl:3])[CH3:19])[C:14](=[O:16])[CH3:15]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)N(CC(C)O)c1c(C)cccc1C
Solvent: c1ccccc1
Product: CC(=O)N(CC(C)Cl)c1c(C)cccc1C
Yield: 81.9 %

Procedure:
6.5 ml (10.76 g, 90.4 mmoles) of thionyl chloride are added dropwise, within 20 minutes, to a solution of 20 g (90.4 mmoles) of 1[N-(2,6-dimethylphenyl)-acetamido]-2-propanol in 200 ml of benzene, and the mixture is boiled until the gas evolution ceases (for about 0.25 hours). The mixture is cooled, the solvent is evaporated under reduced pressure, and the oily residue is distilled under reduced pressure. 17.75 g (81.9%) of 1-[N-(2,6-dimethylphenyl)-acetamido]-2-chloro-propane are obtained; b.p.: 138°-140° C./93.3 Pa, m.p.: 41°-42° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][CH:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[NH:18][C:17]1=[O:27]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([NH:15][CH:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[NH:18][C:17]1=[O:27])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC1CCc2ccccc2NC1=O
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)NC1CCc2ccccc2NC1=O

Procedure:
Prepared from 2-(t-butoxycarbonylamino)-2-methylpropanoic acid and 3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (Example 1, Step A) by the procedure described in Example 25, Step A. 1H NMR (200 MHz, CDCl3): 1.38 *s,12H), 1.44 (s,3H), 1.90 (m,1H), 2.5-3.0 (m,3H), 4.45 (m,1H), 5.10 (s,1H), 6.97 (m,1H), 7.20 (m,3H), 8.45 (s,1H).
Reaction SMILES: [CH2:1]([CH2:4][NH:5][C:6]([CH3:10])([CH3:9])[CH2:7][NH2:8])[CH:2]=[CH2:3].[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[Cl:21])[C:15](Cl)=[O:16]>C1C=CC=CC=1.C(OCC)(=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[Cl:21])[C:15]([NH:8][CH2:7][C:6]([NH:5][CH2:4][CH2:1][CH:2]=[CH2:3])([CH3:10])[CH3:9])=[O:16]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: C=CCCNC(C)(C)CN
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: C=CCCNC(C)(C)CNC(=O)c1ccc(Cl)c(Cl)c1

Procedure:
A mixture of 2-allylmethylamino-2-methylpropylamine (1.3 g.,) and 3,4-dichlorobenzoyl chloride (3.15 g.,) was heated under reflux in dry benzene (150 ml.) for 1 hrs. The cooled mixture was washed with dilute sodium hydroxide solution (2 × 30 ml.), water (2 × 30 ml.), dried (MgSO4) and the solvent was removed in vacuo to give a yellow oil (3.9 g.). The oil was passed through a column of alumina 40 × 2.5 cm. using ethyl acetate as an eluent to give 3,4-dichloro-N-(2-allylmethylamino-2-methylpropyl)-benzamide as a pale yellow liquid (2.25 g., 71%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=3)[CH:18]=[C:17]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO>[CH3:30][O:29][C:27](=[O:28])[CH2:26][C:17]1[CH:16]=[C:15]([O:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=2)[CH:18]=1
Reactant: COC(=O)Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c2cc(F)ccc2c1
Agent: Cl
Solvent: CO
Product: COC(=O)Cc1cc(OC2CCNCC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.8 %

Procedure:
To a solution of 4-(7-fluoro-3-methoxycarbonylmethyl-naphthalen-1-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (prepared as described above, 400 mg, 0.99 mmol) in methanol (4 mL) was added a 5N solution of hydrogen chloride in methanol (4 mL). After being stirred at room temperature for 3 hours, the mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (10 mL), and treated with a saturated aqueous sodium bicarbonate solution (10 mL). The aqueous layer was separated and extracted with dichloromethane (10 mL×2). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (elution with 10% methanol in dichloromethane) to afford [6-fluoro-4-(piperidin-4-yloxy)-naphthalen-2-yl]-acetic acid methyl ester (260 mg, 85%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]([OH:10])=[O:9].S(=O)(=O)(O)O.[CH3:16]O>>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]([O:10][CH3:16])=[O:9]
Reactant: CO
Reactant: Nc1ccncc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cnccc1N

Procedure:
A mixture of compound 4-aminopyridine-3-carboxylic acid (100 g, 0.7 mol) and concentrated sulfuric acid (400 g, 4.0 mol) in absolute methanol (1.5 L) was stirred under reflux for 24 hours. The reaction mixture was concentrated in vacuo. The residue was diluted with ice-water (800 mL), basified with 2 N of aqueous solution of sodium hydroxide to about pH 10 and then extracted with ethyl acetate (300 mL×3). The combined organic layers were washed with water (500 mL), dried over sodium sulfate and concentrated in vacuo to afford the crude product, which was used for next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN1C(=O)N(C)CCC1>[C:25]1([CH2:24][NH:31][C:2]2[N:7]=[CH:6][C:5]([C:8]([N:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[CH2:14][N:13]4[CH:21]=[CH:22][CH:23]=[C:12]4[CH2:11]3)=[O:9])=[CH:4][CH:3]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(c1ccc(Cl)nc1)N1Cc2cccn2Cc2ccccc21
Reactant: NCc1ccccc1
Solvent: CN1CCCN(C)C1=O
Product: O=C(c1ccc(NCc2ccccc2)nc1)N1Cc2cccn2Cc2ccccc21
Temperature: 110 °C

Procedure:
A mixture of 0.16 g of 10-[(6-chloro-3-pyridinyl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 0.5 ml of benzylamine and 0.2 ml of N,N'-dimethylpropyleneurea is stirred and heated at 110° C. for 7 hours. After cooling to room temperature, the mixture is washed with hexane (3 times 10 ml). The residue is dissolved in water and made alkaline with 1N NaOH. The suspension is washed with H2O and extracted with ethyl acetate. The organic extract is washed with brine, dried (Na2SO4) and filtered through a thin pad of hydrous magnesium silicate. The filtrate is evaporated and the residue triturated with diethyl ether-hexane to give 0.20 g of white solid; mass spectrum (CI) 395 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([O:12][CH3:13])[C:10]#[CH:11]>C(N(CC)CC)C.[Cu](I)I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]#[C:10][CH2:9][O:12][CH3:13])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C#CCOC
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COCC#Cc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
2,5-Dibromopyridine (16-582 g) was dissolved in triethylamine (200 ml), followed by the addition of methyl propargyl ether (5.9 ml), copper iodide (267 mg) and bis(triphenylphosphine)palladium (II) chloride (46 mg). The resulting mixture was stirred in nitrogen atmosphere at room temperature for 1 hr. Subsequently, it was stirred at room temperature for further 3 hr. After the resulting insoluble matters were filtered off, the resulting solution was evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a brown solid (12.411 g, yield; 79%).
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]([CH3:20])([N:12]2[CH:16]=[C:15]([N+:17]([O-])=O)[N:14]=[CH:13]2)[CH3:11])[CH2:3]1.[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([NH:32][C@@H:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:34](O)=[O:35])=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1>>[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([NH:32][C@@H:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:34]([NH:17][C:15]2[N:14]=[CH:13][N:12]([C:10]([CH3:20])([CH3:11])[CH2:9][N:4]3[CH2:3][C@@H:2]([CH3:1])[O:7][C@@H:6]([CH3:8])[CH2:5]3)[CH:16]=2)=[O:35])=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: O=C(Cc1cc(F)cc(F)c1)N[C@H](C(=O)O)c1ccccc1
Reactant: CC1CN(CC(C)(C)n2cnc([N+](=O)[O-])c2)CC(C)O1
Product: C[C@@H]1CN(CC(C)(C)n2cnc(NC(=O)[C@@H](NC(=O)Cc3cc(F)cc(F)c3)c3ccccc3)c2)C[C@H](C)O1

Procedure:
2,6-Dimethyl-4-[2-methyl-2-(4-nitro-imidazol-1-yl)-propyl]-morpholine (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) was reduced and coupled with (S)-2-(2-(3,5-difluorophenyl)acetamido)-2-phenylacetic acid to afford the title compound: MS 540 m/z (M+1).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][N:17]=[CH:18]2>C(Cl)Cl.CO>[Cl:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][N+:17]([O-:9])=[CH:18]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1cccc2cnccc12
Solvent: ClCCl
Solvent: CO
Product: [O-][n+]1ccc2c(Cl)cccc2c1
Yield: 79.5 %

Procedure:
According to Scheme 28 Step 1: A solution of MCPBA (1.9, 15.0 mmol, 3.6 g) and 5-chloroisoquinoline (1 eq, 7.80 mmol, 1.27 g) in CH2Cl2 (30 mL) was stirred for 2 hours at room temperature. The reaction mixture was diluted with CH2Cl2 (20 mL) and MeOH (10 mL) and the organic phase washed with 2M NaOH solution. The aqueous layer was extracted with CH2Cl2. The organic fractions were combined, dried over MgSO4, filtered and evaporated to yield the title compound (6.20 mmol, 1.12 g, 79%) as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:12]([CH2:16][C:17](Cl)=[O:18])([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1>ClCCl>[CH3:13][C:12]([CH3:15])([CH3:14])[CH2:16][C:17]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)=[O:18]
Reactant: Nc1ccc2ncccc2c1
Reactant: CC(C)(C)CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)CC(=O)Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.5 %

Procedure:
Following the procedure of Example 1, Step 3, 6-nitroquinoline (2.5 g) and 5% palladium on carbon (0.10 g) in ethanol (40 mL) was hydrogenated to give 6-aminoquinoline (2.2 g). A mixture of 6-aminoquinoline (2.2 g, 15 mmol), t-butylacetyl chloride (2.2 mL, 16 mmol), and pyridine (2.5 mL, 31 mmol) in dichloromethane (40 mL) was then stirred at ambient temperature for 4 h and then extracted with 1 N HCl. The acidic layer was separated and treated with 50% NaOH until basic. The basic phase was extracted with dichloromethane. The combined extracts were dried (MgSO4) and concentrated. The crude material was triturated with hexane and the solid was collected by filtration to provide 3,3-dimethyl-N-quinolin-6-ylbutanamide (3.0 g). MS (ES) m/z 241.1.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C([Li])(C)(C)C.[Si:17]([O:24][C@H:25]1[CH2:34][C:33]([CH3:36])([CH3:35])[CH2:32][C:31]2[N:30]=[C:29]([CH:37]([CH3:39])[CH3:38])[C:28]3[C:40](=[O:48])[O:41][C:42]4([CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[C:27]=3[C:26]1=2)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>O1CCCC1.CCCCC>[Si:17]([O:24][C@H:25]1[CH2:34][C:33]([CH3:35])([CH3:36])[CH2:32][C:31]2[N:30]=[C:29]([CH:37]([CH3:38])[CH3:39])[C:28]3[C:40]([C:2]4[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=4)([OH:48])[O:41][C:42]4([CH2:43][CH2:44][O:45][CH2:46][CH2:47]4)[C:27]=3[C:26]1=2)([C:20]([CH3:22])([CH3:23])[CH3:21])([CH3:18])[CH3:19]
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: CC(C)c1nc2c(c3c1C(=O)OC31CCOCC1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)c1nc2c(c3c1C(O)(c1ccc(C(F)(F)F)cc1)OC31CCOCC1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
0.12 g 1-Iodo-4-(trifluoromethyl)benzene are dissolved in 3 ml tetrahydrofurane, cooled to −78° C. and treated dropwise with 0.54 ml of a 1.6 M solution of tert.-butyllithium in n-pentan. The mixture is stirred for 30 minutes and then a solution of 0.10 g (S)-9-(tert-butyldimethylsilyloxy)-4-isopropyl-7,7-dimethyl-2′,3′,5′,6,6′,7,8,9-octahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran]-3-one in 1 ml tetrahydrofurane is added dropwise. The mixture is stirred for 30 minutes at −78° C. and for 1 hour at −40° C. Then the reaction is quenched by addition of 0.5 ml methanol and purified via reversed phase chromatography (Varian Pursiut XRs C18 10μ, water/methanol/trifluoroacetic acid 90:10:0.1 to 0:100:0.1; 180 mL/min; 18 min).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH2:8]([B:12](O)O)[CH2:9][CH2:10][CH3:11]>C(Cl)Cl.CCOCC>[CH2:8]([B:12]1[O:7][CH2:6][CH2:5][NH:1][CH2:2][CH2:3][O:4]1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCB(O)O
Reactant: OCCNCCO
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCB1OCCNCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,2′-azanediyldiethanol (26.12 g, 246 mmol) in DCM (250 ml) and ether (500 mL) was added n-butylboronic acid (25.4 g, 242 mmol) and molecular sieves (3 A, 4-6 mesh, 65 g). It was stirred at ambient temperature for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting white solid was recrystallized with DCM/ether to provide white crystals as the title product. NMR (300 MHz, CDCl3): δ 0.47 (t, J=9 Hz, 2H), 0.88 (t, J=6 Hz, 3H), 1.20-1.37 (m, 4H), 2.82 (br, 2H), 3.24 (br, 2H), 3.95 (br, 4H), 4.27 (br, 1H). MS (DCI—NH3) m/z 172 (M+H)+.
Reaction SMILES: CC(C1C=CC=C(OC2C=CC=CC=2)N=1)O.[CH3:17][CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[N:21]=1)[OH:19].[CH:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][C:35]=1[CH:44]([CH:48]([CH3:50])[CH3:49])[C:45](O)=[O:46]>>[CH:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][C:35]=1[CH:44]([CH:48]([CH3:50])[CH3:49])[C:45]([O:19][CH:18]([CH3:17])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[N:21]=1)=[O:46]
Reactant: CC(C)C(C(=O)O)c1ccc2ccccc2c1
Reactant: CC(O)c1cccc(Oc2ccc(F)cc2)n1
Agent: CC(O)c1cccc(Oc2ccccc2)n1
Product: CC(OC(=O)C(c1ccc2ccccc2c1)C(C)C)c1cccc(Oc2ccc(F)cc2)n1

Procedure:
Following the procedure of Example 3, each of methyl (6-phenoxy-2-pyridyl)methanol and methyl[6-(4-fluorophenoxy)-2-pyridyl]methanol is reacted with 2-(2-naphthyl)-3-methyl-butanoic acid to yield methyl (6-phenoxy-2-pyridyl) methyl 2-(2-naphthyl)-3-methylbutanoate and methyl[6-(4-fluorophenoxy)-2-pyridyl]methyl 2-(2-naphthyl)-3-methylbutanoate, respectively.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([CH2:21][OH:22])=[CH:10][CH:9]=2)(=[O:4])=[O:3]>C(Cl)Cl.[O-2].[Mn+2]>[CH3:1][S:2]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([CH:21]=[O:22])=[CH:10][CH:9]=2)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cnc2ccc(CO)cc2c1-c1ccccc1
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: CS(=O)(=O)c1cnc2ccc(C=O)cc2c1-c1ccccc1
Temperature: 25 °C

Procedure:
To the solution of (3-methanesulfonyl-4-phenyl-quinolin-6-yl)-methanol (example 61 h, 90 mg, 0.29 mmol) in methylene chloride (10 ml), activated manganese oxide (250 mg, 2.88 mmol) was added. The reaction mixture was heated at the refluxing temperature for 45 min. After cooling to the room temperature, the reaction mixture was filtered through a bed of celit with methylene chloride. The filtrate was collected and concentrated in vacuo to give 3-methanesulfonyl-4-phenyl-quinoline-6-carbaldehyde. LC-MS m/e 312 (MH+).