Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C:14](=[O:18])[N:15]2[CH3:19])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Cc2ccc(OCc3ccccc3)cc2N1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN1C(=O)Cc2ccc(OCc3ccccc3)cc21
Yield: 31 %

Procedure:
A mixture of 6-benzyloxy-1,3-dihydro-2H-indol-2-one (Example 9) (0.12 g; 0.5 mmol), K2CO3 (0.07 g; 0.5 mmol) and CH3I (0.031 ml) in acetone (5 ml) was refluxed under argon atmosphere for 6 hours. After evaporation to dryness, the residue was purified by flash chromatography eluting with petroleum ether/AcOEt 60/40 to give 6-benzyloxy-N-methyl-1,3-dihydro-2H-indol-2-one.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[NH:14]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1COCC1>[N:14]1([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCCNCC1
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc(N2CCCCCC2)c([N+](=O)[O-])c1
Temperature: 60 °C
Yield: 41.9 %

Procedure:
3 g (14.7 mmol) of 2-chloro-3,5-dinitropyridine, 10 ml of THF and 30 mmol of azepane were placed in a round-bottomed flask. The mixture was maintained at 60° C. for 15 hours with stirring and was then poured into an ice-water mixture with stirring. The precipitate formed was filtered off by suction and dried under vacuum to constant weight. 1.64 g of yellow powder were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH2:9])=[N:6][CH:7]=1.[CH:10](O)=[O:11].[OH-].[NH4+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][CH:10]=[O:11])=[N:6][CH:7]=1
Reactant: O=CO
Reactant: NCc1ccc(F)cn1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: O=CNCc1ccc(F)cn1
Yield: 90.1 %

Procedure:
In a round-bottomed flask, (5-fluoro-pyridin-2-yl)methylamine (557 mg, 4.42 mmol) was dissolved in 88% formic acid (3.6 ml, 82.6 mmol). The brown solution was stirred at reflux in an oil bath overnight. The reaction mixture was cooled to 0° C. and adjusted carefully to pH=9 by addition of 25% aqueous ammonium hydroxide. The mixture was diluted with water and the aqueous layer was extracted with dichloromethane (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give 614 mg (90%) of N-(5-fluoro-pyridin-2-ylmethyl)-formamide as a brown oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OCC)=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([CH:21]([CH3:23])[CH3:22])[N:15]=2)[CH:3]=1.[NH3:24].CO>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:24])=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([CH:21]([CH3:23])[CH3:22])[N:15]=2)[CH:3]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1ccc(F)c(C(C)C)n1
Reactant: N
Solvent: CO
Product: CC(C)c1nc(Nc2cc(Cl)nnc2C(N)=O)ccc1F
Temperature: 40 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
To a solution of ethyl 6-chloro-4-(5-fluoro-6-isopropylpyridin-2-ylamino)pyridazine-3-carboxylate (290 mg, 856 μmol) was added 7N ammonia in MeOH (12.2 mL, 85.6 mmol). The mixture was stirred at 40° C. for 18 h, after which the solvent was removed to give 6-chloro-4-(5-fluoro-6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamide (250 mg, 94%) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d6) δ ppm 11.86 (s, 1H), 9.26 (s, 1H), 8.19 (br. s, 1H), 7.36 (t, J=8.8 Hz, 1H), 6.79 (dd, J=8.5, 2.8 Hz, 1H), 5.70 (br. s, 1H), 3.45 (m, 1H), 1.37 (d, J=6.7 Hz, 6H).
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]#[C:10][CH2:11][OH:12])[CH2:5][CH2:4]1.Br[C:14]1[N:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1.C(N(C(C)C)C(C)C)C>>[Br:20][C:17]1[CH:16]=[N:15][C:14]([N:2]([CH3:1])[C@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]#[C:10][CH2:11][OH:12])[CH2:7][CH2:8]2)=[N:19][CH:18]=1
Reactant: Brc1cnc(Br)nc1
Reactant: CN[C@H]1CC[C@H](C#CCO)CC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ncc(Br)cn1)[C@H]1CC[C@H](C#CCO)CC1
Temperature: 80 °C

Procedure:
A mixture of 0.51 g (3.05 mmol) trans-3-(4-Methylamino-cyclohexyl)-prop-2-yn-1-ol, 0.87 g (3.66 mmol) 2,5-dibromo-pyrimidine [Brown, Desmond J.; Arantz, B. W., Pyrimidine reactions. XXII. Relative reactivities of corresponding chloro-, bromo-, and iodopyrimidines in aminolysis. J. Chem. Soc. C (1971), Issue 10, 1889–91] and 1.78 ml (10.34 mmol) N-ethyldiisopropylamine was heated for 2.5 h at 80° C. The reaction was cooled, evaporated and partitioned between aqueous saturated NaHCO3/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (NaSO4) and evaporated. Flash chromatography on silica gel (hexane/EtOAc 95:5) gave 0.72 g (73%) of trans-3-{4-[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-cyclohexyl}-prop-2-yn-1-ol, mp: 156–157° C.; MS: 324 (MH+, 1Br).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([CH2:27]OS(C)(=O)=O)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:33]([O-:36])(=[S:35])[CH3:34].[K+]>CN(C)C=O>[C:33]([S:35][CH2:27][C@@H:11]1[CH2:10][C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH2:13][N:12]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:15])(=[O:36])[CH3:34]
Reactant: CC([O-])=S
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](COS(C)(=O)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
To a solution of (2S,4R)-4-t-butyldimethylsilyloxy-2-methanesulfonyloxymethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (5.21 g) in N,N-dimethylformamide (52 ml) was added potassium thioacetate (1.83 g) and the mixture was stirred at 50°-60° C. for 1 hour. The reaction mixture was poured into ice-water (150 ml) and extracted 3 times with ethyl acetate (50 ml). The extracts were combined, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a residue. The residue was subjected to a column chromatography on silica gel (150 g) and eluted with a mixture of n-hexane and ethyl acetate (3:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-2-acetylthiomethyl-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (4.70 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC)=O.[CH3:23][NH2:24].[Cl-].[Na+]>O1CCCC1.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14](=[O:16])[NH:24][CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: CN
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
9.91 ml of triethylamine were added at -40° C. to a solution of 15.03 g of (2S, 4R)-1-(t-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid dissolved in 250 ml of dry tetrahydrofuran, and then a solution of 6.81 ml of ethyl chloroformate in 30 ml of dry tetrahydrofuran was added at -30° to -40° C. to the resulting mixture, which was then stirred at the same temperature for 1 hour. 16.82 ml of a 40% by volume aqueous methylamine solution were then added at -30° C., and the temperature of the reaction mixture was allowed to rise to room temperature; the reaction was then allowed to continue for 1 hour. At the end of this time, the reaction mixture was mixed with a small amount of an aqueous solution of sodium chloride and extracted thrice with ethyl acetate. The combined extracts were washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, giving 12.76 g of the title compound as a colorless oil.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]([C:11]2[CH:20]=[CH:19][C:14]3[C:15](=[O:18])[O:16][CH2:17][C:13]=3[C:12]=2[CH3:21])[OH:10])[CH2:4]1.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)#[N:23]>>[C:22]([C:24]1[CH:25]=[CH:26][C:27]([S:30]([NH:2][C@@H:3]2[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]([OH:10])[C:11]3[C:12]([CH3:21])=[C:13]4[C:14](=[CH:19][CH:20]=3)[C:15](=[O:18])[O:16][CH2:17]4)[CH2:4]2)(=[O:32])=[O:31])=[CH:28][CH:29]=1)#[N:23]
Reactant: Cc1c([C@@H](O)CN2CC[C@@H](N)C2)ccc2c1COC2=O
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: Cc1c([C@@H](O)CN2CC[C@@H](NS(=O)(=O)c3ccc(C#N)cc3)C2)ccc2c1COC2=O

Procedure:
4-Cyano-N—((R)-1-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)pyrrolidin-3-yl)benzenesulfonamide was prepared in a similar fashion to that described for the synthesis of EXAMPLE 14 starting from 5-{(1R)-2-[(3R)-3-Aminopyrrolidin-1-yl]-1-hydroxyethyl}-4-methyl-2-benzofuran-1(3H)-one hydrochloride [INTERMEDIATE 4] and 4-cyanobenzene-1-sulfonyl chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[H-].[Na+].Cl.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22]Cl)[CH:17]=1.O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:22][C:18]1[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=1)[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: ClCc1cccnc1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(ccn2Cc2cccnc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.2 %

Procedure:
5-Nitroindole (0.49, 3 mmol) was treated with sodium hydride (0.198 g, 6.6 mmol) in dry dimethylformamide (20 ml). After 15 min at room temperature, 3-picolyl chloride hydrochloride (0.49 g, 3 mmol) was added and the mixture was stirred at room temperature for 24 h, then poured into water. The precipitate was filtered off, washed with water and dried to give the title compound (0.67 g, 88%), m.p. 131-4° C.
Reaction SMILES: C(O[C:4]([C:6]1[O:7][C:8]([SH:11])=[N:9][N:10]=1)=[O:5])C.[CH2:12]([NH2:14])[CH3:13]>>[CH2:12]([NH:14][C:4]([C:6]1[O:7][C:8]([SH:11])=[N:9][N:10]=1)=[O:5])[CH3:13]
Reactant: CCN
Reactant: CCOC(=O)c1nnc(S)o1
Product: CCNC(=O)c1nnc(S)o1

Procedure:
This product (m.p. 210° C. with decomp.) was prepared by reacting 2-ethoxycarbonyl-1,3,4-oxadiazole-5-thiol with ethylamine in a manner similar to that described in the procedure of Example XVI, Part C as hereinafter set forth.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][S:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[O:9])[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:21][C:22]1[C:23]([CH3:38])=[N:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1.O>CN(C)C=O>[CH3:38][C:23]1[C:22]([CH2:21][O:17][C:14]2[CH:13]=[CH:12][C:11]([CH2:10][S:8]([CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[N:2]3)=[O:9])=[CH:16][CH:15]=2)=[CH:27][CH:26]=[C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][CH:29]=2)[N:24]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Reactant: O=S(CCn1ccnn1)Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1COc1ccc(CS(=O)CCn2ccnn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
A solution of 126 mg (mmol) 4-(2-[1,2,3]triazol-1-yl-ethanesulfinylmethyl)-phenol in 4.0 ml N,N-dimethylformamide was treated at 0° C. with 14 mg (0.55 mmol) of 95% sodium hydride and stirred at 0° C. for 30 min., then 143 mg (0.50 mmol) 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine were added and stirring continued over night. After addition of 8 ml water, the precipitate was isolated, washed thoroughly with water, methanol/water 1:1, and a small amount of ether. The residue was purified by chromatography on silica (eluent: ethyl acetate/methanol 9:1) to give 130 mg (52%) of the title compound as white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]=[CH2:19])=[CH:14][CH:13]=1.CCN(CC)CC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[F:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:9][OH:10])=[C:2](/[CH:19]=[CH:18]/[C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: OCc1ccc(F)cc1Br
Reactant: C=Cc1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OCc1ccc(F)cc1/C=C/c1ccc(F)cc1
Temperature: 150 °C
Yield: 49.7 %

Procedure:
Charged (2-bromo-4-fluorophenyl)methanol (954 mg, 4.65 mmol), 4-fluoro-1-vinylbenzene (1.14 g, 9.31 mmol), Pd(PPh3)2Cl2 (49 mg, 0.07 mmol), Et3N (942 mg, 9.31 mmol) and DMF (5 mL) to a sealed tube, the mixture was then purged with nitrogen, heated to 150° C. for 3 h in microwave oven. The reaction mixture was filtered, the filtrate was then extracted with ethyl acetate, concentrated and purified by flash column chromatograph to give 569 mg of the title compound (50%). 1H NMR (400 MHz, CDCl3): δ 1.60 (1H, t, J=6.4 Hz), 4.78 (2H, d, J=6.4 Hz), 6.93-7.08 (4H, m), 7.31-7.35 (3H, m), 7.48-7.52 (2H, m).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15](Cl)(=[O:17])=[O:16]>>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH:1][C@@H:2]([CH2:3][OH:4])[C:5]([OH:7])=[O:6])(=[O:17])=[O:16]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: N[C@@H](CO)C(=O)O
Product: O=C(O)[C@H](CO)NS(=O)(=O)c1ccccc1Cl

Procedure:
In analogy to example 2, L-serine was reacted with 2-chlorobenzenesulfonyl chloride to give (S)-2-(2-chloro-benzenesulfonylamino)-3-hydroxy-propionic acid as a colorless solid. MS: 278.1 ([M−H]−)
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]=[C:19]=[O:20]>CN(C=O)C>[F:8][C:7]1[C:2]([NH:1][C:19]([NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH3:10])=[O:20])=[N:3][C:4]([OH:9])=[N:5][CH:6]=1
Reactant: Nc1nc(O)ncc1F
Reactant: COc1ccccc1N=C=O
Solvent: CN(C)C=O
Product: COc1ccccc1NC(=O)Nc1nc(O)ncc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a magnetically stirred mixture of 4-amino-2-hydroxy-5-fluoropyrimidine (150 mg, 1.16 mmol) in dry DMF (3.5 mL) was added 2-methoxyphenyl isocyanate (170 μL, 1.28 mmol) and the white suspension was allowed to stir at room temperature for 60 min. The mixture was heated to 55° C. for 3 h, and then allowed to stir at room temperature overnight. The precipitate was collected by vacuum filtration and washed with Et2O (10×3 mL) to give a solid material, which was air dried for 1 h to give 1-(5-fluoro-2-hydroxypyrimidin-4-yl)-3-(2-methoxyphenyl)urea (269 mg, 83%) as a white solid: mp 247-250° C.; 1H NMR (300 MHz, DMSO-d6) δ 12.24 (bs, 1H), 11.31 (bs, 1H), 10.16 (bs, 1H), 8.14 (d, J=7.91 Hz, 1H) 8.0 (d, J=5.6, 1H), 7.03-6.99 (m, 2H), 6.95-6.88 (m, 1H), 3.87 (s, 3H) MS (ESI) m/z 276.9 (M−H)−.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][Cl:7])=[O:3].[CH2:8]([OH:10])[CH3:9].N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:4][CH2:5][CH2:6][Cl:7])[O:10][CH2:8][CH3:9]
Reactant: O=C(Cl)OCCCl
Reactant: CCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)OCCCl
Reaction time: 0.17 h
Yield: 74.8 %

Procedure:
To a solution of chloroethyl chloroformate (23.16 g, 0.162 mol) and ethanol (7.45 g, 0.162 mol) in methylene chloride (200 ml), pyridine (12.82 g, 0.162 mol) was added at 0° C. After 10 min at 0° C. and 21 hours at 25° C. the reaction mixture was washed with aqueous hydrochloric acid (100 ml), aqueous saturated sodium hydrogen carbonate (100 ml) and water (100 ml). The solvent was removed under reduced pressure after drying (MgSO4), giving 18.5 g (74%) of the intermediate ethyl chloroethyl carbonate as a crude product.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:42])[C@@H:10]([NH:22][C:23](=[O:41])[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][CH:33]([CH:36](OC)[O:37]C)[CH2:32][CH2:31]2)=[CH:26][CH:25]=1)[CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:42])[C@@H:10]([NH:22][C:23](=[O:41])[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:31][CH2:32][CH:33]([CH:36]=[O:37])[CH2:34][CH2:35]2)=[CH:26][CH:25]=1)[CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(OC)C1CCN(c2ccc(C(=O)N[C@@H](CC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=CC1CCN(c2ccc(C(=O)N[C@@H](CC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (2S)-2-{[4-(4-(dimethoxymethyl)piperidin-1-yl)benzoyl]-amino}-butanedioic acid dibenzyl ester (0.21 g, 0.4 mmol) in methylene chloride (10 mL) containing trifluoroacetic acid (0.2 ml, 2.6 mmol) was stirred at ambient temperature for 1 hour. The reaction was concentrated in vacuo to give the product which was used directly in the next step.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19]([C:23]3[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH:28]=3)=[N:18][N:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.[H][H]>[Pd].C(OCC)(=O)C>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19]([CH:23]3[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]3)=[N:18][N:17]=[CH:16]4)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(C3=CCN(C)CC3)nncc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(C3CCN(C)CC3)nncc2c1
Yield: 49.9 %

Procedure:
A mixture of N-cyclopropyl-4-methyl-3-(1-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phthalazin-6-yl)benzamide (20 mg, 50 μmol), 20 mg 10% palladium on activated carbon in 20 mL ethyl acetate was stirred under 50 psi hydrogen at 22° C. After 2 h reaction, the reaction was monitored for product (MS=401) and starting material (MS=399). The reaction mixture was stirred under 50 psi hydrogen at 22° C. for another 2 h, MS showed all starting material was converted to product. The mixture was filtered and washed with methanol 50 mL. After concentrating the filtrate, the residue was purified by PTLC to obtain the title compound (10 mg) as a pale yellow solid. Found MS (ES+): 401 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][N:9]=2)[CH:7]=1.[OH-].[Li+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=2)[CH:7]=1
Reactant: COC(=O)c1ccc(-c2cc(F)ccc2O)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(-c2cc(F)ccc2O)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
methyl 6-(5-fluoro-2-hydroxyphenyl)nicotinate (1.47 g, 6.0 mmol) was dissolved in MeOH (35 ml) and cooled to 0° C. Lithium hydroxide (0.71 g, 30.0 mmol) was then added and the mixture stirred at 0° C. for 0.5 h. The mixture was then allowed to warm to room temperature. Additional lithium hydroxide (0.43 g, 18.0 mmol) was added and the allowed to stir at room temperature for 72 h. The mixture was then concentrated in vacuo and the resulting yellow solid dissolved in water (150 ml). Acidified to pH 1 by addition of 1 N aqueous HCl and the resulting precipitate was filtered and washed with 0.5 M aqueous HCl to afford the title compound as a yellow powder (1.15 g) (72%). 1H NMR (400 MHz, DMSO-d6) □ ppm 9.11 (1H, s), 8.42-8.28 (2H, m) 7.94-7.84 (1H, m), 7.26-7.15 (1H, m), 7.02-6.92 (1H, m). LRMS: ES m/z 234 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:16]2[O:24][C:17]2([CH3:23])[C:18]([O:20]CC)=[O:19])=[C:4]([O:14][CH3:15])[C:5]2[C:10]([C:11]=1[O:12][CH3:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[OH-].[K+]>CCO>[Cl:1][C:2]1[C:3]([CH:16]2[O:24][C:17]2([CH3:23])[C:18]([OH:20])=[O:19])=[C:4]([O:14][CH3:15])[C:5]2[C:10]([C:11]=1[O:12][CH3:13])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CCOC(=O)C1(C)OC1c1c(Cl)c(OC)c2ccccc2c1OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(Cl)c(C2OC2(C)C(=O)O)c(OC)c2ccccc12
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
Darzens esters 70 (0.193 g, 0.550 mmol) were dissolved in EtOH (10.0 mL) and then KOH (0.200 g, 3.56 mmol) was added to the reaction. The reaction was heated to boiling and stirred at this temperature for 30 minutes. The reaction was then cooled, acidified, and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered, and condensed. The resulting acid was then used as crude, or can be purified via flash chromatography (1:3 EtOAc:hexanes 0.5% AcOH) or recrystallization from Et2O/hexanes to provide 102 (0.179 g, 0.555 mmol, 101%) as a yellow oil made up of 4 diastereomers.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([P:28]([O:33][CH2:34][CH3:35])([O:30][CH2:31][CH3:32])=[O:29])[CH2:10][C:11]1[N:15]2[CH:16]=[CH:17][CH:18]=[C:19]([O:20]CC3C=CC=CC=3)[C:14]2=[N:13][CH:12]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]>C(O)C>[CH2:34]([O:33][P:28]([CH:9]([P:4]([O:3][CH2:1][CH3:2])([O:5][CH2:6][CH3:7])=[O:8])[CH2:10][C:11]1[N:15]2[CH:16]=[CH:17][CH:18]=[C:19]([OH:20])[C:14]2=[N:13][CH:12]=1)(=[O:29])[O:30][CH2:31][CH3:32])[CH3:35]
Reactant: CCOP(=O)(OCC)C(Cc1cnc2c(OCc3ccccc3)cccn12)P(=O)(OCC)OCC
Solvent: CCO
Product: CCOP(=O)(OCC)C(Cc1cnc2c(O)cccn12)P(=O)(OCC)OCC
Reaction time: 12 h
Yield: 72 %

Procedure:
As shown in FIG. 7, [2-(8-Benzyloxy-imidazo[1,2-α]pyridin-3-yl)-1-(diethoxy-phosphoryl)-ethyl]-phosphonic acid diethyl ester 35 (Example 21) (1.5 g, 2.86 mmol) and ethanol (30 mL) were mixed in a 250-mL round bottomed flask and purged with nitrogen for 5 minutes. Palladium on carbon (10%, 50% wet, 1.5 g) was then added and the system purged for another 10 minutes. A balloon was then filled with hydrogen and attached to the reaction flask and the reaction allowed to proceed for 12 hours. The reaction mixture was then filtered through celite and concentrated under reduced pressure to afford 39. 860 mg, 72% yield. Dark yellow oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C:6]3[N:13]=[C:14]([CH2:20][CH3:21])[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]=3[C:4]=2[CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1>>[CH2:20]([C:14]1[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]2[C:4]3[CH:3]=[C:2]([C:24]4[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=4)[CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:12])[C:6]=2[N:13]=1)[CH3:21]
Reactant: OB(O)c1cccnc1
Reactant: CCc1nc2c(N)nc3ccc(Br)cc3c2n1CC(C)C
Product: CCc1nc2c(N)nc3ccc(-c4cccnc4)cc3c2n1CC(C)C

Procedure:
8-Bromo-2-ethyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and pyridine-3-boronic acid were coupled according to the general procedure described in Part J of Example 1. Chromatography on silica gel (5%–7% methanol in CH2Cl2 gradient) followed by recrystallization from isopropanol afforded 2-ethyl-1-isobutyl-8-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as white crystals, m.p. >250° C.