Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:23]([N:24]2[CH2:29][CH2:28][N:27]([CH:30]3[CH2:33][CH2:32][CH2:31]3)[CH2:26][CH2:25]2)=[CH:22][C:5]2[C:6]([CH3:21])([CH3:20])[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[C:16](=[O:17])[C:4]=2[CH:3]=1)=[CH:13][CH:12]=[C:11]([C:18]#[N:19])[CH:10]=4.[CH3:34]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:30]1([N:27]2[CH2:26][CH2:25][N:24]([C:23]3[C:2]([CH3:34])=[CH:3][C:4]4[C:16](=[O:17])[C:15]5[C:14]6[C:9](=[CH:10][C:11]([C:18]#[N:19])=[CH:12][CH:13]=6)[NH:8][C:7]=5[C:6]([CH3:21])([CH3:20])[C:5]=4[CH:22]=3)[CH2:29][CH2:28]2)[CH2:33][CH2:32][CH2:31]1
Reactant: CB1OB(C)OB(C)O1
Reactant: CC1(C)c2cc(N3CCN(C4CCC4)CC3)c(Br)cc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1N1CCN(C3CCC3)CC1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 100 °C
Reaction time: 24 h
Yield: 59.6 %

Procedure:
Under nitrogen atmosphere, to the N,N-dimethyl formamide (1.5 ml) solution of 9-bromo-8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound F4-10, 50 mg, 0.099 mmol), trimethyl boroxine (12 mg, 0.1 eq.), tetrakis triphenylphosphine palladium (39 mg, 0.2 eq.), and potassium carbonate (41 mg, 3.0 eq.) were added, and the mixture was stirred at 100° C. for 24 hr. Upon the completion of the reaction, distilled water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/methanol) to obtain the title compound (25 mg, 58%).
Reaction SMILES: Br[C:2]1[N:3]([CH2:21][S:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.C([O-])(=O)C.[K+].Cl>CN(C)C(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:11]1([C:10]2[C:9]3[C:4]([N:3]4[C:2]=2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[S:22][CH2:21]4)=[CH:5][C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=3)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CSc3ccccc3)c2c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CSc1ccccc1-3
Temperature: 100 °C
Reaction time: 3 h
Yield: 11 %

Procedure:
A suspension of methyl 2-bromo-3-cyclohexyl-1-phenylsulfanylmethyl-1H-indole-6-carboxylate (1.10 g, 2.41 mmol), potassium acetate (260 mg, 2.64 mmol) and tetrakis(triphenylphosphine) palladium (279 mg, 0.24 mmol) in N,N-dimethylacetamide (30 ml) was stirred at 100° C. for 3 hr. The reaction mixture was allowed to cool to room temperature, 2N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=20:1-7:1) to give methyl 11-cyclohexyl-5-thia-6a-azabenzo[a]fluorene-8-carboxylate (100 mg, yield 11.0%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[CH3:11].S(Cl)([Cl:14])=O>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:14])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C(=O)O)ccc1F
Product: Cc1cc(C(=O)Cl)ccc1F

Procedure:
14.00 g (90.8 mmol) 4-fluoro-3-methyl-benzoic acid are refluxed for 1 hour together with 50 ml of thionyl chloride and then evaporated down i. vac. The residue is further reacted without any more purification.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:22]5[N:26]=[CH:25][N:24](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[N:23]=5)[CH:20]=4)[N:15](C4CCCCO4)[N:14]=3)[CH:8]=2)=[O:5])[CH2:3][CH2:2]1>Cl.O1CCOCC1>[NH:24]1[CH:25]=[N:26][C:22]([C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[C:9]2[CH:8]=[C:7]([NH:6][C:4]([CH:1]3[CH2:2][CH2:3]3)=[O:5])[CH:12]=[CH:11][CH:10]=2)=[N:23]1
Reactant: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)C1CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
Cyclopropyl-N-(3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)carboxamide was dissolved in 4 mL of 4.0 N HCl in 1,4-dioxane and the reaction was stirred at room temperature overnight. After neutralization with aqueous NaHCO3, the reaction mixture was evaporated to dryness and purified by preparative HPLC. (0.026 g, 30% yield over 2 steps): 1H NMR (DMSO d6) δ 8.75 (s, 1H), 8.36 (br s, 1H), 8.24 (s, 1H), 8.12 (d, 1H), 7.76–7.72 (m, 3H), 7.5 (t, 1H), 1.83 (m, 1H), 0.97–0.84 (m, 4H); ES-MS (m/z) 345.
Reaction SMILES: [CH2:1]([NH:9][C:10]([C:12]1[CH:13]=[C:14]([C:34]2[CH:39]=[C:38]([CH:40]([CH3:42])[CH3:41])[CH:37]=[CH:36][C:35]=2[O:43][CH3:44])[C:15]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[Si]([N:55]=[N+:56]=[N-:57])(C)(C)C>ClCCl>[CH2:19]([O:18][C:17]1[CH:16]=[C:15]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:14]([C:34]2[CH:39]=[C:38]([CH:40]([CH3:42])[CH3:41])[CH:37]=[CH:36][C:35]=2[O:43][CH3:44])=[CH:13][C:12]=1[C:10]1[N:9]([CH2:1][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:57]=[N:56][N:55]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COc1ccc(C(C)C)cc1-c1cc(C(=O)NCCc2ccccc2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1-c1cc(-c2nnnn2CCc2ccccc2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
4,6-Bis-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-3-carboxylic acid phenethyl-amide (193 mg, 0.33 mmole) was dissolved in anhydrous dichloromethane (5 ml), then phosphorus pentachloride (104 mg, 0.5 mmol) was added and the resulting solution was stirred at r.t. for 3 hr. TMSN3 (0.3 ml, neat) was added and the resulting mixture was stirred at r.t. for 3 hr. After quenching the reaction with sodium bicarbonate solution, the mixture was extracted with dichloromethane (3×20 ml). The combined organic were dried over Na2SO4. After filtration and concentration, the residue was purified by flash chromatography on silica gel to give 5-(4,6-bis-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-3-yl)-1-phenethyl-1H-tetrazole (201 mg, 89%). M.p.: 118-120° C.; 400 MHz 1H NMR (CDCl3, δ: 7.32-7.23 (m, 8H), 7.19-7.07 (m, 8H), 6.92 (s, 1H), 6.90 (s, 1H), 6.87 (d, J=8.0 Hz, 1H), 6.68 (s, 1H), 5.05 (s, 2H), 4.99 (s, 2H), 4.43 (t, J=7.6 Hz, 2H), 3.70 (s, 3H), 3.11 (t, J=7.6 Hz, 2H), 2.92-2.84 (m, 1H), 1.24 (d, J=7.2 Hz, 6H); LCMS: 611 [M+H].
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.Cl.[CH2:39]([O:46][P:47]([CH2:56][C@H:57]([OH:60])[CH2:58][NH2:59])([CH2:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1)=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH2:39]([O:46][P:47]([CH2:56][C@H:57]([OH:60])[CH2:58][NH:59][C:13](=[O:15])[C@@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH:10]([CH3:11])[CH3:12])([CH2:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1)=[O:48])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60.1 %

Procedure:
To a solution of N-Boc-L-valine (1.798 g, 7.15 mmol) and HOBT, (1.257 g, 9.30 mmol) in DMF (10 mL) under N2 was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.440 g, 7.51 mmol). The resulting clear solution was stirred at room temperature for 5 min and then a solution of ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride (2.589 g, 7.15 mmol) in DMF (15 mL) was added via cannula. Triethylamine (2.0 mL, 14.3 mmol) was added dropwise to the reaction mixture and the resulting solution was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate (75 mL) and was washed with saturated NaHCO3, half saturated brine and then brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography using 0-5% MeOH/CH2Cl2 as the eluent to yield the title diastereomeric compound (2.254 g, 4.296 mmol). 1H NMR (CD3OD, 300 MHz): δ 7.43-7.30 (m, 5H), 5.03 (m, 2H), 4.07 (m, 1H), 3.83-3.80 (m, 1H), 3.34-3.23 (m, 2H), 2.07-1.94 (m, 3H), 1.91-1.75 (m, 5H), 1.69-1.60 (m, 3H), 1.43 (s, 9H), 1.28-1.17 (m, 3H), 1.07-1.00 (m, 2H), 0.94 (d, J=6.6 Hz, 3H), 0.90 (d, J=6.6 Hz, 3H). 31P NMR (CD3OD, 300 MHz): δ 61.20, 60.48. LCMS m/z: [M+H]+=525.3.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].[C:5]([OH:10])(=[O:9])/[CH:6]=[CH:7]/[CH3:8].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>O1CCOCC1>[C:1]([S:3][CH:7]([CH3:8])[CH2:6][C:5]([OH:10])=[O:9])(=[O:4])[CH3:2]
Reactant: CC(O)=S
Reactant: C/C=C/C(=O)O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)SC(C)CC(=O)O
Yield: 92 %

Procedure:
40 ml of thioacetic acid are added to 43 g of crotonic acid in 100 ml of dioxane. After adding 20 mg of benzoyl peroxide, the mixture is kept at the boiling point under reflux for 6 hours. The solvent and the excess thioacetic acid are removed by distillation and the product is purified by vacuum distillation. 75 g (92% of theory) of 3-acetylmercapto-butyric acid are obtained; boiling point 94° to 95° C/0.45 mm Hg. nD20 1.4908.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH2:5]([O:7][P:8]([O:12]CC)[O:9][CH2:10][CH3:11])[CH3:6]>>[CH2:1]([P:8](=[O:12])([O:9][CH2:10][CH3:11])[O:7][CH2:5][CH3:6])[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: CCOP(OCC)OCC
Product: C=CCP(=O)(OCC)OCC

Procedure:
Allyl bromide was treated with triethylphosphite in the absence of solvent using microwave conditions at 150° C. to give diethyl allylphosphonate. Diethyl allylphosphonate was combined with bromotrimethyl silane and subsequently quenched with methanol to afford diethyl allylphosphonic acid according to Scheme 7.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:18]=2)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[F:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]=[C:45]=[O:46])=[CH:40][CH:39]=1>ClCCl>[F:37][C:38]1[CH:43]=[CH:42][C:41]([NH:44][C:45]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])[CH:18]=3)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:3]=2)=[O:46])=[CH:40][CH:39]=1
Reactant: Nc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)cc1)Nc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.5 %

Procedure:
The 3-[(3-aminophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (50 mg, 0.12 mmol) was dissolved in 1 mL of dichloromethane. Triethylamine (20 μL, 0.14 mmol) followed by 4-fluorophenyl isocyanate (14.6 μL, 0.13 mmol) were added. The solution was stirred at room temperature for 18 hours. The reaction was filtered through pre-wetted celite eluting with ethyl acetate. The solvent was evaporated, and the residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 26 mg (40%) of the desired N-(4fluorophenyl)-N′-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]urea product as a yellow oil, which was greater than 95% pure by reverse phase HPLC analysis. HRMS calcd. for C25H22F8N3O3: 564.1533 [M+H]+, found: 564.1566. 1H NMR (CDCl3) δ3.7 (m, 2H), 4.1 (m, 1H), 4.7 (m, 2H), 5.9 (tt, 1H), 6.6 (d, 1H), 6.9-7.4 (m, 11H), 7.5 (s, 1H), 7.8 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[C:13]([N:23]4[CH:28]=[CH:27][C:26](=[O:29])[NH:25][C:24]4=[O:30])[CH:14]=[C:15]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]=3[O:17][CH3:18])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].N1C=CC=CC=1>C(Cl)Cl>[C:19]([C:15]1[C:16]([O:17][CH3:18])=[C:11]([C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])[S:3][C:4]=3[CH:10]=2)[CH:12]=[C:13]([N:23]2[CH:28]=[CH:27][C:26](=[O:29])[NH:25][C:24]2=[O:30])[CH:14]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(-c2ccc3nc(N)sc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1c(-c2ccc3nc(NS(C)(=O)=O)sc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 4.6 %

Procedure:
To a solution of the product from Example 53 (0.35 g, 0.83 mmol) in anhydrous CH2Cl2 (50 mL) was added methanesulfonyl chloride (194 μL, 2.49 mmol) and pyridine (1.34 mL, 16.6 mmol). The resulting mixture was stirred at room temperature for 16 h and concentrated in vacuo. The crude product was purified by C-18 reverse-phase HPLC using an acetonitrile:H2O (0.1% TFA) gradient to give the title compound (19 mg, 4%). 1H NMR (300 MHz, DMSO-d6) δ 13.09 (s, 1H) 11.41 (d, J=1.84 Hz, 1H) 7.96 (d, J=1.47 Hz, 1H) 7.77 (d, J=8.09 Hz, 1H) 7.57 (dd, 1H) 7.42 (d, J=8.09 Hz, 1H) 7.25-7.32 (m, 2H) 5.64 (dd, J=8.09, 2.21 Hz, 1H) 3.25 (s, 3H) 3.02 (s, 3H) 1.40 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][NH:17][CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:28][CH:29]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)OC(C)(C)C)CC4)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cn2ncc3c4c(cnc32)CNCC4)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.1 %

Procedure:
To a solution of tert-butyl 3-(4-methoxybenzyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxylate (3.5 g, 8.8 mmol) in dichloromethane (35 mL) at room temperature was added trifluoroacetic acid (5.04 g, 44.4 mmol) in a drop wise manner. The reaction mixture was stirred at room temperature for 5 hours. Once the reaction was complete the solvent was removed under reduced pressure and the resulting residue was triturated with diethyl ether to give a solid. The solid was filtered, washed with diethyl ether and dried under reduce pressure. The dried solid was then dissolved in water and basified with saturated Na2CO3 solution. The aqueous layer was extracted with 10% methanol in CH2Cl2 (3×150 mL). The organic extracts were combined, dried using sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with hexane to afford the pure desired product 3-(4-methoxy-benzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine as a white solid (2.1 g, 80%). M.p.=96-102° C. 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.93 (s, 1H), 7.26 (d, J=8.4 Hz, 2H), 6.80 (d, J=8.4 Hz, 2H), 5.61 (s, 2H), 4.11 (s, 2H), 3.73 (s, 3H), 3.219 (t, J=6 Hz, 2H), 3.016 (t, J=6 Hz, 2H) LCMS [M+H]: 295.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].[H-].[Na+].Br[CH2:8][C:9](=[O:29])[CH2:10][C:11]([O:13][CH2:14][CH2:15][CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:12].Cl>O1CCCC1>[Cl:1][CH2:2][CH2:3][O:4][CH2:8][C:9](=[O:29])[CH2:10][C:11]([O:13][CH2:14][CH2:15][CH:16]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:12]
Reactant: OCCCl
Reactant: O=C(CBr)CC(=O)OCCC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(COCCCl)CC(=O)OCCC(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
A solution of 2.09 g (26 mmol) of 2-chloroethanol in 10 ml of tetrahydrofuran was added dropwise to a suspension of 1.84 g (46 mmol) of sodium hydride (60% oily) in 100 ml of tetrahydrofuran at −50° C., and they were stirred for 2 hours. A solution of 7.51 g (20 mmol) of 3,3-diphenylpropyl 4-bromoacetoacetate in 3 ml of tetrahydrofuran was added dropwise to the reaction mixture at −50° C. The temperature was elevated to room temperature, and they were stirred overnight. A small amount of hydrochloric acid was added to the reaction mixture. After the concentration followed by the fractionation with ethyl acetate and water, the extract was washed with 1 N sodium hydroxide and saturated aqueous sodium chloride solution and then dried over sodium sulfate to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([O:13]C)=[O:12])=[N:9][CH:10]=1.[OH-].[Na+]>CO>[F:16][C:2]([F:1])([F:15])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=[O:12])=[N:9][CH:10]=1
Reactant: COC(=O)c1ccc(OCC(F)(F)F)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 0 %

Procedure:
Methyl 5-(2,2,2-trifluoroethoxy)pyridine-2-carboxylate (Intermediate 223, 0.650 g, 2.77 mmol) was dissolved in MeOH (10 mL), 2M aq. sodium hydroxide (3.46 mL, 6.93 mmol) was added and the mixture stirred at room temperature for 2 h. MeOH was removed under vacuum and the aqueous suspension neutralised by adding 2M aq. hydrochloric acid (3.5 mL). The resultant precipitate was filtered, washed with diethyl ether and dried under vacuum to afford the title compound as a white solid (0.179 mg, 29%). 1H NMR (500 MHZ, MeOH-d4) δ ppm 8.41 (1H, d), 8.15 (1H, d), 7.59 (1H, dd) and 4.77 (2H, q).
Reaction SMILES: [NH2:1][CH:2]([C:16]([NH2:18])=[O:17])[C:3]([NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=[O:4].[CH:19]([O-])([O-])OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[F:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:5]2[C:3]([OH:4])=[C:2]([C:16]([NH2:18])=[O:17])[N:1]=[CH:19]2)=[CH:10][CH:11]=1
Reactant: CCOC([O-])[O-]
Reactant: NC(=O)C(N)C(=O)NCCOc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: NC(=O)c1ncn(CCOc2ccc(F)cc2)c1O
Reaction time: 0.5 h

Procedure:
The reagents (1 eq. of 2-amino-N-[2-(4-fluorophenoxy)ethyl]malonamide 3 per 5 eq. of ethyl orthoformate) are placed in a 100 ml three-necked flask equipped with a condenser and a calcium chloride (CaCl2) guard tube, in refluxing absolute ethanol with a catalytic amount of para-toluenesulfonic acid (PTSA), for 2 hours 30 minutes.
Reaction SMILES: [OH-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:11]=[CH:12][C:13](=[CH2:15])[CH3:14].[BH4-].[Na+]>O>[CH2:3]([O:10][CH2:14][CH:13]([CH3:15])[CH2:12][OH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: C=C(C)C=O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(CO)COCc1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.59 g. of sodium hydroxide and 1.6 ml. of water in 402 ml. (420 g; 3.89 moles) of benzyl alcohol was stirred and cooled to -10° C. while 100 ml. (83.7 g.; 1.19 moles) of freshly distilled methacrolein were added dropwise keeping the temperature between -10° C. and -5° C. After the reaction mixture had stirred for 0.5 hr. at -10° C., a solution of 44.9 g. (1.19 moles) of sodium borohydride in 180 ml. of water was added dropwise over 1.75 hr. keeping the temperature below 5° C. Stirring was continued for an additional hour during which time the reaction mixture was allowed to warm to room temperature. The resulting mixture was poured into ice-water and the organic materials were extracted several times with ether. The ether extracts were worked up by first combining the extracts washing with saturated brine and drying over anhydrous magnesium sulfate. After filtration and removal of the solvents in vacuo, the residue was carefully fractionated, giving, after removal of low boiling materials, 39.6 g. of rac. 3benzyloxy-2methyl-1-propanol as a colorless liquid, b.p. 91°-98° C. (0.5 mm Hg.).
Reaction SMILES: [C:1]([NH:4][C@H:5]1[CH2:9][CH2:8][N:7]([C:10]2[C:11]([C:21](N(OC)C)=[O:22])=[CH:12][C:13]([Cl:20])=[C:14]3[C:19]=2[N:18]=[CH:17][CH:16]=[CH:15]3)[CH2:6]1)(=[O:3])[CH3:2].[CH3:27][Mg]Br>O1CCCC1>[C:21]([C:11]1[C:10]([N:7]2[CH2:8][CH2:9][C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6]2)=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[N:18]2)=[C:13]([Cl:20])[CH:12]=1)(=[O:22])[CH3:27]
Reactant: CON(C)C(=O)c1cc(Cl)c2cccnc2c1N1CC[C@H](NC(C)=O)C1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)N[C@H]1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
To a mixture of 8-[(3S)-3-(acetylamino)pyrrolidin-1-yl]-5-chloro-N-methoxy-N-methylquinoline-7-carboxamide (75 mg, 0.20 mmol) in tetrahydrofuran (0.3 mL) was added 1.40 M methylmagnesium bromide in tetrahydrofuran (0.85 mL, 1.2 mmol). The reaction was stirred at room temperature overnight, quenched with saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and then concentrated to dryness under reduced pressure. The resultant residue was purified on silica gel, eluting with 0 to 10% MeOH in dichloromethane, to give the desired product (22 mg, 33%). LCMS calculated for C17H19ClN3O2(M+H)+: m/z=332.1; found: 332.1.