Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7].[H-].[Na+].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18](F)[C:15]=1[C:16]#[N:17]>CN(C)C=O>[F:13][C:14]1[CH:21]=[CH:20][C:19]([O:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: COc1cccc(CO)c1
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(COc2ccc(F)c(C#N)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a solution of 3-methoxybenzyl alcohol (1.0 g, 7.2 mmol) in dimethylformamide was added to a cooled (0° C.) slurry of sodium hydride (0.32 g, 7.91 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour. Again, cooled (0° C.), then a solution of 2,6-difluorobenzonitrile (1.0 g, 7.2 mmol) in dimethylfomamide was added, stirred overnight at room temperature. The reaction mixture was poured on crushed ice-water, stirred, filtered and dried to afford 1.6 g of 2-fluoro-5-(3-methoxybenzyloxy)benzonitrile.
Reaction SMILES: C(OC([NH:11][C@H:12]([C@@H:20]([OH:42])[C@H:21]([OH:41])[C@@H:22]([NH:30]C(OCC1C=CC=CC=1)=O)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)C1C=CC=CC=1.[H][H]>C1COCC1.C(O)C.[Pd]>[NH2:11][C@H:12]([C@@H:20]([OH:42])[C@H:21]([OH:41])[C@@H:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [H][H]
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: N[C@@H](Cc1ccccc1)[C@@H](O)[C@H](O)[C@@H](N)Cc1ccccc1
Yield: 109.9 %

Procedure:
A solution of 10.432 g (18.36 mmol) of compound 6 in 500 ml THF and 500 ml ethyl alcohol was stirred with 1.043 g of 10% palladium on carbon at room 15 temperature. for 18 h over 1 atmosphere hydrogen pressure. The mixture was filtered through celite pad and the filtrate was concentrated to provide 6.06 g (yield) of compound 7. The oil was triturated with diethyl ether and the white solid was filtered and washed to provide pure 7 (M. P. 92-94).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[N:8][C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]2[OH:18])[CH3:2].S(=O)(=O)(O)[OH:20]>[O-2].[O-2].[O-2].[Cr+6]>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[N:8][C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]2[OH:18])(=[O:20])[CH3:2]
Reactant: CCOC(=O)c1nnc2ccc(CC)cc2c1O
Reactant: O=S(=O)(O)O
Agent: [Cr+6]
Agent: [O-2]
Product: CCOC(=O)c1nnc2ccc(C(C)=O)cc2c1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of ethyl 6-ethyl-4-hydroxycinnolin-3-yl carboxylate (5.0 g.) in concentrated sulphuric acid (30 ml.) was stirred at 10° C. as chromium trioxide (6.0 g.) was added. The solution was stirred at room temperature for 5 hours and then was poured onto cracked ice. The resulting aqueous solution was extracted with ethyl acetate (4 × 250 ml.), and the combined extracts were shaken with excess sodium bisulphite solution to extract ketonic material as the bisulphite compound. The aqueous bisulphite solution was washed with ethyl acetate (2 × 250 ml.), and then treated with excess 40% v/v formaldehyde in water and sodium bicarbonate solution. The aqueous solution was extracted with ethyl acetate (3 × 250 ml.) and the combined extracts were dried (MgSO4), and filtered. Evaporation of the filtrate yielded a solid residue which on recrystallisation from a mixture of ethanol and ether gave ethyl 6-acetyl-4-hydroxycinnolin-3-yl carboxylate, m.p. 250°-252° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH2:20][NH:19][CH2:18][CH2:17]2.C(N(CC)CC)C>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH2:20][N:19]([C:7]([C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:8])[CH2:18][CH2:17]2
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc2c(c1)CCNC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CCc3cc(OC)ccc3C2)cc1
Reaction time: 18 h
Yield: 69.5 %

Procedure:
4-Methoxy-benzoyl chloride (2.35 g) was added dropwise to a solution of 6-methoxy-1,2,3,4-tetrahydro-isoquinoline (0.75 g) and triethylamine (1.54 mL) in dichloromethane (40 mL) at 0° C. After 18 h at room temperature, the reaction was washed with 1N NaOH (2×50 mL), then water (2×50 mL). The organic extract was dried over sodium sulfate, filtered through celite and concentrated. The (6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-(4-methoxy-phenyl)-methanone (0.95 g) product was obtained after purification by chromatography on silica gel (eluant: methylene chloride).
Reaction SMILES: Br[C:2]1[C:3](=[O:8])[CH2:4][CH2:5][C:6]=1[CH3:7].[F:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][C:19]=1B1OC(C)(C)C(C)(C)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOCC.C1COCC1>[F:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][C:19]=1[C:2]1[C:3](=[O:8])[CH2:4][CH2:5][C:6]=1[CH3:7]
Reactant: CC1=C(Br)C(=O)CC1
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2=C(C)CCC2=O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 78.1 %

Procedure:
A screw-cap vial was charged with 2-bromo-3-methyl-2-cyclopenten-1-one (available from Aldrich) (0.68 g, 3.9 mmol), 66.56A (1.00 g, 2.6 mmol), potassium phosphate (1.6 g, 7.8 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (available from Aldrich) (0.33 g, 0.80 mmol), palladium(II) acetate (available from Aldrich) (0.058 g, 0.26 mmol), degassed THF (17 mL), and water (0.23 mL, 13 mmol). The mixture was purged three times with N2, stirred for 48 hours at room temperature under N2, filtered through silica gel (EtOAc), and concentrated. Trituration of the crude residue with ether afforded 66.56B (0.72 g, 78% yield) as a pale yellow solid.
Reaction SMILES: COC(=O)C1C=CC(NC(=O)C2C=CC(O)=C(N)C=2)=CC=1F.[CH2:23]([O:25][C:26](=[O:47])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]2[CH:37]=[CH:38][C:39]3[O:44][CH2:43][CH2:42][NH:41][C:40]=3[CH:45]=2)=[O:35])=[CH:29][C:28]=1[F:46])[CH3:24].[F:48][C:49]([F:61])([F:60])[C:50]1[CH:51]=[C:52]([S:56](Cl)(=[O:58])=[O:57])[CH:53]=[CH:54][CH:55]=1>>[CH2:23]([O:25][C:26](=[O:47])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]2[CH:37]=[CH:38][C:39]3[O:44][CH2:43][CH2:42][N:41]([S:56]([C:52]4[CH:53]=[CH:54][CH:55]=[C:50]([C:49]([F:48])([F:60])[F:61])[CH:51]=4)(=[O:58])=[O:57])[C:40]=3[CH:45]=2)=[O:35])=[CH:29][C:28]=1[F:46])[CH3:24]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)NCCO3)cc1F
Agent: COC(=O)c1ccc(NC(=O)c2ccc(O)c(N)c2)cc1F
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(C(F)(F)F)c2)CCO3)cc1F

Procedure:
2-Fluoro-4-{[4-(3-trifluoromethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid, MS (ISP): m/e=523.0 (M−H), was prepared as described for example 14, steps 1 to 8. Step 4 was performed using 4-amino-2-fluoro-benzoic acid ethyl ester, yielding 4-(4-benzyloxy-3-nitro-benzoylamino)-2-fluoro-benzoic acid ethyl ester, which was reduced to 4-(3-amino-4-hydroxy-benzoylamino)-2-fluoro-benzoic acid methyl ester in step 5 and cyclized to 4-[(3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl)-amino]-2-fluoro-benzoic acid ethyl ester in step 6. Step 7 was performed using 3-trifluoromethyl-benzenesulfonyl chloride and yielded 2-fluoro-4-{[4-(3-trifluoromethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 8.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[CH2:10]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C1C=CC=CC=1>O>[CH3:2][C:1](=[N:26][C:25]1[CH:27]=[CH:28][C:22]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:23][CH:24]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: CCCCCCCCCCCCc1ccc(N)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCCCCCc1ccc(N=C(C)c2ccccc2)cc1
Yield: 93.7 %

Procedure:
solution of acetophenone (33.5 g), p-dodecyl aniline (73 g), benzene (50 ml) was refluxed in the presence of molecular sieve (100 g) with continuous removal of water. The crude product was purified by crystallizing it from ethanol to give N-(α-methyl benzylidene)-p-dodecyl aniline (V) (95 g). V had a melting point of 47° C.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[CH:18]=[C:17]([O:22][CH2:23][C:24]#[N:25])[CH:16]=[CH:15]4)=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:26]=[N+:27]=[N-:28].[Na+].[Cl-].[NH4+].[OH-].[Na+]>CN(C=O)C.O>[C:1]1([C:7]2[O:8][C:9]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[CH:18]=[C:17]([O:22][CH2:23][C:24]3[NH:28][N:27]=[N:26][N:25]=3)[CH:16]=[CH:15]4)=[CH:10][N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCOc1ccc2cc(-c3cnc(-c4ccccc4)o3)ccc2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(-c2ncc(-c3ccc4cc(OCc5nnn[nH]5)ccc4c3)o2)cc1
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 68.4 %

Procedure:
A mixture of {[6-(2-phenyl-1,3-oxazol-5-yl)-2-naphthyl]oxy} acetonitrile (187 mg, 0.574 mmol), prepared in the previous step, sodium azide (113 mg, 1.74 mmol) and ammonium chloride (92.7 mg, 1.73 mmol) in 10 mL of DMF was stirred under nitrogen at 100° C. for 4.5 h. The reaction was diluted with 10 mL of water, made basic by the addition of 1 mL of 1 N NaOH and extracted five times with ethyl acetate. The aqueous layer was acidified by the addition of 1 N HCl. The solid that precipitated was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (145 mg, 65%) as an off-white solid, mp 239-241° C. Elemental Analysis for C21H15N5O2+0.44 H2O: Calc'd: C, 66.85; H, 4.24; N, 18.56. Found: C, 66.36; H, 4.34; N, 18.41.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O>>[Cl:20][C:21]1[CH:22]=[C:23]([CH2:24][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[CH:26]=[CH:27][CH:28]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cccc(Cl)c4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-chlorobenzaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(3-chlorophenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[Mg].Cl[C:11]1[CH:16]=[CH:15][C:14]([Mg]Br)=[CH:13]C=1.C1(=O)CCCC1.Cl>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[CH2:14][CH2:15][CH2:16][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(Br)cc1
Reactant: Clc1ccc([Mg]Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: O=C1CCCC1
Solvent: CCOCC
Product: Clc1ccc(C2=CCCC2)cc1
Reaction time: 8 h

Procedure:
From 575 g of p-chlorophenyl bromide and 78 g of magnesium turnings in 2.6 liters of anhydrous ether was prepared p-chlorophenyl magnesium bromide to which was added dropwise a solution of 252 g of cyclopentanone in 1 liter of ether. The mixture was stirred overnight and was decomposed by careful addition of dilute hydrochloric acid. The organic phase was separated, washed and dried, and the solvent was evaporated. The resulting solid was recrystallized from ethanol to give 316 g of 1-(p-chlorophenyl)cyclopentene, M.P. 71°-73° C., which was dissolved in 2.9 liters of acetic acid containing 6 ml of concentrated sulfuric acid. To this solution 133 g of 50% hydrogen peroxide was added dropwise during which time the reaction temperature was maintained at 30° to 35° C. The reaction mixture was stirred overnight after which water was added and the product was extracted into ether. The extract was washed, dried and the solvent evaporated leaving crude 2-(p-chlorophenyl)cyclopentanone which was distilled, B.P. 135°-154° C. (0.1 mm) yielding 140 g. The oxime, M.P. 154°-155° C. was reduced using Raney nickel in alcoholic ammonia to give 2-(p-chlorophenyl)cyclopentylamine which was subsequently converted to the hydrochloride salt, M.P. 226°-228° C. Following the procedure of Example 1, only substituting for cis-2-phenylcyclopentylamine hydrochloride, an appropriate amount of 2-(p-chlorophenyl)cyclopentylamine hydrochloride, the desired product was obtained, M.P. 253°-255° C.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7](=[CH:12][CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])([O-])=O.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([O-:24])=[CH:22][CH:21]=1.[Na+]>CN(C=O)C>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([O:24][C:4]2[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7](=[CH:12][CH:13]=2)[C:8]([O:10][CH3:11])=[O:9])=[CH:22][CH:21]=1
Reactant: COc1ccc([O-])cc1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C(=O)OC
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ccc(OC)cc2)cc1C(=O)OC

Procedure:
Dimethyl 4-nitrophthalate was reacted in DMF with sodium 4-methoxyphenoxide to give dimethyl 4-(4-methoxyphenoxy)phthalate in analogy to a process known from the literature (J. Org. Chem. Vol. 42, No. 21, 1977, 3419-3425). After standard working up and chromatography using hexane/EA, the diester was isolated as a brownish oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[CH:32]1([CH2:35][OH:36])[CH2:34][CH2:33]1.C([O-])([O-])=O.[K+].[K+].[I-].[Na+]>>[CH:32]1([CH2:35][O:36][CH2:2][CH2:3][CH2:4][S:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:22]4[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:21]=4)[NH:16][CH:15]=3)[CH2:10][CH2:9]2)(=[O:7])=[O:6])[CH2:34][CH2:33]1
Reactant: OCC1CC1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCOCC4CC4)CC3)c[nH]c12
Yield: 12.1 %

Procedure:
Following the general procedure of example 159, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indole-7-carboxamide (40.0 mg, 0.087 mmol), cyclopropylmethanol (72 mg, 0.87 mmol), K2CO3 (35.0 mg, 0.35 mmol) and sodium iodide (0.5 mg) were reacted to give the title compound (5.2 mg, 12%).
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([C:21]3[CH:25]=[CH:24][O:23][N:22]=3)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[O:28][C:29]([F:32])([F:31])[F:30].[CH3:33][C:34]1([CH3:48])[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH2:36][CH2:35]1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:33][C:34]1([CH3:48])[C:35]([C:2]2[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]3[CH:13]=[CH:12][C:11]([C@@H:14]([C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=3)=[CH:4][C:3]=2[O:28][C:29]([F:32])([F:31])[F:30])=[CH:36][CH2:37][CH2:38]1
Reactant: CC1(C)CCC=C1B1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)C[C@@H](c1ccc(OCc2ccc(Cl)c(OC(F)(F)F)c2)cc1)c1ccon1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: CCOC(=O)C[C@@H](c1ccc(OCc2ccc(C3=CCCC3(C)C)c(OC(F)(F)F)c2)cc1)c1ccon1
Temperature: 80 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
Compound 35.4 (1.60 g, 3.40 mmol), 36.3 (0.91 g, 4.10 mmol), Pd(OAc)2 (0.11 g, 0.51 mmol), S-phos (0.42 g, 1.02 mmol) and K3PO4 were added to a flask. The flask was flushed with nitrogen and charged with dioxane (9.0 mL) and water (3.0 mL). The mixture was then stirred at 80° C. overnight. The solvent was removed, and the residue was purified by column chromatography to give an intermediate, (S)-ethyl 3-(4-(4-(5,5-dimethylcyclopent-1-enyl)-3-(trifluoromethoxy)benzyloxy)-phenyl)-3-(isoxazol-3-yl)propanoate (0.45 g, 0.85 mmol) that was treated with LiOH (1.0 mL, 3.33 M in water) in MeOH (6.0 mL) at room temperature overnight. The reaction mixture was purified by preparative HPLC (reverse phase) to give the title compound 36. 1H NMR (CD3CN) δ 1.04 (s, 6 H), 1.85 (m, 2 H), 2.41 (m, 2 H), 2.97 (dd, J=7.5, 16.4 Hz, 1 H), 3.17 (dd, J=7.5, 16.4 Hz, 1H), 4.52 (m, 1 H), 5.07 (s, 2 H), 5.26 (m, 1 H), 6.23 (d, J=1.5 Hz, 1 H), 6.94 (d, J=6.6 Hz, 2 H), 7.22 (d, J=6.6 Hz, 2 H), 7.35-7.39 (m, 3 H), 8.41, (d, J=1.5 Hz, 1 H). MS ESI (pos.) m/e: 502 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][O:5][CH2:6][CH2:7]O.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:34]I>CCOCC.CC#N.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:9])[CH2:4][O:5][CH2:6][CH2:7][I:34]
Reactant: COC(=O)COCCO
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)COCCI
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To solution of methyl(2-hydroxyethoxy)acetate (540 mg), imidazole (411 mg) and triphenylphosphine (1.37 g) in ether (2 mL) and CH3CN (1 mL) was added iodine (1.43 g) under ice-water cooling and the mixture was stirred at 0° C. for 2 hours. After insolubles were filterred off, the filtrates were diluted with AcOEt, washed with aq Na2SO3 solution and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (20:1-5:1) to give methyl(2-iodoethoxy)acetate as colorless oil (898 mg).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][C:8]([N:10]1[CH2:14][CH2:13][C:12](=O)[CH2:11]1)=[O:9].C(=O)([O-])[O-].[K+].[K+]>CCOCC.C1(C)C=CC=CC=1>[N:1]1([C:12]2[CH2:11][N:10]([C:8]([O:7][CH3:6])=[O:9])[CH2:14][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)N1CCC(=O)C1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)N1CC=C(N2CCCC2)C1

Procedure:
Pyrrolidine (25 ml) is slowly added dropwise to a stirred suspension of 28.63 g of N-methoxycarbonyl-3-oxo-tetrahydropyrrole [prepared according to J Med Chem 5, 752 (1962)] and 29.5 g of anhydrous potassium carbonate in 200 ml ether and 100 ml toluene at 0°-5° under a nitrogen atmosphere. After 3 hours the suspension is filtered and the filtrate evaporated under reduced pressure to yield 3-pyrrolidino-N-methoxycarbonyl-2,5-dihydropyrrole as an oil. NMR (CDCl3): 4.12 (s), 4.01 (m), 3.63 (s), 3.00 (m), and 1.85 (m). Triethylamine (28 ml) and 2,4 g of 4-dimethylaminopyridine are added to a solution of 39.3 g (0.2 moles) of 3-pyrrolidino-N-methoxycarbonyl-2,5-dihydropyrrole in 850 ml of dry ether. The reaction mixture is cooled in an ice bath. A solution of 25.6 ml of ethyl malonyl chloride in 850 ml ether is added dropwise keeping the internal temperature below 5°. After 1 hour at 5° and 2 hours at room temperature, the suspension is filtered, the ether solution is washed with 10% ice cold citric acid and saturated NaHCO3 solution. The organic layer is dried over MgSO4, filtered and evaporated to yield 3-carboethoxyacetyl-4-pyrrolidino-N-methoxycarbonyl-2,5 dihydropyrrole as an oil; NMR (CDCl3) 4.44 (s), 4.37 (s), 4.17 (q) 3,73 (s), 3,42 (m), 3.32 (s), 1.90 (m) and 1.26 (t).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10](SC)[N:9](C)[N:8]=[C:7](C3C=CC=CC=3)[C:6]=2[CH:21]=1.[CH3:22][O:23][CH:24]([O:27][CH3:28])[CH2:25][NH2:26]>C(OCCO)C>[CH3:22][O:23][CH:24]([O:27][CH3:28])[CH2:25][NH:26][C:10]1[NH:11][C:5]2[CH:4]=[CH:3][CH:2]=[CH:21][C:6]=2[CH:7]=[N:8][N:9]=1
Reactant: CSC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NN1C
Reactant: COC(CN)OC
Solvent: CCOCCO
Product: COC(CNC1=NN=Cc2ccccc2N1)OC

Procedure:
A mixture of 2.66 grams (8.42 m moles) of 7-chloro-3-methyl-2-(methylthio)-5-phenyl-3H-1,3,4-benzotriazepine, 1.0 grams (9.32 m moles) of aminoacetaldehyde dimethyl acetal (98%), and 10 ml of 2-ethoxyethanol was stirred and refluxed under nitrogen for about 18 hours. The solvent was removed in vacuo on a rotary evaporator, and the residue was dissolved in diethyl ether. The resulting solution was washed in water, dried with magnesium sulfate and concentrated in vacuo. The dark residue was found to be a mixture and was chromatographed on a column containing 170 grams of alumina. The column was washed with benzene. The desired dimethoxyethylamino-1,3,4-benzotriazepine intermediate was obtained on elution with successive portions of methylene chloride and chloroform. The reactions were combined and evaporated to yield a red viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([CH3:19])[CH2:17][OH:18])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH3:29][S:30]([O:18][CH2:17][C@@H:16]([CH3:19])[CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([C:6]2[C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:10][CH2:11]1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](CO)CN1CCC(c2noc3cc(F)ccc23)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](COS(C)(=O)=O)CN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of (S)-(+)-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-1-propanol (8.8 g, 30 mmol), triethylamine (3.2 g, 32 mmol) in dichloromethane (DCM, 150 ml), methanesulfonyl chloride (4 g, 35 mmol) was added dropwise at 0° C. over 10 minutes. The mixture was stirred at room temperature for 1 hour, then concentrated. Triethylamine HCl salt was filtered off with a little DCM as solvent. The crude oil was purified with a flash chromatography column (SiO2, 90 g; eluted with DCM). The colorless oil thus purified weighed 5.28 g (47%) was used immediately in the following step.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[CH3:2].[H-].[Na+].[Cl:22][C:23]1[N:28]=[C:27]([NH:29][CH:30]([CH3:32])[CH3:31])[CH:26]=[C:25](Cl)[N:24]=1>CN(C=O)C>[Cl:22][C:23]1[N:24]=[C:25]([NH:14][CH:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:6]3[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)[CH2:13][CH2:12]2)[CH:26]=[C:27]([NH:29][CH:30]([CH3:32])[CH3:31])[N:28]=1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Reactant: CC(C)Nc1cc(Cl)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(CN2CCC(Nc3cc(NC(C)C)nc(Cl)n3)CC2)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.1 %

Procedure:
To a solution of 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (39.7 mg, 0.15 mmol, 1.2 equiv; intermediate A1) in dry DMF (1.5 mL) was added sodium hydride (6.6 mg, 0.15 mmol, 1.2 equiv; 55% free-flowing powder moistened with oil) and the reaction mixture stirred at rt under Ar. After 2 h, (2,6-dichloro-pyrimidin-4-yl)-isopropyl-amine (25.8 mg, 0.125 mmol, 1.0 equiv) was added and the mixture heated to 120° C. for 48 h. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 7.1 mg (13%) of the title compound. MS (ISP): 434.3 [M+H]+.