Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[N:11]([CH:29]=[CH:30][C:31]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:12]([C:15]2[CH:16]=[C:17]([S:21]([NH:24]C(C)(C)C)(=[O:23])=[O:22])[CH:18]=[N:19][CH:20]=2)=[N:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O>[CH2:1]([NH:8][C:9]1[C:10]2[N:11]([CH:29]=[CH:30][C:31]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:12]([C:15]2[CH:16]=[C:17]([S:21]([NH2:24])(=[O:22])=[O:23])[CH:18]=[N:19][CH:20]=2)=[N:13][N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cncc(-c2nnc(NCc3ccccc3)c3c(-c4ccccc4)ccn23)c1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cncc(-c2nnc(NCc3ccccc3)c3c(-c4ccccc4)ccn23)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
5-(1-(Benzylamino)-8-phenylpyrrolo[1,2-d][1,2,4]triazin-4-yl)-N-(tert-butyl)pyridine-3-sulfonamide (0.150 g, 0.293 mmol) was dissolved in TFA (10 mL) and stirred at 50° C. for 1 h. TFA was removed under reduced pressure and the resulting residue was diluted with saturated sodium bicarbonate (100 mL). The aqueous mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure to give a residue which was purified by preparative HPLC (Condition B-5 described in general methods) to yield 5-(1-(benzylamino)-8-phenylpyrrolo[1,2-d][1,2,4]triazin-4-yl)pyridine-3-sulfonamide (0.060 g, 45.0%) as a white solid. LCMS Method B-3: retention time 1.99 min, [M+1]=457.0. HPLC Method B-1: retention time 6.12 min, Purity 99.48%. 1H NMR (400 MHz, DMSO-d6) δ ppm: 4.67 (d, J=5.6 Hz, 2H), 5.64 (t, J=5.6 Hz, 1H), 6.97 (d, J=2.8 Hz, 1H), 7.25-7.35 (m, 5H), 7.42-7.44 (m, 1H), 7.47-7.50 (m, 2H), 7.55-7.57 (m, 2H), 7.69 (d, J=2.8 Hz, 1H), 7.75 (s, 2H), 8.63 (t, J=2.0 Hz, 1H), 9.16 (d, J=2.0 Hz, 1H), 9.24 (d, J=2.0 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6](=[O:13])[CH2:7][CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][OH:19].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:13])[CH2:7][CH:8]2[CH2:12][CH2:11][N:10]([CH2:17][CH2:18][OH:19])[CH2:9]2)=[CH:14][CH:15]=1
Reactant: O=C(CC1CCNC1)c1ccc(F)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(CC1CCN(CCO)C1)c1ccc(F)cc1

Procedure:
A mixture of 30.5 g of 3-(4-fluorophenacyl)pyrrolidine (Chem. Pharm. Bull., 1977, 25(8), p. 1911-1922), 19.4 g of 2-bromoethanol, 15.6 g of sodium carbonate and 400 ml of acetonitrile is heated to reflux for 6 hours. The mixture is concentrated, the residue is taken up in 150 ml of aqueous saline, the product is extracted 5 times with 150 ml of dichloromethane and this organic phase is dried over anhydrous sodium sulfate and concentrated. The oil obtained is purified by chromatography on 650 g of silica (70-230 mesh), using a mixture of dichloromethane, methanol and ammonia solution (96:4:0.4 V/V) as eluant. A colorless oil is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[N:11]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[NH:14][C:13](=[O:20])[CH2:12]2>>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:14]2[CH:15]3[CH2:18][CH2:19][N:11]([CH2:17][CH2:16]3)[CH2:12][C:13]2=[O:20])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: O=C1CN2CCC(CC2)N1
Product: O=C1CN2CCC(CC2)N1c1ccc([N+](=O)[O-])nc1
Yield: 64 %

Procedure:
Following general N—C coupling procedure 1, 5-bromo-2-nitropyridine and 1,4-diazabicyclo[3.2.2]nonan-3-one were combined and gave 4-(6-nitropyridin-3-yl)-1,4-diazabicyclo[3.2.2]nonan-3-one (418 mg) in 64% yield.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:5][C:4]=1[CH:22]=[N:23][O:24][CH2:25][CH3:26]>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:5][C:4]=1[CH2:22][NH:23][O:24][CH2:25][CH3:26]
Reactant: CCON=Cc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Agent: Cl
Solvent: CCO
Product: CCONCc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Reaction time: 4 h

Procedure:
Borane-pyridine complex (3 ml) and 10-percent hydrochloric acid (30 ml) were added dropwise in succession at 0° C. to a solution of 3-(4-chloro-3-ethoxyiminomethylphenyl)-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (3.8 g) in 40 ml of ethanol. In the course of 16 hours, another 12 ml of boranepyridine complex were added. The solution was subsequently stirred for 4 hours at reflux temperature, whereupon the solvent was distilled off. The residue was taken up in 200 ml of dichloromethane. The organic phase was washed twice using 50 ml of water in each case, then dried over sodium sulfate, and finally concentrated. This gave the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([CH3:21])[CH:15]=1)#[CH:13].N>>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([CH3:21])[CH:15]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: ON=C(Cl)c1cncc(Cl)c1
Reactant: C#Cc1ccc(F)c(C)c1
Agent: N
Product: Cc1cc(-c2cc(-c3cncc(Cl)c3)no2)ccc1F

Procedure:
The titled compound was prepared according to Method CB using the product of Example 69B (57 mg, 0.3 mmol) and 4-ethynyl-1-fluoro-2-methylbenzene (Aldrich, 40 mg, 0.3 mmol). 1H NMR (300 MHz, DMSO-d6) δ2.34 (d, J=2.0 Hz, 3H), 7.38 (t, J=9.2 Hz, 1H), 7.72 (s, 1H), 7.74-7.81 (m, 1H), 7.84-7.91 (m, 1H), 8.42 (t, J=2.1 Hz, 1H), 8.80 (d, J=2.4 Hz, 1H), 9.07 (d, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 289 (M+H)+, 291 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:12]=[C:11]([NH2:13])[NH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:14]NN>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:12]=[C:11]([NH2:13])[N:10]([CH3:14])[N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CNN
Reactant: Nc1cc(-c2ccnc(Cl)c2)n[nH]1
Product: Cn1nc(-c2ccnc(Cl)c2)cc1N
Yield: 89 %

Procedure:
This title intermediate was prepared starting from 18.B (3.10 g, 17.3 mmol) according the procedure described above for conversion of 18.B to 18.C, except that methylhydrazine (3.5 equiv.) was used. The crude product was purified by flash chromatography on silica gel using 0-8% MeOH/CH2Cl2 for elution to provide 23.A (3.44 g mg, 89%) as a brown solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12]2[C:13](=[O:19])[NH:14][C:15](=[S:18])[NH:16][CH:17]=2)=[CH:3]1.[Cl:20][C:21]1[CH:37]=[CH:36][C:24]([O:25][C:26]2[CH:33]=[CH:32][C:31]([CH2:34]Cl)=[CH:30][C:27]=2[C:28]#[N:29])=[CH:23][C:22]=1[C:38]([F:41])([F:40])[F:39].CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:20][C:21]1[CH:37]=[CH:36][C:24]([O:25][C:26]2[CH:33]=[CH:32][C:31]([CH2:34][S:18][C:15]3[NH:16][CH:17]=[C:12]([CH2:11][C:4]4[C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:2]([CH3:1])[CH:3]=4)[C:13](=[O:19])[N:14]=3)=[CH:30][C:27]=2[C:28]#[N:29])=[CH:23][C:22]=1[C:38]([F:39])([F:40])[F:41]
Reactant: Cn1cc(Cc2c[nH]c(=S)[nH]c2=O)c2ccccc21
Reactant: N#Cc1cc(CCl)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(Cc2c[nH]c(SCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)c(C#N)c3)nc2=O)c2ccccc21
Yield: 71.1 %

Procedure:
The same procedure as E80 from 5-[(1-methyl-1H-indol-3-yl)methyl]-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (50 mg, 0.184 mmol), 2-(4-chloro-3-(trifluoromethyl)phenoxy)-5-(chloromethyl)benzonitrile (77 mg, 0.221 mmol) and DIPEA (0.097 mL, 0.553 mmol) in chloroform (2 mL) was added to afford the title compound (76 mg, 71.0% yield). LCMS: rt=3.99 min, [M+H+]=581
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:34]#[N:35])=[C:13]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][N:18]([CH:23]([CH2:31][CH3:32])[C:24]([O:26]C(C)(C)C)=[O:25])[C:17](=[O:33])[CH:16]=2)[CH:14]=1>ClCCl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:34]#[N:35])=[C:13]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][N:18]([CH:23]([CH2:31][CH3:32])[C:24]([OH:26])=[O:25])[C:17](=[O:33])[CH:16]=2)[CH:14]=1
Reactant: CCC(C(=O)OC(C)(C)C)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon and at RT, 7.8 ml (101.8 mmol, 10 eq.) of trifluoroacetic acid were added to a solution of 4.1 g (10.2 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoate (racemate) in 40 ml of dichloromethane, the mixture was stirred at RT for 1 h, a further 7.8 ml (101.8 mmol, 10 eq.) of trifluoroacetic acid were added, the mixture was stirred at RT for 1 h, a further 7.8 ml (101.8 mmol, 10 eq.) of trifluoroacetic acid were added and the mixture was stirred at RT for 1 h. Once the reaction had gone to completion, the reaction mixture was concentrated under reduced pressure and the residue was co-evaporated in each case three times with dichloromethane and once with toluene and dried under reduced pressure. The residue was taken up in 100 ml of ethyl acetate and washed repeatedly with a strongly diluted aqueous sodium bicarbonate solution (where the pH of the washing water should not exceed pH 3-4 since otherwise the product is well soluble in water). The organic phase was subsequently dried (sodium sulphate), filtered and concentrated under reduced pressure. The residue was triturated with methyl tert-butyl ether, filtered, washed twice with methyl tert-butyl ether and dried under reduced pressure. Yield: 2.9 g (83% of theory)
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:22]3[N:21]=[CH:20][C:19](=[O:23])[NH:18][C:17]=3[N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:24]([C:28]1[CH:32]=[C:31]([N:33]=[C:34]=[O:35])[N:30]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:32]=[C:31]([NH:33][C:34]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([O:12][C:13]3[C:22]4[N:21]=[CH:20][C:19](=[O:23])[NH:18][C:17]=4[N:16]=[CH:15][CH:14]=3)=[CH:4][CH:3]=2)=[O:35])[N:30]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)cnc23)c2ccccc12
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc4[nH]c(=O)cnc34)c3ccccc23)n(-c2ccccc2)n1

Procedure:
Method F2 was used with 8-(4-aminonaphthalen-1-yloxy)pyrido[2,3-b]pyrazin-3(4H)-one and 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole to afford the title compound as a slightly yellow solid (65 mg, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].Cl[C:11]1[C:20]2[C:15](=[C:16]([O:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[O:14][C:13](=[O:29])[CH:12]=1>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:11]1[C:20]2[C:15](=[C:16]([O:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[O:14][C:13](=[O:29])[CH:12]=1
Reactant: Cc1cccc(Cl)c1N
Reactant: COc1ccc2c(Cl)cc(=O)oc2c1OC1CCCC1
Product: COc1ccc2c(Nc3c(C)cccc3Cl)cc(=O)oc2c1OC1CCCC1

Procedure:
The title compound was prepared from 2-chloro-6-methylaniline and 4-chloro-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one following the procedure outlined in Example 16. 1H NMR (400 MHz, DMSO-d6): δ 9.18 (s, 1H), 7.94 (d, 1H), 7.50 (dd, 1H), 7.42-7.34 (m, 2H), 7.16 (d, 1H), 4.82 (m, 1H), 4.28 (s, 1H), 3.90 (s, 3H), 2.21 (s, 3H), 1.90-1.45 (m, 8H); MS (ESI): 399.9.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1(OCC1C=CC=CC=1)[CH2:13][O:14][CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=[O:26])C>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:26])[CH2:10][CH:9]1[CH2:13][O:14][CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: COCC1(OCc2ccccc2)CCCN1C(=O)OC(C)(C)C
Product: COCC1CC(O)CN1C(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
The benzyloxy-2-methoxymethyl-pyrrolidine-1-carboxylic acid t-butyl ester (217.00 mg, 0.68 mmol) was taken up in ethyl acetate in a Paar vessel. The solution was flushed with argon and Pd/C (100 mg) was added to the vessel. The argon atmosphere was replaced by hydrogen at 50 psi. The vessel was shaken for 12 h. The hydrogen atmosphere was replaced by argon and the solution was filtered through a celite pad. The pad was washed twice with ethyl acetate. The solvent was removed under reduced pressure. The product was used without further purification. Yield 148.35 mg. 1H NMR (CDCl3, 300 MHz): δ 1.42 (s, 9H), 1.80-2.10 (m, 2H), 3.05 (bs, 1H), 3.30 (s, 3H), 3.34-3.50 (m, 3H), 4.00 (bs, 1H), 4.33-4.40 (m, 1H).
Reaction SMILES: Br[C:2]1[C:7]2[N:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:9]([C@@H:11]([NH:13][C:14]3[N:22]=[CH:21][N:20]=[C:19]4[C:15]=3[N:16]=[CH:17][N:18]4[CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:35].[CH:36]1(B(O)O)[CH2:38][CH2:37]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:36]1([C:2]2[C:7]3[N:8]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[C:9]([C@@H:11]([NH:13][C:14]4[N:22]=[CH:21][N:20]=[C:19]5[C:15]=4[N:16]=[CH:17][N:18]5[CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[CH3:12])=[N:10][C:6]=3[CH:5]=[CH:4][C:3]=2[F:35])[CH2:38][CH2:37]1
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(Br)c2n1-c1ccccn1
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(C3CC3)c2n1-c1ccccn1
Yield: 24.2 %

Procedure:
To a solution of [(S)-1-(7-bromo-6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)ethyl]-[9-(tetrahydro-pyran-2-yl)-9H-purin-6-yl]amine (267 mg, 0.49 mmol) in dioxane (10 mL) and water (0.5 mL) was added cyclopropylboronic acid (64 mg, 0.75 mmol), cesium carbonate (242 mg, 0.75 mmol) and tetrakis(triphenylphosphine)palladium (0) (57 mg, 0.05 mmol) and the reaction mixture degassed by bubbling argon through the mixture whilst under sonication. The reaction mixture was heated at reflux for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to preparative HPLC (C18 Phenomenex column, 10-90% MeCN in water 0.1% formic acid, 25 min gradient) to yield the title compound as a white solid (59 mg, 24%). LCMS (Method C): RT=2.98 min, [M+H]+=499.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]2[O:8][CH2:9][O:10][C:5]2=[CH:4][C:3]=1[C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][C:17]([O:21][CH3:22])=[CH:18]2)=[CH:13][CH:12]=1.Cl.[N:24]([O-])=O.[Na+].O>C(O)(=O)C>[CH3:22][O:21][C:17]1[CH:16]=[CH:15][C:14]2=[CH:13][CH:12]=[C:11]3[C:20]([N:24]=[N:1][C:2]4[CH:7]=[C:6]5[O:8][CH2:9][O:10][C:5]5=[CH:4][C:3]3=4)=[C:19]2[CH:18]=1
Reactant: COc1ccc2ccc(-c3cc4c(cc3N)OCO4)cc2c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2ccc3c4cc5c(cc4nnc3c2c1)OCO5
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
7-(2-Amino-4,5-methylenedioxyphenyl)-2-methoxynaphthalene 49 (70 mg, 0.24 mmol) was dissolved in acetic acid (2.0 mL) and concentrated hydrochloric acid (0.4 mL). The solution was cooled in an ice bath and diazotized by the dropwise addition of a solution of sodium nitrite (0.16 g in 1.6 mL water). The resulting diazonium solution was allowed to warm slowly to room temperature and left overnight. To the resulting red solution containing some precipitate was added 50 mL water and the reaction mixture was extracted with ethyl acetate (30 mL×3). The organic layers were combined and washed with diluted sodium hydroxide solution first, then with water and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The crude product was purified by column chromatography on silica gel using 55:45 hexanes:ethyl acetate to give compound 44 (60 mg 83%); mp 259-261° C.; IR (KBr) 2923, 1612, 1498, 1468, 1234, 1199 cm−1; UV (MeOH) 270, 250, 228 nm (log ε=4.68, 4.37, 4.44); 1H NMR (CDCl3) δ4.12 (3H, s), 6.24 (2H, s), 7.37 (1H, dd, J1=8.8, J2=2.7), 7.80 (1H, s), 7.88 (1H, d, J=8.8), 7.96 (1H, s), 8.03 (1H, d, J=9.1), 8.09 (1H, d, J=9.0), 9.15 (1H, d, J=2.7); 13C NMR δ56.32, 98.31, 102.93, 104.03, 107.49, 116.36, 120.40, 120.50, 121.09, 127.96, 130.00, 132.54, 133.34, 141.99, 146.10, 150.53, 152.09, 160.28; HRMS (EI) calcd for C18H12N2O3 m/z: 304.0848; found: 304.0852.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH2:9][N:10]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:17]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]2[CH2:16][CH2:15][CH2:14][N:13]([CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=3)[CH2:12][CH2:11]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(C(CCN2CCCNCC2)c2ccccc2)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: c1ccc(C(CCN2CCCN(Cc3ccc4ccccc4n3)CC2)c2ccccc2)cc1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
The resulting 1-(3,3-diphenylpropyl)homopiperazine was dissolved in 3 mL of ethanol, mixed with 228 mg of 2-(chloromethyl)quinoline hydrochloride and 141 mg of potassium carbonate, and stirred at 70° C. for 14 hours. The mixture was cooled to room temperature and the ethanol was removed under reduced pressure, 20 mL of aqueous 2N sodium hydroxide was added and the mixture was extracted with 20 mL×2 of ethyl acetate. The organic layers were combined, washed with 20 mL of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, ethyl acetate/methanol 95:5), to obtain 109 mg of the titled compound. This was treated with a hydrogen chloride solution in ether and the solvent was removed under reduced pressure and the residue was dried to give the hydrochloride salt of the titled compound.
Reaction SMILES: [ClH:1].[CH2:2]([N:6]1[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[CH2:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)[CH2:8][CH2:7]1)[CH2:3][CH2:4][CH3:5]>CO.[Pd]>[ClH:1].[CH2:2]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[CH2:21][C:20]([CH3:26])([CH3:27])[CH2:19]2)[CH2:8][CH2:7]1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCN1CC=C(c2ccccc2C2CC(C)(C)CC(C)(C)C2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCCN1CCC(c2ccccc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 19.1 %

Procedure:
To a solution of 1-butyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1,2,3,6-tetrahydropyridine hydrochloride (48 mg, 0.12 mmol) produced in Example (102f) in methanol (3 mL) was added 10% palladium on carbon (100 mg, wet), followed by stirring for 4 hours at room temperature and atmospheric pressure under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Ether and hexane were added to the obtained residue to produce a solid, which was then triturated by sonication. The solid was filtered and dried under reduced pressure to give 9 mg of the title compound as a light yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[C:23]([NH:25][CH2:26][CH2:27][N:28]1[C@@H:33]([CH3:34])[CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][C@H:29]1[CH3:42])=[O:24]>ClCCl>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[C:23]([NH:25][CH2:26][CH2:27][N:28]1[C@H:33]([CH3:34])[CH2:32][NH:31][CH2:30][C@@H:29]1[CH3:42])=[O:24]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1CCNC(=O)[C@@H]1CCCCN1c1nc2ccccc2o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CNC[C@H](C)N1CCNC(=O)[C@@H]1CCCCN1c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.2 %

Procedure:
Trifluoroacetic acid (10 ml) was added to a solution of tert-butyl (cis)-4-[2-([(2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinyl]carbonylamino)ethyl]-3,5-dimethyl-1-piperazinecarboxylate (0.95 g) [see Preparation 8] in dichloromethane (10 ml) at 0° C. The reaction mixture was then stirred at room temperature for 1.5 hours, after which time the solvent was removed under reduced pressure and the residue partitioned between saturated potassium carbonate solution and ethyl acetate. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The product was azeotroped several times with dichloromethane to afford (2S)-1-(1,3-benzoxazol-2-yl)-N2 -2-[(cis)-2,6-dimethyl-1-piperazinyl]ethyl-2-piperidinecarboxamide (0.65 g) as a white foam.
Reaction SMILES: [CH:1]([C:3]1[C:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][CH:6]=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:4]=1)=[O:2].[BH4-].[Na+]>C1COCC1.C(O)C>[OH:2][CH2:1][C:3]1[C:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][CH:6]=[C:5]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:4]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)nc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)nc1CO
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94.3 %

Procedure:
To a solution of 1E (2.37 g, 7.94 mmol) in THF (10 mL) and ethanol (20 mL) at 0° C. was added sodium borohydride (300 mg, 7.94 mmol) in several portions. After addition, the reaction was stirred at 0° C. for 10 min, and no starting material was detected by LC-MS. The resultant mixture was quenched with saturated aqueous NaHCO3 (30 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with saturated NaCl, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by silica gel (120 g) column chromatography eluting with a isocratic of 15% EtOAc in hexane to give the title compound as a white solid (2.25 g, 95%). LC/MS (method A): retention time=3.06 min, (M+H)+=301.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[CH2:13]1[CH:22]2[CH:17]([CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:16][CH2:15][NH:14]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:14]1[CH2:15][CH2:16][CH:17]3[CH:22]([CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:13]1)=[N:7][N:6]=[CH:5]2
Reactant: Clc1nncc2cc(Br)ccc12
Reactant: C1CCC2CNCCC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc2c(N3CCC4CCCCC4C3)nncc2c1
Temperature: 180 °C
Yield: 105.4 %

Procedure:
A mixture of 6-bromo-1-chlorophthalazine (Example 1, 0.1 g, 411 μmol), decahydroisoquinoline (114 mg, 821 μmol), potassium carbonate (57 mg, 411 μmol) and 5 mL acetonitrile was added to a glass microwave reaction vessel. The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 180° C. for 20 min. The mixture was concentrated under vacuum and purified via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOH/DCM to 6% 2M ammonia in MeOH/DCM to give 6-bromo-1-(octahydroisoquinolin-2(1H)-yl)phthalazine (0.15g) as a yellow solid. Found MS (ES+): 346, 348(M+H)+.