Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[C:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:32])[CH3:31]>>[C:30]([N:33]1[CH2:38][CH2:37][N:36]([C:2]2[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=2)[C:5]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:10][CH:9]=2)=[O:6])[CH2:35][CH2:34]1)(=[O:32])[CH3:31]
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(Cl)c1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(c2cc(C(=O)Nc3ccc(OCCN4CCOCC4)c4ccccc34)ccn2)CC1

Procedure:
Compound is formed by reacting 2-chloro-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide and 4-acetylpiperazine under conditions described in general procedure A. 1H NMR (300 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.32 (d, 1H, J=5.4), 8.20 (m, 1H), 7.84 (m, 1H), 7.58 (m, 2H), 7.46 (d, 2H), 7.23 (d, 1H, J=5.4), 7.05 (d, 1H, J=8.1), 4.31 (t, 2H), 3.58 (m, 12H), 2.88 (t, 2H), 2.57 (t, 4H), 2.06 (s, 3H). MS: 504.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:6][CH:5]=1.[C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1)#[CH:24]>CCCCCCC>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]#[C:24][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:9][CH:8]=2)=[CH:26][C:27]=1[O:33][CH3:34]
Reactant: C#Cc1ccc(OC)c(OC)c1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(OC(F)(F)F)cc2)cc1
Solvent: CCCCCCC
Product: COc1ccc(C#Cc2ccc(OC(F)(F)F)cc2)cc1OC

Procedure:
This product was prepared from toluene-4-sulfonic acid 4-trifluoromethoxy-phenyl ester and 4-ethynyl-1,2-dimethoxy-benzene following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane; yield (140 mg, 87%); 1H NMR δ (CDCl3): 7.52 (d, J=8.40 Hz, 2H), 7.21-7.16 (m, 3H), 6.83 (d, J=8.41 Hz, 2H), 3.85 (s, 6H); LCMS m/z: 322.
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:40])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:31])[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[CH:17][C:16]=1[Cl:32].[N:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[C:43]([CH:51]=O)[CH:42]=1>O1CCCC1>[CH3:9][O:10][C:11](=[O:40])/[C:12](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:31])[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[CH:17][C:16]=1[Cl:32])=[CH:51]/[C:43]1[CH:42]=[N:41][C:50]2[C:45]([CH:44]=1)=[CH:46][CH:47]=[CH:48][CH:49]=2
Reactant: O=Cc1cnc2ccccc2c1
Reactant: COC(=O)C(NC(=O)c1ccc(C(=O)CCc2cccc(O)c2)cc1Cl)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1cnc2ccccc2c1)NC(=O)c1ccc(C(=O)CCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
1,1,3,3-Tetramethylguanidine (94 μL, 0.75 mmol) was added to a solution of rac.-N-[2-chloro-4-[3-(3-hydroxyphenyl)-1-oxopropan-1-yl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 133; 244 mg, 0.5 mmol) in tetrahydrofuran (7 mL) at −20° C. After 30 min, quinoline-3-carboxaldehyde (82.5 mg, 0.525 mmol) was added and the solution was stirred at room temperature for 16 h. The solvent was evaporated and ethyl acetate (30 mL) was added. The solution was washed with saturated sodium bicarbonate solution (15 mL) and the aqueous layer was extracted with ethyl acetate (10 mL). Each organic layer was washed with brine. The combined organic layers were dried (MgSO4), filtered, evaporated and chromatographed over silica gel (20-50% ethyl acetate/hexanes) to (Z)-2-[[2-chloro-4-[3-(3-hydroxyphenyl)-1-oxopropan-1-yl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid methyl ester (221 mg, 86% yield) as an orange-yellow solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:14]([CH3:20])=[N:15][CH:16]=[CH:17][C:18]=1[Cl:19].FC(F)(F)C(OC(=O)C(F)(F)F)=O.CO>ClCCl>[Cl:12][C:13]1[C:14]([CH2:20][OH:9])=[N:15][CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: Cc1nccc(Cl)c1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: OCc1nccc(Cl)c1Cl
Reaction time: 16 h

Procedure:
m-Chloroperbenzoic acid (32.63 g) in dichloromethane (400 ml) was added dropwise to a solution of 3,4 -dichloro-2 -picoline (25.53 g)in dichloromethane (100 ml) maintaining the temperature at 20°-25°. After standing for 16 hours at room temperature the solution was washed with 1 N NAOH, dried (K2CO3 ) and filtered to give a pale yellow solution. Trifluoroacetic anhydride (30 ml) was added dropwise to this solution maintaining the temperature at 15°-20°. After standing for 2 days at room temperature, methanol (100 ml) was added and the solution evaporated under reduced presure. The residue was treated with aqueous sodium carbonate and extracted into dichloromethane. After drying (K2CO3 ) and removal of solvent, the residue was recrystallised from pet. ether (60/80 ) to give 3,4 -dichloro-2 -hydroxymethylpyridine, 15.76 g, m.p. 66°-8°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.O=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C[O-].[Na+]>CO>[NH2:13][C:11]([C:9]1[CH:10]=[C:2]([Br:1])[CH:3]=[C:4]2[C:8]=1[NH:7][CH:6]=[C:5]2[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NC(=O)c1cc(Br)cc2cc[nH]c12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1

Procedure:
To a solution of 5-bromo-1H-indole-7-carboxamide (10 g, 41.84 mmol) in methanol (5 mL), 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (684 mg, 3.42 mmol) and sodium methoxide (0.5 M in THF, 13.7 mL, 6.84 mmol) were added. The reaction mixture was stirred at reflux temperature for 16 hours. All solvent was evaporated under reduced pressure. The residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The combined organic phase was dried over MgSO4 and concentrated under reduced pressure, and purified by flash column chromatography (ethyl acetate/hexanes, 1/1) to give the desired product (7.4 g, 43
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[C:23]3[C:18](=[C:19]([CH2:25][S:26][CH3:27])[CH:20]=[C:21]([F:24])[CH:22]=3)[NH:17][CH:16]=2)[CH2:9][C:10](OCC)=[O:11])=[C:4]([F:28])[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[C:23]3[C:18](=[C:19]([CH2:25][S:26][CH3:27])[CH:20]=[C:21]([F:24])[CH:22]=3)[NH:17][CH:16]=2)[CH2:9][CH2:10][OH:11])=[C:4]([F:28])[CH:3]=1
Reactant: CCOC(=O)CC(c1ccc(Cl)cc1F)c1c[nH]c2c(CSC)cc(F)cc12
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CSCc1cc(F)cc2c(C(CCO)c3ccc(Cl)cc3F)c[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 1.1 g (2.57 mmol) of the compound from Example 37A in 20 ml of tetrahydrofuran was added dropwise to 9.0 ml (9.0 mmol) of a 1N solution of lithium aluminum hydride in tetrahydrofuran in 50 ml of tetrahydrofuran at RT under argon. The mixture was stirred at RT for 15 min and then 1N hydrochloric acid was added. The mixture was extracted with dichloromethane, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 715 mg (73% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](OC)=[O:10])=[CH:5][C:4]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:17][CH2:16]2)[CH:5]=1
Reactant: COC(=O)c1ccc(OC)c(OCC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CO)cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
1,1-Dimethylethyl 4-[({2-(methyloxy)-5-[(methyloxy)carbonyl]phenyl}oxy) methyl]piperidine-1-carboxylate (3.34 g, 8.8 mmol) was dissolved in THF (30 mL) and the resulting solution was cooled with an ice bath. A solution of LAH in THF (1 M, 8.8 mmol, 8.8 mL) was added by syringe. The reaction vessel was removed from the ice bath, and the reaction mixture was allowed to warm to rt. After 2 h at rt, the mixture was quenched by cautious sequential addition of water (0.33 mL), 15% NaOH (aq) (0.33 mL), and water (1 mL). During the quench, a white precipitate formed. The solid was removed by filtration through celite and was rinsed with ether. The combined organic layers were washed with dilute hydrochloric acid to then dried over sodium sulfate, filtered, and concentrated to provide 1.88 g of 1,1-dimethylethyl 4-({[5-(hydroxymethyl)-2-(methyloxy)phenyl]oxy}methyl)piperidine-1-carboxylate (5.4 mmol, 61% yield). 1H NMR (400 MHz, CDCl3): δ6.93-6.85 (m, 3H), 4.62 (d, 2H), 4.15 (br m, 2H), 3.87 (m, 2H), 3.86 (s, 3H), 2.76 (br m, 2H), 2.06 (m, 1H), 1.88 (br d, 2H), 1.47 (s, 9H), 1.28 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH2:10][C:11]#[N:12])[N:3]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:19][C:2]2[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH2:10][C:11]#[N:12])[N:3]=2)=[CH:16][CH:15]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: Cc1cc(Cl)nc(SCC#N)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(NCc2ccc(Cl)cc2)nc(SCC#N)n1

Procedure:
A stirred mixture of 5.97 g. (0.03 mole) of (4-chloro-6-methyl-2-pyrimidinylthio)acetonitrile, 4.2 g. (0.03 mole) of 4-chlorobenzylamine and 3.15 g. (0.03 mole) of sodium carbonate in 150 ml of absolute ethanol was heated under reflux for 6 hours. The mixture was filtered and the filtrate evaporated in a rotary evaporator. The residue was triturated with petroleum ether containing a little ethanol. The solid which crystallized was collected and recrystallized from ethyl acetate with petroleum ether added to induce precipitation affording 3.2 g. of product, m.p. 99°-101°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:23]=[N:24][CH:25]=[C:26]([CH:31]=4)[C:27](OC)=[O:28])=[N:14][CH:13]=[N:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:32][NH2:33]>C(O)CCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:23]=[N:24][CH:25]=[C:26]([CH:31]=4)[C:27]([NH:33][CH3:32])=[O:28])=[N:14][CH:13]=[N:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: COC(=O)c1cncc(OCCCCc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Solvent: CCCCO
Product: CNC(=O)c1cncc(OCCCCc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Yield: 19.9 %

Procedure:
Methyl 5-{4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butoxy}nicotinate (0.010 g, 0.023 mmol) and methylamine (0.124 g, 0.004 mol) were mixed in 1-butanol (2.00 mL) and the resulting mixture subjected to microwave radiation for 2000 seconds at 170° C., followed by irradiation for 4000 seconds at 180° C. The solvent was removed by evaporation, and the product purified by preparative HPLC to give 2 mg (20%) 5-{4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butoxy}-N-methylnicotinamide hydroformate as a white solid. MS [M+H]=437.1, LC/MS (EI) tR 3.55 min (Method D), 1H NMR (10% MeOD/CDCl3) δ (ppm) 8.93 (s, 1H), 8.43 (s, 1H), 8.20 (s, 1H), 7.70 (s, 1H), 7.60 (s, 1H), 7.40-7.28 (m, 4H), 7.11 (t, J=8.7 Hz, 2H), 3.84 (t, J=6.0 Hz, 2H), 2.95 (d, J=3.6 Hz, 3H), 2.67 (t, J=7.2 Hz, 2H), 1.75-1.59 (m, 2H), 1.59-1.45 (m, 2H)
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:32]=[CH:31][N:30]([CH2:33][C:34]([CH3:37])([OH:36])[CH3:35])[N:29]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])[CH:13]=[N:12]2)[C:8]([NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH2:33][C:34]([OH:36])([CH3:37])[CH3:35])[N:29]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc(F)c2F)cc1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3cccc(F)c3F)cc2=O)n1
Yield: 53 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[4-(2,3-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 44) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-2-[4-(2,3-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as a white solid (0.68 g, 53%); ES+-HRMS m/e calcd for C25H29N5O4F2 [M+H+] 502.2261 found 502.2260. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.08 (m, 1H), 1.24-1.77 (m, 8H), 1.92 (m, 1H), 2.28 (m, 1H), 3.89 (s, 2H), 4.68 (s, 1H), 5.47 (dd, J=4.1, J=10.7 Hz, 1H), 6.06 (d, J=2.6 Hz, 1H), 6.39 (d, J=2.2 Hz, 1H), 7.30-7.38 (m, 2H), 7.40-7.51 (m, 1H), 7.52 (d, J=2.2 Hz, 1H), 8.22 (d, J=2.6 Hz, 1H), 10.84 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[NH:7][C:8]2[CH:14]=[C:13]([O:15][S:16]([C:19]3[CH:29]=[CH:28][C:22]([O:23][CH2:24][C:25](O)=[O:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:12]=[CH:11][C:9]=2[N:10]=1)=[O:4].[CH:30]([N:33]([CH:36]([CH3:38])C)CC)([CH3:32])C.N1CCCC1>CN(C)C=O>[CH3:1][O:2][C:3]([NH:5][C:6]1[NH:10][C:9]2[CH:11]=[CH:12][C:13]([O:15][S:16]([C:19]3[CH:20]=[CH:21][C:22]([O:23][CH2:24][C:25](=[O:26])[N:33]4[CH2:30][CH2:32][CH2:38][CH2:36]4)=[CH:28][CH:29]=3)(=[O:18])=[O:17])=[CH:14][C:8]=2[N:7]=1)=[O:4]
Reactant: COC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(OCC(=O)O)cc3)cc2[nH]1
Reactant: CCN(C(C)C)C(C)C
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: COC(=O)Nc1nc2cc(OS(=O)(=O)c3ccc(OCC(=O)N4CCCC4)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of [4-(2-methoxycarbonylamino-3H-benzoimidazol-5-yloxysulfonyl)-phenoxy]-acetic acid (40 mg, example 64-e) in dry dimethylformamide (3 ml) was treated with N-{(dimethylamino)(1H-1,2,3-triazolo[4,5-b]pyridin-1-yl)methylene}-N-methylmethanaminium hexafluorophosphate N-oxide (39 mg) and diisopropylethylamine (50 μl). After stirring at ambient temperature for 30 minutes, pyrrolidine (21 μl) was added and the mixture stirred at room temperature for a further 3 hours. The solvent was removed in vacuo and the residue was purified by triggered LC/MS to give 4-(2-oxo-2-pyrrolidin-1-yl-ethoxy)-benzenesulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl-ester as an off-white solid. Mass spectrum: 475[M+H]+; retention time=8.39 minutes.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[O:17][CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12][O:11]1)C1C=CC=CC=1.[H][H]>[OH-].[Pd+2].[OH-].C(OCC)(=O)C>[CH2:14]1[C:13]2([CH2:16][O:17][CH:10]([CH2:9][OH:8])[O:11][CH2:12]2)[CH2:15]1
Reactant: c1ccc(COCC2OCC3(CC3)CO2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: OCC1OCC2(CC2)CO1
Yield: 98.7 %

Procedure:
The 6-((benzyloxy)methyl)-5,7-dioxaspiro[2.5]octane (6.1 g, 26 mmol) obtained by the step (2a) was mixed with 20% palladium hydroxide (800 mg) and ethyl acetate (70 ml) and the mixture was stirred in a hydrogen atmosphere for 24 hours. The reaction vessel was purged with nitrogen and the catalyst was filtered off and then the solvent was distilled off to obtain the title compound (3.7 g, yield: 98.7%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[NH2:18][CH2:19][C:20]1[CH:31]=[CH:30][C:23]([CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:18][CH2:19][C:20]2[CH:31]=[CH:30][C:23]([CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:22][CH:21]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CCN(CC)Cc1ccc(CN)cc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CCN(CC)Cc1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)cc1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, (4-aminomethyl-benzyl)-diethyl-amine and DBU in DME. ES-MS m/e (%): 377 (M+H+, 100), 304 ([M+H-Et2NH]+, 40).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[C:3]=1[Cl:13].O([CH2:22][C:23]([F:26])([F:25])[F:24])S(C(F)(F)F)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH2:22][C:23]([F:26])([F:25])[F:24])[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[C:3]=1[Cl:13]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CCc1nc2c(Cl)c(Br)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1nc2c(Cl)c(Br)ccc2n1CC(F)(F)F
Temperature: 90 °C

Procedure:
5-Bromo-4-chloro-2-ethyl-1H-benzimidazole (0.049 g, 0.188 mmol), trifluoroethyl triflate (0.065 g, 0.282 mmol), and Cs2CO3 (0.092 g, 0.282 mmol) were combined in DMF (5 mL) and the resulting solution was heated to 90° C. for 30 min. The reaction mixture was partitioned between H2O and Et2O and further extracted with Et2O. The combined organic portions were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Chromatography (SiO2, EtOAc/hexanes) allowed separation of the regioisomers. 0.083 g of desired regioisomer was isolated: 1NMR (400 MHz, CDCl3) δ 7.5 (d, J=8.5 Hz, 1H), 7.2 (d, J=8.5 Hz, 1H), 4.6 (q, J=8.3 Hz, 2H), 2.9 (q, J=7.4 Hz, 2H), 1.45 (t, J=7.4 Hz, 3H); MS (ESI) m/z 343 (M+1).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C(=O)([O-])[O-].[K+].[K+].O=O.N#N.[CH3:39][O:40][C:41](=[O:49])[C:42]1[CH:47]=[CH:46][C:45](Br)=[CH:44][CH:43]=1.[CH:50]([N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)([CH3:52])[CH3:51]>COCCOC>[CH3:39][O:40][C:41](=[O:49])[C:42]1[CH:47]=[CH:46][C:45]([N:56]2[CH2:57][CH2:58][N:53]([CH:50]([CH3:52])[CH3:51])[CH2:54][CH2:55]2)=[CH:44][CH:43]=1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: CC(C)N1CCNCC1
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: COC(=O)c1ccc(N2CCN(C(C)C)CC2)cc1

Procedure:
Tris-(dibenzylidene-acetone)-dipalladium (0.05 mmol), (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (0.1 mmol) and potassium carbonate (4.6 mmol) are suspended in 1,2-dimethoxyethane (10 ml) in an oxygen-free atmosphere (N2). 4-Bromo-benzoic acid methyl ester (3.3 mmol) and 1-isopropyl-piperazine (3.9 mmol) are added and the stirred mixture is heated under reflux for 28 hours. After cooling the solvent is evaporated and water is added to the residue, which is then extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with (CH2Cl2/MeOH=95:5) as mobile phase. The product containing fractions are combined and evaporated. The residue is suspended in diethylether/pentane and the solid filtered of and dried (vacuum). A pale-brown powder with Rf=0.23 (CH2Cl2/MeOH=95:5) is obtained.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:19][CH2:18][C:17]2[NH:16][C:15](=[O:20])[CH2:14][CH2:13][C:12]=2[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](OC1CC=C2C(CCC(=O)N2)C1)(=O)[C:22]1C=CC=C[CH:23]=1.C(I)CC.[H-].[Na+]>>[CH2:21]([N:16]1[C:17]2[CH2:18][CH2:19][CH:10]([O:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][C:12]=2[CH2:13][CH2:14][C:15]1=[O:20])[CH2:22][CH3:23]
Reactant: O=C1CCC2=C(CCC(OC(=O)c3ccccc3)C2)N1
Reactant: O=C1CCC2CC(OC(=O)c3ccccc3)CC=C2N1
Agent: [H-]
Agent: [Na+]
Solvent: CCCI
Product: CCCN1C(=O)CCC2=C1CCC(OC(=O)c1ccccc1)C2

Procedure:
Following the above procedure, 59 g. of a mixture of 6-benzoyloxy-3,4,5,6,7,8-hexahydro-2(1H)-quinolinone and 6-benzoyloxy-3,4,4a,5,6,7-hexahydro-2(1H)-quinolinone were reacted with n-propyl iodide in the presence of sodium hydride to yield 1-n-propyl-6-benzoyloxy-3,4,5,6,7,8-hexahydro-2(1H)-quinolinone and the corresponding 3,4,4a,5,6,7-hexahydro isomer. The compounds were purified by chromatography over florisil using an ether-chloroform solvent mixture as the eluant. Also following the above procedure, a mixture of the 1-benzyl-6-benzoyloxyhexahydro-2(1H)-quinolinones was prepared by substituting benzyl bromide for methyl iodide.
Reaction SMILES: [Si](OC[C@@H]1C(C)=C[C@H](O)CN1C(OC(C)(C)C)=O)(C(C)(C)C)(C)C.[Si:25]([O:32][CH2:33][C@@H:34]1[CH:39]=[C:38]([CH2:40][OH:41])[C:37](=[O:42])[CH2:36][N:35]1[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>>[Si:25]([O:32][CH2:33][C@@H:34]1[CH:39]=[C:38]([CH2:40][OH:41])[C@H:37]([OH:42])[CH2:36][N:35]1[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C(CO)=C[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: CC1=C[C@H](O)CN(C(=O)OC(C)(C)C)[C@@H]1CO[Si](C)(C)C(C)(C)C
Product: CC(C)(C)OC(=O)N1C[C@@H](O)C(CO)=C[C@H]1CO[Si](C)(C)C(C)(C)C

Procedure:
The title compound was prepared as a colorless oil (13.7 g, 88%), according to the procedure described for Intermediate 79, from (S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-4-(hydroxymethyl)-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 117).
Reaction SMILES: [Br-].[O:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]1[CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[N+:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:20][CH:21]=1>[Pt]=O.C(O)(=O)C>[C:23]1([CH2:22][N:18]2[CH2:19][CH2:20][CH2:21][CH:16]([CH2:15][CH2:14][CH2:13][N:4]3[C:5](=[O:12])[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:3]3=[O:2])[CH2:17]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1ccc[n+](Cc2ccccc2)c1
Agent: O=[Pt]
Agent: [Br-]
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1CCCC1CCCN(Cc2ccccc2)C1
Reaction time: 6 h
Yield: 85 %

Procedure:
A mixture of 1.10 g (2.5 mmol) of 3-[3-(2,3-dihydro-1,3-dioxo-1H-isoindol-2-yl)propyl]-1-(phenylmethyl)pyridinium bromide, 50 mL of glacial acetic acid and 0.11 g of platinum oxide was hydrogenated at room temperature and atmospheric pressure for 6 hours with rapid stirring. The reaction mixture was filtered and concentrated, and the residue was dissolved in water. The aqueous solution was made strongly basic with aqueous potassium hydroxide and extracted several times with ethyl acetate. The combined organic extracts were washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried and evaporated to give 0.77 g of 2-[3-[1-(phenylmethyl)-3-piperidinyl]propyl]-1H-isoindole-1,3(2H)-dione as a yellow oil.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][N:5]([CH3:30])[C:6]([C:8]1[C:13]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])=[CH:12][C:11]([Cl:29])=[CH:10][N:9]=1)=[O:7].[CH3:31][O:32][CH2:33]Cl>C1COCC1>[CH3:3][O:4][N:5]([CH3:30])[C:6]([C:8]1[C:13]([N:14]([CH2:31][O:32][CH3:33])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([C:25]([F:28])([F:26])[F:27])[CH:19]=2)(=[O:17])=[O:16])=[CH:12][C:11]([Cl:29])=[CH:10][N:9]=1)=[O:7]
Reactant: COCCl
Reactant: CON(C)C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(C)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)N(C)OC)S(=O)(=O)c1ccc(C)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a mixture of sodium hydride (164 mg, 4.10 mmol) in 5 mL of THF was added a mixture of 5-chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid methoxy-methyl-amide (1.50 g, 3.42 mmol) and chloromethyl methyl ether (0.388 mL, 5.13 mmol) in 5 mL of THF. The mixture was stirred at room temperature overnight. After the removal of the solvents the residue was purified by flash column (20% ethyl acetate in hexane) to afford 1.50 grams of the title compound as a white solid: (M++H) expect 482.0. found 482.0.