Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1[C:14](=[O:30])[NH:15][C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:20][C:19]([Cl:29])=[CH:18][CH:17]=2)C1C=CC=CC=1>ClC(OC(Cl)=O)C>[Cl:29][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:30])[C:13]([C:9]1[NH:10][CH:11]=[CH:12][N:8]=1)=[C:22]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)c1-c1nccn1Cc1ccccc1
Agent: CC(Cl)OC(=O)Cl
Product: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)c1-c1ncc[nH]1
Temperature: 100 °C
Yield: 66 %

Procedure:
A solution of 3-(1-benzyl-1H-imidazol-2-yl)-6-chloro-4-phenyl-1H-quinolin-2-one (110 mg) in α-chloroethylchloroformate (5 mL) was heated at 100° C. for 2 hr. The reaction was evaporated and the resulting residue was dried in vacuo. The residue was dissolved in HOAc (5 mL) and NH4Ac (100 mg) was added. The reaction mixture was heated at 100° C. for 12 hr. Solvents were removed and the title compound was isolated by reversed phase HPLC. Yield 66%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26](O)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:74][O:75][CH2:76][CH2:77][NH2:78]>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH:78][CH2:77][CH2:76][O:75][CH3:74])=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COCCN
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCNC(=O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (100 mg, 0.24 mmol), PyBOP® (125 mg, 0.24 mmol), DIEA (125 μL, 0.72 mmol) in CH2Cl2:DMF (4 mL:0.5 mL) stirred at RT for 10-15 minutes. To this solution of activated acid was added 2-methoxyethanamine (21 μL, 0.24 mmol) and the reaction mixture was stirred at RT for 3 h. Concentrated in vacuo and the crude product was purified using prep HPLC (method 10-35_90 mins) and was further washed with ethyl ether and drops of CH2Cl2 to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(2-methoxyethyl)acetamide. (25 mg, 0.053 mmol, 22%)
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=O.[CH2:19]([NH2:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+]>CO>[CH2:19]([NH:27][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)cc1
Reactant: NCCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3ccccc3)cc2)cc1
Yield: 64.9 %

Procedure:
Combine 4-(4-Formyl-phenoxy)-benzamide (from Example 247, step 2) (0.39 g, 1.6 mmol), phenethylamine (0.15 g, 1.2 mmol), 20 mL of methanol and 2 g of 3 Å molecular sieves, and stir at ambient temperature ambient under nitrogen for 5 h. Add sodium borohydride (0.18 g, 4.8 mmol), and stir at ambient temperature for 18 h at ambient temperature. Filter the reaction mixture through Celite, and adsorb on silica gel. Purify by Biotage Flash 40S, eluting with 95:5:0.5 chloroform/ethanol/ammonium hydroxide to afford 0.27 g (93%) of the title compound: mass spectrum (ion spray): m/z=347.28 (M+1); HPLC retention time: 6.01 min (HPLC method in this experiment and subsequent experiments: 5:95-95:5 ACN/0.1% TFA in water over 10 minutes using a 15 cm Zorbax column, running at 1 mL/minute, ultraviolet detector set at 254 nM).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH3:13])[CH:7]=[CH:6]2.[Br:14]N1C(=O)CCC1=O>C(#N)C>[Br:14][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([CH3:13])=[N:9]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2nc(C)ccc2c1
Solvent: CC#N
Product: COc1ccc2nc(C)ccc2c1Br
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.4 %

Procedure:
A solution of 6-methoxy-2-methylquinoline (177 g, 1.02 mol) in acetonitrile (1.77 L) was cooled to 0–3° C. followed by portion-wise addition of N-bromo-succinimide (200 g, 1.12 mol) over a period of 30 minutes while maintaining the same temperature. The resulted brown slurry was warmed to ambient temperature and stirred for an additional 6 hours. The reaction was then quenched by a 10% NaHSO3 solution (211 mL). The reaction mixture was concentrated to a volume of 600 mL then slowly poured into 0.1 N NaOH (2.5 L). The slurry (pH=9) was stirred at room temperature for 1 hour then filtered, washed with water (2×1 L) and dried in a vacuum oven to give 253 g (98.6%) of the title compound as a brown solid: Rf=0.39 (3:7) EtOAc:heptane; 1H NMR (DMSO) δ 8.30 (d, J=6.5 Hz, 1H), 7.98 (d, J=6.9 Hz, 1H), 7.70 (d, J=7.0 Hz, 1H), 7.47 (d, J=6.5 Hz, 1H), 4.02 (s, 3H), 2.66 (s, 3H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[F:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:28][C:27]=1[NH:41][C:42]1[O:43][C:44]2[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=2[N:46]=1>>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:30]3[CH:29]=[CH:28][C:27]([NH:41][C:42]4[O:43][C:44]5[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=5[N:46]=4)=[C:26]([F:25])[CH:31]=3)[C:10]=12
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: CC1(C)OB(c2ccc(Nc3nc4ccccc4o3)c(F)c2)OC1(C)C
Product: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(Nc5nc6ccccc6o5)c(F)c4)c4c(N)ncnc43)CC2)CC1

Procedure:
Trans-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-1,3-benzoxazol-2-amine was prepared from trans-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g, 0.227 mmol) and N2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazol-2-amine (0.151 g, 0.425 mmol) in a manner similar to that used for the cis-isomer. The compound was formed as a white powder (0.053 g, 43%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH:6]=O.Cl.[NH2:15][OH:16]>CCO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH:6]=[N:15][OH:16]
Reactant: NO
Reactant: COc1cc(C=O)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C=NO)ccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 75.9 %

Procedure:
To 3-methoxy-4-nitrobenzaldehyde (53.5 g, 295.5 mmol)) in EtOH (285 ml) was slowly added a solution of hydroxylamine hydrochloride (30.8 g, 443 mmol) in water (50 ml). The reaction mixture was stirred overnight, poured into ice-cold water, and the formed precipitate was collected by filtration to furnish 44 g of 3-methoxy-4-nitrobenzaldehyde oxime. The filtrate was extracted with DCM, and the organic phase was washed with water and brine, dried over sodium sulfate, and concentrated to furnish additional 8.2 g of the title product. 1H NMR (CDCl3) δ: 8.13 (s, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.51 (s, 1H), 7.35 (s, 1H), 7.18 (dd, J=8.4, 1.4 Hz, 1H), 4.01 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[CH3:10][O:11][C:12](=[O:16])[C:13](Cl)=[O:14].O>O1CCCC1>[CH3:10][O:11][C:12]([C:13]([NH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6])=[O:14])=[O:16]
Reactant: Nc1cccc(CO)c1
Reactant: COC(=O)C(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(=O)Nc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4.93 g of m-aminobenzyl alcohol in 50 ml of tetrahydrofuran was added dropwise a solution of 3.7 ml of chloroglyoxylic acid methyl ester in 20 ml of tetrahydrofuran, and this was stirred at room temperature for 1.5 hours. To the reaction solution was added water, and this was extracted with ethyl acetate, and washed with an aqueous saturated sodium chloride solution. After dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography to obtain 5.10 g of 3-[(methoxycarbonyl)carbonylamino]benzyl alcohol as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH:13]2[O:15][CH2:14]2)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39].[NH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1.O>CN(C)C(=O)C>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH:13]([OH:15])[CH2:14][N:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39]
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(OCC3CO3)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)n1c(-c2cc(OCC(O)CN3CCCCC3)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Temperature: 60 °C
Reaction time: 72 h
Yield: 70.3 %

Procedure:
4-Chloro-5-(2,3-epoxypropoxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (44.9 mg, 0.081 mmol) was dissolved in N,N-dimethylacetoamide (1.0 mL), and the solution was added with piperidine (0.160 mL, 1.61 mmol), followed by stirring at 60° C. for 72 hours. The reaction mixture was added with water. The obtained solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 4-chloro-5-[2-hydroxy-3-(piperidin-1-yl)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (36.3 mg, yield 70%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:5][CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:22]>C(Cl)Cl>[F:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:22])=[CH:7][CH:8]=1
Reactant: Fc1ccc(SCc2ccccn2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: O=S(Cc1ccccn1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.3 %

Procedure:
A stirred suspension of 2-(((4-fluorophenyl)thio)methyl)pyridine, hydrochloride (2 g) in methylene chloride (50 ml) at 0° C. was treated portionwise with m-chloroperoxy-benzoic acid (1.8 g) over 1/2 hour. The mixture was allowed to warm to ambient temperature and the mixture was stirred for a further 4 hours. The solution was washed with saturated Na2CO3 solution and water, dried (MgSO4) and evaporated. The residue was recrystallised from diisopropyl ether to give the title compound (1.0 g) mp 92°-4° C. (Found, C,60.9; H,4.6; N,5.6 C12H10FNOS requires C,61.3; H,4.3; N,5.95%).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]1[N:9]=[CH:10][N:11]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1)[C:3]([O:5]C)=[O:4].[Li+].[OH-]>C1COCC1>[CH3:1][CH:2]([CH2:7][C:8]1[N:9]=[CH:10][N:11]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)O
Reaction time: 36 h
Yield: 96.2 %

Procedure:
The faster eluting enantiomer of methyl 2-methyl-3-(1-trityl-1H-imidazol-4-yl)propanoate (0.186 g, 0.453 mmol) was saponified by stirring in THF (2 mL) and 1 N LiOH (0.45 mL) for 2 hours. HPLC analysis shows 50% conversion to product. Nearly complete conversion (97.5%) required two additional additions of 1 N LiOH (0.1 mL each) and stirring for a total of 36 hrs. After concentrating under reduced pressure and addition of water (20 mL), the aqueous phase was extracted with DCM (3×20 mL) and the combined DCM extracts were washed with water, saturated sodium chloride (each 1×20 mL) and dried over MgSO4. The DCM was removed and the resulting solid was dried in vacuo to yield 0.1728 g of 97% pure (+)-2-methyl-3-(1-trityl-1H-imidazol-4-yl)propanoic acid; retention time, 9.36 min.; column: YMC ODS-A (3 μm, 50×4.6 mm); gradient: 10% to 100% B in A over 15 min. at 1.25 mL/min. Solvent A: 0.1% TFA in water, solvent B: 0.1% TFA in AcCN. LC/MS: ESI (M+H)+=397.30, (M−H)-=395.30. Optical rotation, [α]D=+12.8° (c=1.03 in CHCl3). 1H-NMR (CD3OD, 500 MHz): δ 1.13 (d, 3H), 2.57-2.65 (m, 1H), 2.67-2.80 (m, 1H), 2.82-2.92 (m, 1H), 6.75 (s, 1H), 7.10-7.17 (m, 6H), 7.34-7.41 (m, 9H), 7.58 (s, 1H).
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][CH:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21](OCC)(=[O:26])[C:22]#[C:23][CH2:24][CH3:25]>C(O)C>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][CH:13]3[O:17][C:16]4=[N:18][C:21](=[O:26])[CH:22]=[C:23]([CH2:24][CH3:25])[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC1=NCC(COc2ccc(C3CCCCC3)cc2)O1
Reactant: CCC#CC(=O)OCC
Solvent: CCO
Product: CCc1cc(=O)nc2n1CC(COc1ccc(C3CCCCC3)cc1)O2
Temperature: 170 °C
Yield: 39.4 %

Procedure:
To a solution of 5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (300 mg, 1.095 mmol) in ethanol (6 mL) was added ethyl 2-pentynoate (276 mg, 2.19 mmol). The reaction mixture was heated in a microwave oven at 170° C. for 70 min. The solvent was removed under vacuum, and the residue purified via flash column chromatography (silica gel, 1-12% EtOH/CH2Cl2) to afford 153 mg of 2-(4-cyclohexyl-phenoxymethyl)-5-ethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one as a slightly yellow solid.
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:30])[CH:8]([O:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16]CC3C=CC=CC=3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>CCOC(C)=O.[Pd]>[CH:1]1([O:6][C:7](=[O:30])[CH:8]([O:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(OC1CCCC1)C(Cc1ccc(OCc2ccccc2)cc1)OC1CCCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(OC1CCCC1)C(Cc1ccc(O)cc1)OC1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.4 %

Procedure:
A mixture of 3-(4-benzyloxy-phenyl)-2-cyclopentyloxy-propionic acid cyclopentyl ester (0.137 g, 0.335 mmol) and 10% Pd/C (0.14 g) in EtOAc (70 mL) was purged with N2 then H2 and then stirred under a H2 balloon atmosphere for 3 h at room temperature. Upon reaction completion, MgSO4 was added and the mixture filtered through hyflo. The solvent was removed in vacuo to afford 0.090 g (84%) 2-cyclopentyloxy-3-(4-hydroxy-phenyl)-propionic acid cyclopentyl ester. 1H NMR. MS (ES−) Calc'd for C19H25O4 (M−1) 317. Found m/z 317 (100%).
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[CH:5]1([P:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)([SH:13])=[S:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>>[OH:4][CH2:3][CH2:2][S:13][P:11]([CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[S:12]
Reactant: OCCBr
Reactant: S=P(S)(C1CCCCC1)C1CCCCC1
Product: OCCSP(=S)(C1CCCCC1)C1CCCCC1

Procedure:
2-Bromoethanol was reacted with the ammonium salt of dicyclohexylphosphinodithioic acid to obtain 2-hydroxyethyldicyclohexylphosphinodithioate, m.p. 82°-84° C, which on testing lasted 500 hours longer than the control. The total number of hours required to reach failure was 2.0 times that of the control.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][S:19](=[O:22])[CH2:18][CH2:17]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][CH2:14][OH:15])[C:6]=2[N:7]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[OH:15][CH2:14][CH2:13][NH:12][C:8]1[C:6]2[N:7]=[C:2]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[N:3]=[C:4]([N:16]3[CH2:21][CH2:20][S:19](=[O:22])[CH2:18][CH2:17]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: C1CNCCN1
Reactant: O=S1CCN(c2nc(Cl)nc3c(NCCO)ncnc23)CC1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(NCCO)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 118 from 2-chloro-8-(2-hydroxyethyl-amino)-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 227°-229° C.) and piperazine.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([OH:10])[CH:7]=2)[O:2]1.Br[CH:15]([CH2:20][CH2:21][CH2:22][Br:23])[C:16]([O:18][CH3:19])=[O:17]>>[Br:23][CH2:22][CH2:21][CH2:20][CH:15]([O:10][C:6]1[CH:7]=[C:8]2[O:9][CH2:1][O:2][C:3]2=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12])[C:16]([O:18][CH3:19])=[O:17]
Reactant: O=[N+]([O-])c1cc2c(cc1O)OCO2
Reactant: COC(=O)C(Br)CCCBr
Product: COC(=O)C(CCCBr)Oc1cc2c(cc1[N+](=O)[O-])OCO2

Procedure:
In a manner similar to that of Reference Example 5, 4,5-methylenedioxy-2-nitrophenol was allowed to react with methyl 2,5-dibromovalerate to give methyl 5-bromo-2-(4,5-methylenedioxy-2-nitrophenoxy)valerate, which was then allowed to react, in a manner similar to that of Reference Example 8, with 1-(4-fluorophenyl)piperazine to obtain methyl 5-[4-(4-fluorophenyl)-1-piperazinyl]-2-(4,5-methylenedioxy-2-nitrophenoxy)valerate as crystals, m.p. 98°-99° C. The overall yield was 15.6%.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:21])[CH2:18][CH:19]=[CH2:20])=[CH:13][CH:12]=1)[CH:8]([CH3:10])[CH3:9]>ClCCl.[O-2].[Cr+6].[O-2].[O-2]>[CH2:7]([C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:21])[CH2:18][CH:19]=[CH2:20])=[CH:15][CH:16]=1)[CH:8]([CH3:10])[CH3:9]
Reactant: C=CCC(O)c1ccc(CC(C)C)cc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCC(=O)c1ccc(CC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
To a stirred solution of pyridine (1.98 ml) in dichloromethane (15 ml) was added chromium(VI) oxide (1.23 g) at 0° C. After 30 minutes, 1-(4-isobutylphenyl)-3-buten-1-ol (525 mg) in dichloromethane (2 ml) was added and stirred for 20 minutes at ambient temperature. The reaction mixture was filtered through Florisil and washed with ether. The filtrate was concentrated in vacuo and chromatographed on silica gel (hexane:dichloromethane=1:1) to give 1-(4-isobutylphenyl)-3-buten-1-one (424 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][C:5]=1[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14])([O-])=O.[H][H]>CO.[Pt]=O>[NH2:1][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][C:5]=1[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14]
Reactant: [H][H]
Reactant: NC(=O)c1ccc([N+](=O)[O-])c(C(=O)Nc2ccc(Cl)cc2)c1
Agent: O=[Pt]
Solvent: CO
Product: NC(=O)c1ccc(N)c(C(=O)Nc2ccc(Cl)cc2)c1
Yield: 98.4 %

Procedure:
4-Nitro-3-N-(4-chlorophenyl)-isophthalamide (46 mg) obtained in Example 1-2-20 was dissolved in 7 mL of methanol, and 10 mg of platinum oxide was added to the solution, followed by stirring the mixture for 30 minutes at room temperature in an atmosphere of hydrogen. The reaction mixture was filtered to remove insolubles, and the filtrate was concentrated under reduced pressure. The resulting solid was dried under reduced pressure to obtain 41 mg (99%) of 4-amino-3-N-(4-chlorophenyl)-isophthalamide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([F:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[CH2:11][C:10]2([CH3:23])[CH3:22])=[O:4].Cl.[C:26]1([CH3:38])[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([F:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:35]3[CH2:36][CH2:37][N:32]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[CH3:38])[CH2:33][CH2:34]3)[CH:16]=1)[CH2:11][C:10]2([CH3:23])[CH3:22])=[O:4]
Reactant: COC(=O)c1cc(F)cc2c1NC(c1cccc(Br)c1)CC2(C)C
Reactant: Cc1ccccc1N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(F)cc2c1NC(c1cccc(N3CCN(c4ccccc4C)CC3)c1)CC2(C)C
Temperature: 120 °C
Yield: 59 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-6-fluoro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (3.0 g, 7.65 mmol), 1-o-tolyl-piperazine hydrochloride (1.95 g, 9.2 mmol), palladium (II) acetate (172 mg, 0.77 mmol), xantphos (266 mg, 0.46 mmol) and cesium carbonate (5.0 g, 15.3 mmol) in toluene (20 mL) was heated for 3 h at 120° C. After colling to room temperature, the mixture was treated with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (50% ethyl acetate/hexanes) to afford 6-fluoro-4,4-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (2.2 g, 60%) as a white solid: MS (ESI) M+1=488.4.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.F[C:22]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:23]=1[C:24]([OH:26])=[O:25]>>[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:22]2[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])=[CH:16][CH:15]=1
Reactant: O=C(O)c1cc(F)c(F)cc1F
Reactant: Nc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cc(F)c(F)cc1Nc1ccc(F)cc1
Yield: 88.1 %

Procedure:
Using General Method 1, the reaction of 2.5 M solution of n-BuLi in hexanes (14 mL, 35 mmol), diisopropylamine (4.8 mL, 34 mmol), 4-fluoro-aniline (1.1 mL, 11 mmol), and 2,4,5-trifluorobenzoic acid (2 g, 11 mmol) provided 2.59 g of the crude title compound.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:25]=[CH:24][C:10]([CH2:11][O:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[N:21][OH:22])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[C:26]([C:28]1[C:29]([NH2:34])=[N:30][CH:31]=[CH:32][CH:33]=1)#[CH:27].C(N(CC)CC)C>O>[F:6][C:7]1[CH:25]=[CH:24][C:10]([CH2:11][O:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][C:20]3[CH:27]=[C:26]([C:28]4[C:29]([NH2:34])=[N:30][CH:31]=[CH:32][CH:33]=4)[O:22][N:21]=3)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(OCc2ccc(F)cc2)nc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3ccc(F)cc3)nc2)no1
Temperature: 60 °C
Reaction time: 4 h
Yield: 22.2 %

Procedure:
To a tetrahydrofuran (10.0 mL) solution of (6-(4-fluoro-benzyloxy)-pyridin-3-yl)-acetohydroximoyl chloride (150 mg, 0.508 mmol) described in Manufacturing Example 58-1-5 and 3-ethynyl-pyridin-2-ylamine (30.0 mg, 0.254 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (106 μL, 0.762 mmol) at room temperature, which was stirred for 4 hours at 60° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:2) to obtain the title compound (21.2 mg, 22.2%).