Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(Br)ccc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cc(Br)ccc1OCc1ccccc1

Procedure:
A suspension of 2-benzyloxy-5-bromobenzaldehyde (14.5 g, 50.2 mmol) in absolute ethanol (250 ml) was treated with sodium borohydride (2.6 g, 68.8 mmol). The reaction was stirred and the temperature slowly rose to 33 ° C. After 1 hour the reaction mixture was evaporated and the residue dissolved in ethyl acetate and poured into a mixture of ice water (200 ml) and 1N HCl (25 ml). The organic layer was separated, washed with aqueous sodium hydrogen carbonate, brine, dried (Na2SO4) and evaporated to give 2-benzyloxy-5-bromobenzylalcohol as a pale yellow oil (14.85 g, quantitative).
Reaction SMILES: [C:1]1([C@H:7]([CH2:11][CH3:12])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[CH2:34]([N:41]1[CH2:45][C@H:44]2[C@H:46]([NH2:49])[CH2:47][CH2:48][C@H:43]2[CH2:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[CH2:34]([N:41]1[CH2:45][C@H:44]2[C@H:46]([NH:49][C:8](=[O:10])[C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:11][CH3:12])[CH2:47][CH2:48][C@H:43]2[CH2:42]1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Reactant: CC[C@H](C(=O)O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC[C@H](C(=O)N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(S)-2-Phenylbutanoic acid (41.7 mg, 0.254 mmol), 1-hydroxybenzotriazole (38.9 mg, 0.254 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.045 mL, 0.254 mmol) were combined in dichloromethane (1 mL). The reaction was stirred at room temperature for 10 minutes, and then (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine (50 mg, 0.231 mmol) from Step E was added in 0.5 mL of dichloromethane. The reaction was stirred at room temperature for 20 hours, and then quenched with 0.5 mL of water. The organic layer was separated. The crude material was chromatographed using a silica gel cartridge (Analogix®, Burlington, Wis., RS-4) eluting with 1-10% methanol(ammonia)/dichloromethane to give the title compound: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.47 (d, J=7.0, 1H), 7.59 (m, 2H), 7.42 (d, J=7.1, 2H), 7.34 (dd, J=7.6, 16.5, 4H), 7.25 (dt, J=5.0, 10.1, 2H), 4.45-4.29 (m, 1H), 3.62-3.51 (m, 2H), 3.44 (d, J=13.2, 1H), 2.85 (dd, J=2.7, 9.0, 1H), 2.58-2.50 (m, 1H), 2.50-2.42 (m, 2H), 2.40-2.31 (m, 1H), 2.31-2.22 (m, 2H), 1.97 (dq, J=6.1, 12.1, 1H), 1.85 (td, J=6.9, 13.6, 1H), 1.74 (dt, J=6.4, 14.3, 1H), 1.46 (dt, J=7.1, 19.2, 1H), 1.31 (dt, J=6.2, 20.5, 1H), 0.96 (dd, J=5.5, 9.1, 3H); MS (ESI+) m/z 363 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([OH:5])=O.[CH2:32]([NH:36][CH2:37][CH:38]([CH3:40])[CH3:39])[CH:33]([CH3:35])[CH3:34]>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([N:36]([CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:32][CH:33]([CH3:35])[CH3:34])=[O:5]
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: CC(C)CNCC(C)C
Product: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)N(CC(C)C)CC(C)C

Procedure:
Starting materials: 2,6,10,14,18-pentamethyl-22-oxo-2,6,10,14,18-tricosapentaenoic acid and diisobutylamine.
Reaction SMILES: C([O:8][C:9](=[O:33])[C@@H:10]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:11][CH2:12][C:13]1[N:14](CC2C=CC=CC=2)[NH:15][NH:16][N:17]=1)C1C=CC=CC=1>C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[C:29]([O:28][C:26]([NH:25][C@@H:10]([CH2:11][CH2:12][C:13]1[N:14]=[N:15][NH:16][N:17]=1)[C:9]([OH:33])=[O:8])=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC1=NNNN1Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CCc1nn[nH]n1)C(=O)O
Reaction time: 12 h

Procedure:
To a solution of 4.63 g (S)-4-(4-benzyl-2H-tetrazol-5-yl)-2-tert-butoxycarbonylamino-butyric acid benzyl ester in 400 ml ethyl acetate were added 800 mg Pd(OH)2/C (10%) and the suspension stirred under an atmosphere of hydrogen (4 bar) for 12 h. The reaction mixture was filtrated over a plug of Celite® and washed with ethyl acetate. Yield: 2.84 g colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[NH:8][C:7](=O)[CH2:6][C:5]12[CH2:17][CH2:16][CH2:15]1.B.C1COCC1.Cl>C1COCC1>[CH3:12][C:11]1[C:10]([CH3:13])=[C:9]2[C:4]([C:5]3([CH2:15][CH2:16][CH2:17]3)[CH2:6][CH2:7][NH:8]2)=[CH:3][C:2]=1[OH:1]
Reactant: Cc1c(O)cc2c(c1C)NC(=O)CC21CCC1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: Cc1c(O)cc2c(c1C)NCCC21CCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 16.2 %

Procedure:
A solution of 6′-hydroxy-7′,8′-dimethyl-1′H-spiro[cyclobutane-1,4′-quinolin]-2′(3′H)-one (4.6 g) in THF was added to BH3-THF (45 mL) at 0° C. The mixture was stirred at room temperature for 20 minutes and allowed to reflux overnight. The mixture was cooled down and at 0° C., 3 N HCl was added to quench the excess BH3. The solvent was removed by evaporation. The solid present was collected by filtration and washed with hexane (×3), giving 7′,8′-dimethyl-2′,3′-dihydro-1′H-spiro[cyclobutane-1,4′-quinolin]-6′-ol (700 mg) as a light yellow solid. 1H-NMR (300 MHz, CDCl3) δ=6.54 (s, 2H); 4.21 (t, J=6 Hz, 2H); 2.15 (m, 5H); 2.02 (m, 8H); 2.19 (m, 8H); 1.94 (t, J=6 Hz, 2H) ppm. MS: (m/z)=218 (100, M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:14]2[C:15](=[O:31])[N:16]([CH3:30])[C:17](=[O:29])[C:18]=2[C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH3:28])[CH:20]=2)[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[CH:13]=1.[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33]>CN1CCCC1.C(OCC)(=O)C>[CH2:32]([N:34]([CH2:35][CH3:36])[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:14]2[C:15](=[O:31])[N:16]([CH3:30])[C:17](=[O:29])[C:18]=2[C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH3:28])[CH:20]=2)[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[CH:13]=1)[CH3:33]
Reactant: CN1C(=O)C(c2cn(C)c3ccccc23)=C(c2cc(OCCBr)cc3ccoc23)C1=O
Reactant: CCNCC
Agent: CN1CCCC1
Solvent: CCOC(C)=O
Product: CCN(CC)CCOc1cc(C2=C(c3cn(C)c4ccccc34)C(=O)N(C)C2=O)c2occc2c1
Reaction time: 8 h

Procedure:
Add to a solution of 3-[5-(2-bromoethoxy)benzofur-7-yl]-1-methyl-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione (600 mg, 1.25 mmol) in 1-methylpyrrolidine (8 ml), diethylamine (0.65 ml, 6.28 mmol). Stir overnight under nitrogen atmosphere. Heat the reaction to 60° C. for 4 hours. Dilute with ethyl acetate, wash with water, brine, dry over magnesium sulfate, filter and concentrate to red oil. Flash chromatography through SCX column affords the title compound as a red oil. MS(ES+): 472.1; HRMS: calculated 472.2236 found 472.2235.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9]CC)=O)=[CH:5][C:4]([CH3:12])=[N:3]1.Cl.[CH2:14]([NH2:22])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)(=O)C.O.[Rh](Cl)(Cl)Cl>[CH2:14]([NH:22][C:7]([C:6]1[N:2]([CH3:1])[N:3]=[C:4]([CH3:12])[CH:5]=1)=[O:9])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1cc(C)nn1C
Reactant: NCCc1ccccc1
Agent: Cl[Rh](Cl)Cl
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)NCCc2ccccc2)n(C)n1
Reaction time: 21 h

Procedure:
A solution of 1.68 g of ethyl 2,5-dimethyl-2H-pyrazole-3-carboxylate in 3.8 ml of phenethylamine was treated with 0.10 g of rhodium(III) trichloride.trihydrate and heated to 140° C. while stirring for 21 h. Subsequently, the mixture was taken up in ethyl acetate/water, adjusted to pH 2-3 with 2N HCl and extracted three times with ethyl acetate. The combined organic phases were washed neutral with sat. aqueous sodium chloride solution, dried over sodium sulfate and evaporated. Chromatographic purification on silica gel with hexane/ethyl acetate 50:50 yielded 1.92 g (79%) of cryst. product of m.p. 97°-98° C. Recrystallization of a sample from tBuOMe gave 2,5-dimethyl-2H-pyrazole-3-carboxylic acid phenethyl-amide as colorless crystals of m.p. 97.5°-98.5° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:21])[N:14]([CH3:20])[N:15]=[C:16]([CH3:19])[C:17]=1[OH:18])[CH3:2].C(Cl)(Cl)Cl.Cl[CH2:27][N:28]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:29](=[O:33])[O:30][CH2:31][CH3:32]>C(N(CC)CC)C>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:21])[N:14]([CH3:20])[N:15]=[C:16]([CH3:19])[C:17]=1[O:18][CH2:27][N:28]([C:29]([O:30][CH2:31][CH3:32])=[O:33])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:2]
Reactant: CCOC(=O)N(CCl)c1ccccc1
Reactant: CCc1cc(C)cc(CC)c1-c1c(O)c(C)nn(C)c1=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N(COc1c(C)nn(C)c(=O)c1-c1c(CC)cc(C)cc1CC)c1ccccc1
Temperature: 25 °C
Reaction time: 13.5 h

Procedure:
To a mixture of 0.30 g of 4-(2,6-diethyl-4-methylphenyl)-5-hydroxy-2,6-dimethyl-3(2H)-pyridazinone [compound (II-1-2)] and 5 mL of chloroform, 0.22 mL of triethylamine and 0.52 mL of ethyl N-chloromethyl-N-phenylcarbamate were added, followed by stirring at room temperature for 13.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain 0.27 g of 4-(2,6-diethyl-4-methylphenyl)-5-(N-ethoxycarbonyl-N-phenylaminomethoxy)-2,6-dimethyl-3(2H)-pyridazinone [compound (I-6-1)].
Reaction SMILES: [NH2:1][C@@H:2]([C:8]([O-:10])=[O:9])[CH2:3][CH2:4][C:5]([O-:7])=[O:6].[OH-].[Na+].Cl>CO>[NH2:1][C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: N[C@H](CCC(=O)[O-])C(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N[C@H](CCC(=O)O)C(=O)O

Procedure:
29.5 g (80.7 mmol) of dimethyl N-(2-naphthalenesulfonyl)-L- or D-glutamate were dissolved in 500 ml of methanol and stirred with 170 ml (340 mmol) of 2N sodium hydroxide solution overnight. The pH was adjusted to 1 with concentrated hydrochloric acid, the solution was evaporated to dryness under reduced pressure, the residue was partitioned between a large volume of methylene chloride and a small volume of water, the methylene chloride phase was dried over magnesium sulfate and evaporated, and the residue was recrystallized from methylene chloride to give 20.3 g (75% of theory) of N-(2-naphthalenesulfonyl)-L- or D-glutamic acid as white solid.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:25][CH:26]1[CH:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:30][CH2:29][NH:28][CH2:27]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>ClCCCl.O>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:28]2[CH2:29][CH2:30][CH:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:26]([CH3:25])[CH2:27]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CCNCC1C
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)C1CCN(Cc2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)CC1C
Temperature: 50 °C
Reaction time: 3 h

Procedure:
The mixture of 6-((trans-4-(tert-butyl)cyclohexyl)oxy)-2-naphthaldehyde (6.85 g, 22.10 mmol, 1.2 eq) and ethyl 3-methylpiperidine-4-carboxylate hydrochloride (3.15 g, 18.42 mmol, 1.0 equiv) in anhydrous DCE (30 mL) was stirred at 50° C. for 3 h, and then cooled to room temperature, NaBH(OAc)3 (7.81 g, 36.84 mmol, 2.0 equiv) was added. The resulted mixture was stirred at room temperature for 4 h. The reaction mixture was adjusted to pH=7 with aq. Na2CO3. Then the mixture was diluted with water (20 mL) and extracted with DCM (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuum to give the residue, which was purified by silica gel column chromatography (PE/EA=5:1) to give ethyl 1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-methylpiperidine-4-carboxylate as a yellow oil (5.0 g, Y: 58% for two steps). ESI-MS (M+H)+: 466.2. 1H NMR (400 MHz, CDCl3) (mixture of isomers) δ ppm 7.63-7.56 (m, 3H), 7.38-7.37 (m, 1H), 7.07-7.03 (m, 2H), 4.21-4.16 (m, 1H), 4.09-4.03 (m, 2H), 3.58-3.41 (m, 2H), 2.82-2.78 (m, 1H), 2.62-2.59 (m, 1H), 2.44-2.38 (m, 1H), 2.22-1.80 (m, 8H), 1.64-1.52 (m, 1H), 1.40-1.31 (m, 2H), 1.17 (t, J=6.8 Hz, 3H), 1.13-1.02 (m, 3H), 0.93 (d, J=6.8 Hz, 3H), 0.82 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13]OS(C)(=O)=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(C2(C[C:31]#[N:32])CCCC2)C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][C:31]#[N:32])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#CCC1(c2ccccc2)CCCC1
Reactant: CS(=O)(=O)OCC1(c2ccc(Cl)cc2)CCCC1
Product: N#CCC1(c2ccc(Cl)cc2)CCCC1
Yield: 49.16 %

Procedure:
[1-(4-chlorophenyl)-cyclopentyl]-acetonitrile (25-02) (12 g, 49.16%) was synthesized from methanesulfonic acid 1-(4-chlorophenyl)-cyclopentylmethyl ester (24-02) (32 g, 111.11 mmol) as a colourless liquid following the procedure as described for 1-phenyl-cyclopentyl)-acetonitrile (25-01).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]1[C:13]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=2[N:11](C(OC(C)(C)C)=O)[C:10]1=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]>FC(F)(F)C(O)=O.ClCCl>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]2[NH:11][C:10](=[O:26])[N:9]([CH2:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C:13]=2[CH:14]=1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)n(C(=O)OC(C)(C)C)c2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccc(Cl)cc21

Procedure:
A solution of 1.8 g (4.70 mmol) of tert-butyl 3-tert-butoxycarbonylmethyl-5-chloro-2-oxo-2,3-dihydrobenzimidazole-1-carboxylate (VIIg) in 100 ml of 2% trifluoroacetic acid in dichloromethane was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was dried in vacuo. Yield: 1.32 g (100%) of colorless solid
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([OH:15])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH:23][C:24]([C:26]1[S:30][C:29](Br)=[N:28][C:27]=1[CH3:32])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([NH:23][C:24]([C:26]1[S:30][C:29]([N:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:10]2=[O:15])=[N:28][C:27]=1[CH3:32])=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Oc1ncccc1OCc1ccccc1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Product: Cc1nc(-n2cccc(OCc3ccccc3)c2=O)sc1C(=O)NCc1ccccc1
Yield: 7 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 3-(benzyloxy)pyridin-2-ol in place of 4-aminopyridin-2(1H)-one to react with N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 7% yield: mp 198-201° C.; 1H NMR (300 MHz, CDCl3) δ 8.45 (dd, J=6.0, 3.0 Hz, 1H), 7.46-7.29 (m, 10H), 6.73 (d, J=6.0 Hz, 1H), 6.32 (t, J=6.0 Hz, 1H), 6.13 (br, 1H), 5.15 (s, 2H), 4.61 (d, J=6.0 Hz, 2H), 2.71 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 187.9, 162.1, 152.1, 148.9, 137.7, 135.5, 128.8, 128.7, 128.3, 127.8, 127.7, 127.3, 122.9, 114.8, 106.7, 106.7, 96.8, 71.1, 44.1, 17.3; MS (ES+) m/z 432.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]3[O:23][CH2:24][C:25](O)=[O:26])=[N:10]2)=[CH:5][CH:4]=1.[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>CN(C)C=O>[OH:28][CH:29]1[CH2:34][CH2:33][N:32]([C:25](=[O:26])[CH2:24][O:23][CH:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21](=[O:22])[N:13]2[C:9]2[CH:8]=[CH:7][C:6]3[C:11](=[N:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=2)[CH2:31][CH2:30]1
Reactant: OC1CCNCC1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)O)nc2n1
Solvent: CN(C)C=O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)N3CCC(O)CC3)nc2n1
Yield: 101.8 %

Procedure:
The procedure is as in Example 44, but starting with [2-(7-methoxy-1,8-napthyridin-2-yl)-3-oxo-1-isoindolinyloxy] acetic acid (3.5 g) in anhydrous dimethylformamide (70 cc), N,'-carbonyldiimidazole (1.6 g) and 4-hydroxypiperidine (0.82 g). After recrystallization in ethanol, 3-[2-(4-hydroxy-1-piperidyl)-2-oxoethoxy]-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (3.7 g), m.p. 167° C., is obtained.
Reaction SMILES: Br[C:2]1[C:3]2[NH:22][N:21]=[C:20]([NH:23][CH2:24][CH3:25])[C:4]=2[CH:5]=[N:6][C:7]=1[NH:8][C:9]([NH:11][C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])=[O:10].O1CCOC[CH2:27]1.C[Zn]C>CN1C(=O)CCC1>[CH2:24]([NH:23][C:20]1[C:4]2[CH:5]=[N:6][C:7]([NH:8][C:9]([NH:11][C@@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])=[O:10])=[C:2]([CH3:27])[C:3]=2[NH:22][N:21]=1)[CH3:25]
Reactant: C1COCCO1
Reactant: CCNc1n[nH]c2c(Br)c(NC(=O)N[C@H](C)c3ccccc3)ncc12
Agent: C[Zn]C
Solvent: CN1CCCC1=O
Product: CCNc1n[nH]c2c(C)c(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 100 °C
Reaction time: 17 h

Procedure:
An oven-dried 5 mL microwave vial was charged with (R)-1-(7-bromo-3-(ethylamino)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (100 mg, 0.198 mmol), PdOAc2 (8.5 mg, 0.038 mmol), and PCy3-BF4H (30 mg, 0.08 mmol). The reaction mixture was sealed under N2, then charged with dioxane (1.0 mL) and NMP (0.25 mL), followed by drop-wise addition of dimethylzinc (1.653 mL, 1.984 mmol, 1.2 M in toluene). The reaction was heated to 100° C. and stirred for 17 h. The reaction was quenched with TFA until gas evolution ceased and then poured into sat. aq. NaHCO3. The aqueous layer was extracted with EtOAc (×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (0-20% MeOH/DCM) followed by purification via mass-triggered reverse-phase HPLC. Fractions containing pure compound were filtered through a PS-HCO3 cartridge and the filtrate was concentrated in vacuo to give (R)-1-(3-(ethylamino)-7-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. for C18H22N6O [M+1]+ 339. found 339. 1H NMR (500 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.42-7.19 (m, 5H), 5.01 (q, J=6.9 Hz, 1H), 3.36 (m, 2H), 2.29 (s, 3H), 1.53 (d, J=7.0 Hz, 3H), 1.30 (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:5]=[C:4]([Cl:13])[N:3]=1>NC(C)(C)C>[Cl:13][C:4]1[N:3]=[C:2]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[N:7]=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:5]=1
Reactant: CC(C)(C)Nc1cc(Cl)nc(Cl)n1
Solvent: CC(C)(C)N
Product: CC(C)(C)Nc1cc(Cl)nc(NC(C)(C)C)n1

Procedure:
A solution of 10 g of 2,6-dichloro-4-(1,1-dimethylethylamino)pyrimidine in 50 ml of 1-amino-1,1-dimethylethane is heated in a closed tube at 130° C. for 15 hours. Thereafter, the reaction mixture is evaporated and the residue is distributed between 150 ml of chloroform and 30 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 10 ml of water each, then dried and evaporated. The evaporation residue is subjected to chromatography on a silica gel column by using a 9:1 mixture of hexane/ethyl acetate as eluent to give 6-chloro-2,4-bis(1,1-dimethylethylamino) pyrimidine which is recrystallized from hexane to result in a yield of 9.92 g (85.1%), m.p.: 125°-127° C. By continuing the elution with a 4:1 mixture of hexane/ethyl acetate 2-chloro-4,6-bis(1,1-dimethylethylamino)pyrimidine as a more polar product is obtained which is recrystallized from hexane to result in a yield of 0.49 g (4.2%), m.p.: 132°-135° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][C:12](=O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:23][OH:24]>C(O)C>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][C:12](=[N:23][OH:24])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CCCC(COCc2ccccc2)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=C1CCCC(COCc2ccccc2)C1
Temperature: 0 °C
Yield: 74.5 %

Procedure:
To a solution of the compound (11) (1.0 g; 4.6 mmol), in ethanol (25 ml), sodium acetate (0.754 g; 9.2 mmol) and hydroxylamine hydrochloride (0.384 g; 5.5 mmol) are added, and the resultant mixture is stirred at room temperature for 3 hours. The reaction mixture is poured into ice-water, extracted with chloroform, washed with water and dried. After concentration under reduced pressure, the residue is chromatographed on a silica gel column to give 3-benzyloxymethylcyclohexanone oxime (12) (0.8 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:24]([O:26]C)=[O:25])[CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+:29]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:24]([O-:26])=[O:25])[CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:11])=[CH:6][CH:7]=1.[Na+:29]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(C=Cc1ccc(F)cc1)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)[O-]
Yield: 98 %

Procedure:
The same procedures as in Example 60 were carried out from the compound obtained in Example 7 (3.0 g), 1 mol/L of an aqueous sodium hydroxide solution (35 mL), and methanol (150 mL), to give the captioned compound (3.0 g, 98%) as crystals.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(S(F)(F)[F:16])CC)C.O>C(Cl)Cl>[F:16][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCCCCCCCO
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCF
Yield: 90.8 %

Procedure:
A solution of 13.0 g (0.1 mole) of 1-octanol in 25 ml of methylene chloride was added dropwise to a solution of 16.1 g (0.1 mole) of diethylaminosulfur trifluoride in 60 ml methylene chloride cooled to -70° to -65°. The reaction mixture was then warmed to 25° and 50 ml of water was added. The lower organic layer was separated, dried (MgSO4) and then distilled to give 12.0 g (90%) of 1-fluorooctane as a colorless liquid: bp 42°-43° (20 mm), 19F nmr (CCl3F) δ -218.8 ppm (t, t, 1F, J = 49, 25 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([C:17]#[N:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[ClH:19].[CH3:20][CH:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1)[CH3:22].C(N(CC)CC)C.C([BH3-])#N.[Na+]>C(O)C>[ClH:19].[CH3:37][O:36][C:30]1[CH:29]=[C:28]([CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH:21]([CH3:22])[CH3:20])[CH:14]2[CH2:13][CH2:12][C:11]([C:17]#[N:18])([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:16][CH2:15]2)[CH:33]=[CH:32][C:31]=1[O:34][CH3:35]
Reactant: COc1ccc(C2(C#N)CCCCC2)cc1OC
Reactant: COc1ccc(CCCCNC(C)C)cc1OC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(CCCCN(C(C)C)C2CCC(C#N)(c3ccc(OC)c(OC)c3)CC2)cc1OC

Procedure:
A solution of 4-(3,4-dimethoxyphenyl)-4-cyanocyclohexane (5 mmol), N-(1-methylethyl)-4-(3,4-dimethoxyphenyl)butylamine hydrochloride (5 mmol), triethylamine (6 mmol) and sodium cyanoborohydride (6 mmol) in 25 ml ethanol was stirred at 25° C. for 72 hours and worked up and recrystallized. ##STR8##