Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:13]([SH:16])[CH2:14][SH:15]>>[C:1]1([CH:11]2[S:16][CH2:13][CH2:14][S:15]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: SCCS
Product: c1ccc2c(C3SCCS3)cccc2c1
Yield: 95.9 %

Procedure:
Following the general procedure as in Example 1, 38.27 gm (0.245 moles) of α-naphthaldehyde and 23.58 gm (0.25 moles) of 1,2-ethanedithiol gave, after evacuating the volatiles, 54.56 gm (0.235 moles) of an orange colored oil (96% yield).
Reaction SMILES: [H-].[Na+].C(OC(=O)[NH:9][C@@H:10]([CH3:25])[CH2:11][C:12]1[C:20]2[CH:19]=[C:18]([OH:21])[CH:17]=[CH:16][C:15]=2[N:14]2[CH2:22][CH2:23][CH2:24][C:13]=12)(C)(C)C.Br[CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:34].O>CN(C)C=O.C(OCC)(=O)C>[CH3:34][O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:21][C:18]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:22][CH2:23][CH2:24][C:13]3=[C:12]([CH2:11][C@@H:10]([NH2:9])[CH3:25])[C:20]=2[CH:19]=1
Reactant: C[C@@H](Cc1c2n(c3ccc(O)cc13)CCC2)NC(=O)OC(C)(C)C
Reactant: COCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COCCOCCOc1ccc2c(c1)c(C[C@H](C)N)c1n2CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
25 mg sodium hydride 55-65% in oil was added to a solution of 165 mg (S)-[2-(6-hydroxy-2,3-dihydro-1H-3a-aza-cyclopenta[a]inden-8-yl)-1-methyl-ethyl]-carbamic acid tert-butyl ester in 1.5 mL N,N-dimethylformamide. The mixture was stirred at room temperature for 30 min, then 122 mg 1-bromo-2-(2-methoxyethoxy)-ethane was added to the mixture and the mixture was stirred at room temperature for an additional 7 h. The reaction mixture was distributed between water and ethyl acetate. The phases were separated, the organic phase is washed with water, 10% citric acid, 10% sodium bicarbonate and brine, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel with hexane:ethyl acetate=4:1. The product fractions were evaporated and the residue taken up in 1.5 mL of a 2.16 M solution of hydrochloric acid in ethyl acetate. The mixture was stirred at room temperature for 3 h. The solid was collected by filtration, neutralised with aqueous ammonium hydroxide and purified by chromatography on silica gel with dichloromethane:methanol:aqueous ammonium hydroxide=90:9:1. The product fractions are dried over magnesium sulfate and evaporated to yield 82 mg (S)-2-{6-[2-(2-methoxy-ethoxy)-ethoxy]-2,3-dihydro-1H-3a-aza-cyclopenta[a]inden-8-yl}-1-methyl-ethylamine as light brown oil. MS: M+H=333.3; M+H−NH3=316.3.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.C(OC([N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1)=O)(C)(C)C.[F-].[Cs+].C(Cl)Cl>C(COC)OC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[F:22][C:21]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[CH2:11][N:8]1[C:6]2=[N:7][C:2]([C:33]3[CH:34]=[N:30][NH:31][CH:32]=3)=[CH:3][N:4]=[C:5]2[N:10]=[N:9]1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Fc1cc2ncccc2cc1Cn1nnc2ncc(Br)nc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: Fc1cc2ncccc2cc1Cn1nnc2ncc(-c3cn[nH]c3)nc21
Temperature: 85 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
To a suspension of 6-[(6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl]-7-fluoroquinoline (250 mg, 0.696 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester (225 mg, 0.766 mmol) in dimethoxyethane (8.0 ml) was added CsF (317 mg, 2.09 mmol) and water (1.05 ml) at R.T. After degassed several times, to the suspension, 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium (11) 1:1 complex with CH2Cl2 (25.5 mg, 0.04 mmol) was added and the reaction mixture was degassed again. After stirring at 85° C. for 16 h, the reaction mixture was cooled down to R.T. diluted with water (10 ml) and filtered. The aqueous layer was extracted with CH2Cl2 (2×50 ml) EtOAc (1×10 ml). The combined the organic layer was dried with K2CO3 filtered and combined this with the solid filtered initially, and concentrated under reduced pressure. The resulting residue was purified via flash column chromatography eluted with 0-7% CH2Cl2:MeOH to give the desired product (220 mg 91%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.18 (s, 2H) 7.53 (dd, J=8.21, 4.17 Hz, 2H) 7.84 (d, J=11.37 Hz, 1H) 8.17 (d, J=8.59 Hz, 1H) 8.29 (s, 1H) 8.41-8.46 (m, 1H) 8.70 (s, 1H) 8.92 (dd, J=4.29, 1.77 Hz, 1H) 9.25 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[N:24]=[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]3[CH:23]=[CH:22][C:17]4[O:18][CH2:19][CH2:20][O:21][C:16]=4[CH:15]=3)[N:8]2[N:7]=1)=[O:4].C(N(CC)CC)C.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>ClCCl>[O:18]1[C:17]2[CH:22]=[CH:23][C:14]([C:13]3[N:8]4[N:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:36]5[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]5)[N:24]=[C:9]4[CH:10]=[CH:11][CH:12]=3)=[CH:15][C:16]=2[O:21][CH2:20][CH2:19]1
Reactant: O=C(CCl)Nc1nc2cccc(-c3ccc4c(c3)OCCO4)n2n1
Reactant: CN1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(CC(=O)Nc2nc3cccc(-c4ccc5c(c4)OCCO5)n3n2)CC1
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-N-[5-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-acetamide (0.1 g, 0.29 mmol) in dichloromethane (2 mL), triethylamine (0.061 mL, 0.43 mmol) and N-methylpiperazine (0.036 mL, 0.32 mmol) were added successively and the mixture was stirred overnight. The solvent was removed under reduced pressure and the crude then purified by prep LCMS. LCMS Method: 2, RT=2.19 min, MI=409 [M+1], NMR 1H (DMSO): 2.29 (s, 3H), 2.48-2.50 (m, 4H), 2.53-2.58 (m, 4H), 3.25 (brs, 2H), 4.33 (brs, 4H), 7.03 (d, 1H), 7.25 (dd, 1H), 7.47 (dd, 1H), 7.62-7.71 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([S:22]([C:25]2[S:26][C:27]([Cl:30])=[CH:28][CH:29]=2)(=[O:24])=[O:23])[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[NH:13][N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:31][N:32]([CH3:44])[CH2:33][CH2:34][O:35][C:36]1[CH:37]=[C:38]([CH2:42]O)[CH:39]=[CH:40][CH:41]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1.C(Cl)Cl>[Cl:30][C:27]1[S:26][C:25]([S:22]([N:10]([S:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:8])=[O:9])[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[N:13]([CH2:42][C:38]3[CH:39]=[CH:40][CH:41]=[C:36]([O:35][CH2:34][CH2:33][N:32]([CH3:31])[CH3:44])[CH:37]=3)[N:12]=2)(=[O:23])=[O:24])=[CH:29][CH:28]=1
Reactant: CN(C)CCOc1cccc(CO)c1
Reactant: COc1cccc2[nH]nc(N(S(=O)(=O)c3ccc(Cl)s3)S(=O)(=O)c3ccc(Cl)s3)c12
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cccc2c1c(N(S(=O)(=O)c1ccc(Cl)s1)S(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(OCCN(C)C)c1
Temperature: 65 °C
Yield: 70 %

Procedure:
A mixture of 5-chloro-N-[(5-chloro-2-thienyl)sulfonyl]-N-[4-(methyloxy)-1H-indazol-3-yl]-2-thiophenesulfonamide (for a preparation see Intermediate 10) (150 mg, 0.28 mmol), (3-{[2-(dimethylamino)ethyl]oxy}phenyl)methanol (73 mg, 0.37 mmol), triphenylphosphine (113 mg, 0.43 mmol) and di-tert-butyl azodicarboxylate (132 mg, 0.57 mmol) in THF (15 mL) was heated to 65° C., O/N. The mixture was evaporated under reduced pressure, the residue was dissolved in MeOH, and then loaded on a SCX-2 ion-exchange cartridge (20 g) and eluted with sequential solvents methanol, 2M ammonia in methanol. The appropriate fractions were combined and evaporated in vacuo to give the crude product. This was dissolved in DCM and purified by chromatography on silica (20 g cartridge) on Flashmaster using a 0-15% methanol (containing 1% Et3N)-dichloromethane over 20 min. The appropriate fraction was evaporated in vacuo to give the title product (140 mg, 70%) as a white foam. LCMS (System F) RT=1.27 min, ES+ve m/z 701/703 (M+H)+.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][CH2:13][S:12][CH:11]2[C:15]([OH:17])=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:24][CH:25]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[CH2:26][CH2:27][OH:28]>>[C:1]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][CH2:13][S:12][CH:11]2[C:15]([NH:24][CH:25]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[CH2:26][CH2:27][OH:28])=[O:17])(=[O:8])=[O:9])=[CH:3][CH:2]=1
Reactant: NC(CCO)c1ccc(F)cc1
Reactant: O=C(O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1
Product: O=C(NC(CCO)c1ccc(F)cc1)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general strategies and protocols outlined in Example 1, starting from 3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidine-2-carboxylic acid (Intermediate 8) and 3-amino-3-(4-fluorophenyl)-1-propanol (Intermediate 2), the title compound was obtained in 92% purity by HPLC.
Reaction SMILES: Cl.[CH:2]1[C:3]2[N:4]([CH:11]=[CH:12][CH:13]=2)[CH:5]=[C:6]([C:8]([OH:10])=O)[N:7]=1.Cl.Cl.[N:16]12[CH2:23][C@H:20]([CH2:21][CH2:22]1)[CH2:19][C@@H:18]([NH2:24])[CH2:17]2>>[N:16]12[CH2:23][C@H:20]([CH2:21][CH2:22]1)[CH2:19][C@@H:18]([NH:24][C:8]([C:6]1[N:7]=[CH:2][C:3]3[N:4]([CH:11]=[CH:12][CH:13]=3)[CH:5]=1)=[O:10])[CH2:17]2
Reactant: O=C(O)c1cn2cccc2cn1
Reactant: N[C@@H]1C[C@H]2CCN(C1)C2
Agent: Cl
Product: O=C(N[C@@H]1C[C@H]2CCN(C2)C1)c1cn2cccc2cn1
Yield: 83 %

Procedure:
Example 15 is prepared from pyrrolo[1,2-a]pyrazine-3-carboxylic acid hydrochloride and (3R,5R)-1-azabicyclo[3.2.1]octan-3-amine dihydrochloride using Procedure C to give a mixture purified by silica gel chromatography (9% MeOH/1%NH3OH/CHCl3 as the eluent) salted with fumaric acid, and crystallized from acetone to give a white solid. Yield 83%. HRMS (FAB) calcd for C15H18N4O MH+271.1559, found 271.1550.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][CH:4]([NH2:17])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(N[C@H](C(O)=O)CCC(O)=O)(=O)C.CO>CC(C)=O>[CH3:1][CH:2]([CH3:18])[CH2:3][C@H:4]([NH2:17])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)CC(N)c1ccccc1N1CCCCC1
Agent: CC(=O)N[C@@H](CCC(=O)O)C(=O)O
Solvent: CO
Solvent: CC(C)=O
Product: CC(C)C[C@H](N)c1ccccc1N1CCCCC1

Procedure:
Equimolar quantities of racemic 3-methyl-1-(2-piperidino-phenyl)-1-butylamine and of N-acetyl-L-glutamic acid were refluxed in aceton, whereby methanol was added in such an amount to yield a clear solution.
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[NH2:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][CH:23]=[N:24]2>CCCCCC.C(OCC)(=O)C>[N:24]1[C:25]2[C:20](=[C:19]([NH:18][CH2:6][C:4]([C:7]([F:10])([F:9])[F:8])([OH:5])[CH2:3][C:2]([CH3:11])([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:1])[CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1ccccc1
Reactant: Nc1cccc2ncccc12
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(CC(O)(CNc1cccc2ncccc12)C(F)(F)F)c1ccccc1
Yield: 17.9 %

Procedure:
Analogously to Example 1, 300 mg (1.22 mmol) of 2-(2-methyl-2-phenylpropyl)-2-(trifluoromethyl)oxirane and 882 mg (6.12 mmol) of 5-aminoquinoline are reacted. After chromatography on silica gel with hexane-ethyl acetate (0-75%), 85 mg of product is obtained.
Reaction SMILES: [OH-].[Li+].[C:3]1(CC(=O)C(O)=O)C=CC=CC=1.Cl.[O:16]=[C:17]([CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])[C:18]([OH:20])=[O:19]>O1CCCC1>[O:16]=[C:17]([C:21]([CH3:3])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])[C:18]([OH:20])=[O:19]
Reactant: CC(C(=O)C(=O)O)c1ccccc1
Reactant: O=C(O)C(=O)Cc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C(=O)C(=O)O)c1ccccc1
Yield: 85 %

Procedure:
A 2.25N aqueous solution of lithium hydroxide (4.0 ml, 9.0 mmoles) and 6 ml of tetrahydrofuran were added to 0.492 g (3.0 mmoles) of phenylpyruvic acid. The mixture was gradually heated with ice cooling to react it for 12 hours. After the reaction, 20 ml of 1N hydrochloric acid was added, and the mixture was extracted with ether. The organic layer was dried over magnesium sulfate. The drying reagent was separated by filtration, and the solvent was evaporated under reduced pressure to give a pale white solid. The NMR spectral analysis of this product led to the determination that 2-oxo-3-phenylbutanoic acid formed in a yield of 85 %, and 2-oxo-3-methyl-3-phenylbutanoic acid, in a yield of 4 %.
Reaction SMILES: O=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@H:6]([C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)[CH2:5][O:4][CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>COCCOC>[C:19]1([CH2:18][NH:17][CH2:15][C@@H:6]2[CH2:5][O:4][CH2:3][CH2:2][N:7]2[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(NCc1ccccc1)[C@@H]1COCC(=O)N1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Product: c1ccc(CNC[C@@H]2COCCN2Cc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 66.5 %

Procedure:
To a solution of (3S)-5-oxo-N,4-bis(phenylmethyl)-3-morpholinecarboxamide (6.3109 g, 19.45 mmol) in 1,2-dimethoxyethane (100 mL) was added LiAlH4 (2.6 g, 68.51 mmol). The mixture was heated at 100° C. and stirred for 6 h, and then cooled to 60° C. and stirred overnight. The mixture was cooled to 0° C. and quenched by slow addition of 1 N aq. NaOH (100 mL). The mixture was extracted with Et2O (2×150 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by gradient silica gel chromatography (1% to 5% MeOH in DCM) to give 1-phenyl-N-{[(3R)-4-(phenylmethyl)-3-morpholinyl]methyl}methanamine (3.8342 g, 66%) as a light yellow oil. LCMS: (M+H)+: 297.1.
Reaction SMILES: [N:1]1[NH:2][CH:3]=[C:4]2[C:9]=1[CH2:8][CH2:7][CH:6]=[C:5]2[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.C1COCC1>[Pd].CO>[N:1]1[NH:2][CH:3]=[C:4]2[C:9]=1[CH2:8][CH2:7][CH2:6][CH:5]2[C:10]1[CH:11]=[CH:12][C:13]([C:14]#[N:15])=[CH:16][CH:17]=1
Reactant: N#Cc1ccc(C2=CCCc3n[nH]cc32)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ccc(C2CCCc3n[nH]cc32)cc1
Yield: 97.3 %

Procedure:
4-(6,7-dihydro-2H-indazol-4-yl)benzonitrile (3.21 g, 14.5 mmol) is added to THF (10 mL), MeOH (10 mL), and 5% Pd/C (0.2 g) and hydrogenated under a balloon of H2 at room temperature for two hours. The mixture is filtered through a pad of diatomaceous earth and evaporated to dryness. The residue is purified by silica gel flash chromatography eluting with 50%-70% ethyl acetate/hexanes, to give the title compound (3.15 g, 97%).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[N:11]=[CH:10][C:9]([CH2:13][CH2:14][C:15]3[CH:32]=[CH:31][C:18]([O:19][CH2:20][CH2:21][CH2:22][P:23](=[O:30])([O:27]CC)[O:24]CC)=[CH:17][C:16]=3[CH3:33])=[CH:8][C:7]=2[C:6]2[CH:34]=[CH:35][C:36]([CH3:38])=[CH:37][C:5]=2[N:4]=1>>[NH2:2][C:3]1[C:12]2[N:11]=[CH:10][C:9]([CH2:13][CH2:14][C:15]3[CH:32]=[CH:31][C:18]([O:19][CH2:20][CH2:21][CH2:22][P:23](=[O:24])([OH:27])[OH:30])=[CH:17][C:16]=3[CH3:33])=[CH:8][C:7]=2[C:6]2[CH:34]=[CH:35][C:36]([CH3:38])=[CH:37][C:5]=2[N:4]=1
Reactant: CCOP(=O)(CCCOc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1)OCC
Agent: Cl
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCCP(=O)(O)O)cc3C)cc12
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A 12 N solution of hydrochloric acid (0.10 M) was added to diethyl 3-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)propylphosphonate (from Example 149) and the resulting mixture was allowed to stir at 100° C. for 18 hours. At this point, hydrochloric acid was removed under reduced pressure and the resulting residue was purified by RP-HPLC using a 10-50% MeCN in water gradient. The resulting trifluoroacetate salt was then converted to the free base form by the addition of a saturated aqueous solution of sodium bicarbonate, followed by washing three times with ethyl acetate. The combined organic layers were dried with anhydrous Na2SO4, and the volatiles were removed in vacuo to deliver 3-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)propylphosphonic acid as a solid. 1H NMR (Dimethylsulfoxide-d6): δ 9.72 (br, 1H), 9.01 (s, 1H), 8.96 (br, 1H), 8.85 (s, 1H), 8.54 (d, 1H), 7.54 (s, 1H), 7.42 (d, 1H), 7.08 (d, 1), 6.74 (s, 1H), 6.66 (d, 1H), 3.95 (t, 2H), 3.14 (t, 2H), 2.97 (t, 2H), 2.50 (s, 3H), 2.27 (s, 3H), 1.81-1.91 (m, 2H), 1.56-1.67 (m, 2H). LRMS [M+H]=466.2
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12]O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(F)cc1
Product: COC(=O)Cc1ccc(F)cc1

Procedure:
4-Fluorophenyl acetic acid (25 g) was dissolved in anhydrous methanol, stirred under nitrogen and cooled in an ice/methanol bath. Dry HCl gas was bubbled through the reaction for 1 hr. The methanol was removed by rotary evaporator and the residue was dispersed between aqueous sodium hydrogen carbonate and dichloromethane. The organic layer was washed with brine, dried (MgSO4) and concentrated to afford the title compound as a clear oil (24.4 g). 1H NMR (360 MHz, CDCl3) δ 3.61 (2H, s), 3.70 (3H, s), 6.97-7.06 (2H, m), 7.20-7.27 (2H, m). MS Cl+ 169 [M+H]+.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:18][CH2:17][C:16]2[N:15]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[CH:13]=[CH:12][C:11]=2[CH2:10]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[ClH:1].[N:15]1[C:16]2[CH2:17][CH2:18][NH:9][CH2:10][C:11]=2[CH:12]=[CH:13][C:14]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc2c(n1)CCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc2c(n1)CCNC2
Temperature: 25 °C
Reaction time: 13 h
Yield: 112.8 %

Procedure:
The crude methyl 6-benzyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate hydrochloride (1.20 g, 3.76 mmol) was dissolved in MeOH (100 mL) and thoroughly degassed. Palladium hydroxide (0.185 g, 1.32 mmol) was added to the solution before being purged with H2 gas three times. The reaction was allowed to stir at rt for 13 h under 1 atm of H2 gas. The mixture was then filtered through a pad of Celite and rinsed with EtOH. The filtrate was then concentrated down to yield methyl 5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate hydrochloride (0.97 g, 100%). LC-MS: (FA) ES+ 220; 1H NMR (Methanol-d4, 400 MHz) δ 8.05 (d, J=8.0 Hz, 1 H), 7.89 (d, J=8.0 Hz, 1 H), 4.52 (s, 2 H), 3.98 (s, 3 H), 3.66 (t, J=6.5 Hz, 2 H), 3.33 (m, 2 H).
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:15]=[CH:14][S:13][C:12]=2[CH:16]=1.CI>C1COCC1.C([O-])(O)=O.[Na+]>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:15]=[C:14]([CH3:1])[S:13][C:12]=2[CH:16]=1
Reactant: COc1ccc2ccsc2c1
Reactant: [Li]CCCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc2cc(C)sc2c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A 2.5 M solution of n-butyllithium in hexanes (20 ml, 50 mmole) was added under argon to a solution of 6-methoxybenzo[b]thiophene 1a (3.68 g, 22.4 mmole) in THF (150 ml) at −75°. After stirring at −75° for a further 30 minutes, the cooling bath was exchanged and the reaction warmed to −10° C. prior to addition of CH3I (4.2 ml, 9.58 g, 67 mmole). The resultant mixture was stirred at 0° C. for an additional 30 minutes, then allowed to gradually warm to room temperature before diluting with saturated NaHCO3 (150 ml). The layers were separated and the aqueous phase was extracted with EtOAc (2×100 ml). The combined organic extracts were dried over Na2SO4 and concentrated, in vacuo, to give 4.2 g of an amber oil which was purified by silica gel chromatography. Elution with hexane: Et2O (98:2) and evaporation of the appropriate fractions gave 3.639 (91%) of a colourless oil. 1H NMR (DMSO-d6) δ 7.57 (1H, d, J=8.7 Hz), 7.43 (1H, d, J=2.4 Hz), 6.99 (1H, s), 6.92 (1H, dd, J=2.4, 8.7 Hz), 3.78 (3H, s), 2.50 (3H, s). Anal. Calcd. for C10H10OS: C, 67.38; H, 5.66; S, 17.99. Found: C, 67.42; H, 5.74; S, 17.87.
Reaction SMILES: O.O.[Sn](Cl)Cl.[N+:6]([C:9]1[CH:10]=[C:11]([C:18]([F:21])([F:20])[F:19])[C:12]([CH2:15][C:16]#[N:17])=[N:13][CH:14]=1)([O-])=O>CC(=O)OCC>[NH2:6][C:9]1[CH:10]=[C:11]([C:18]([F:21])([F:19])[F:20])[C:12]([CH2:15][C:16]#[N:17])=[N:13][CH:14]=1
Reactant: N#CCc1ncc([N+](=O)[O-])cc1C(F)(F)F
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: N#CCc1ncc(N)cc1C(F)(F)F
Reaction time: 3 h
Yield: 61.5 %

Procedure:
A suspension of tin(II) chloride dihydrate (58.6 mg, 0.260 mmol) in EA (60 mL) was added to a solution of 2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetonitrile (30 mg, 0.130 mmol) in EA (60 mL). The mixture was at 50° C. for 3 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The resulting 2-(5-amino-3-(trifluoromethyl)pyridin-2-yl)acetonitrile (16 mg, 0.080 mmol, 61.3% yield) was used in the next step without further purification. TLC (PE/EA=1:1, Rf=0.5): 1H NMR (400 MHz, CDCl3) δ: 8.19-8.27 (m, 1H), 7.22 (d, J=2.5 Hz, 1H), 3.97 (s, 2H); ES-LCMS m/z 202.0 (M+H).
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[C:35](=[O:39])[N:34]([C:40]1[C:41]([CH2:55][OH:56])=[C:42]([C:46]3[N:50]([CH3:51])[C:49]([C:52](O)=[O:53])=[CH:48][CH:47]=3)[CH:43]=[CH:44][CH:45]=1)[N:33]=[CH:32]2)([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[C:25]([C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[C:35](=[O:39])[N:34]([C:40]1[C:41]([CH2:55][OH:56])=[C:42]([C:46]3[N:50]([CH3:51])[C:49]([C:52]([NH2:2])=[O:53])=[CH:48][CH:47]=3)[CH:43]=[CH:44][CH:45]=1)[N:33]=[CH:32]2)([CH3:28])([CH3:26])[CH3:27]
Reactant: Cn1c(C(=O)O)ccc1-c1cccc(-n2ncc3cc(C(C)(C)C)ccc3c2=O)c1CO
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cn1c(C(N)=O)ccc1-c1cccc(-n2ncc3cc(C(C)(C)C)ccc3c2=O)c1CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.2 %

Procedure:
HATU (110 mg, 0.288 mmol) was added to a solution of 5-[3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-1H-pyrrole-2-carboxylic acid (113 mg, 0.262 mmol) in dry THF (15 mL). Ammonia gas was bubbled through the solution. The mixture was stirred at room temperature under NH3 (g) for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 5-[3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-1H-pyrrole-2-carboxylic acid amide (25 mg, yield 22%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 8.42 (s, 1H), 8.27 (d, J=8.5 Hz, 1H), 8.02-7.90 (m, 2H), 7.54-7.35 (m, 2H), 7.24-7.13 (m, 2H), 7.02 (d, J=1.9 Hz, 1H), 4.37 (s, 2H), 3.87 (s, 3H), 1.37 (s, 9H). LC-MS calcd for C25H26N4O3 (m/e) 430.20, obsd 883 [2M+Na]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>O1CCCC1.O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH2:4][OH:5]
Reactant: COc1cccc(F)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(F)c1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a solution of 2-fluoro-6-methoxybenzaldehyde (0.63 g) in tetrahydrofuran (5 mL) were added water (0.5 mL) and sodium borohydride (0.17 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water, and the resulting mixture was extracted with diethyl ether. The extract was washed with brine, and the solvent was removed under reduced pressure to give the title compound (0.58 g).