Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:14][OH:15])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH2:18][CH2:17]1>C(Cl)Cl>[C:1]1([CH2:14][O:15][C:16](=[O:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OCc1cccc2c1Cc1ccccc1-2
Reactant: O=C1CCC(=O)O1
Solvent: ClCCl
Product: O=C(O)CCC(=O)OCc1cccc2c1Cc1ccccc1-2
Reaction time: 6 h

Procedure:
Fluorenemethanol (10.0 g, 51.0 mmol) was dissolved in 150 ml CH2Cl2, and succinic anhydride (5.6 g, 56 mmol) was added. The solution was stirred for 6 h, and a further portion of succinic anhydride (2.5 g, 25 mmol) was added, and stirring continued overnight. The reaction appeared complete by TLC. The solvent was then removed, and the residue extracted with ethyl acetate, washed with 1% HCl, water, brine, dried (MgSO4) and evaporated to an oil which crystallized on standing. A quantitative yield of crude product was obtained which was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)=[C:5]([F:21])[CH:4]=1)[CH3:2].[CH3:22][C:23]1([CH3:31])[O:28][CH2:27][CH:26]([O:29][NH2:30])[CH2:25][O:24]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCl>[CH3:22][C:23]1([CH3:31])[O:28][CH2:27][CH:26]([O:29][NH:30][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][C:17]([F:20])=[C:18]([F:19])[C:10]=2[NH:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=2[F:21])[CH2:25][O:24]1
Reactant: CCc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Reactant: CC1(C)OCC(ON)CO1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(Nc2c(C(=O)NOC3COC(C)(C)OC3)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a stirring solution of the product of Example 1, Step D, 2-[(4-ethyl-2-fluorophenyl)amino]-3,4-difluorobenzoic acid (0.480 g, 1.626 mmol) in dichloromethane (15 mL) is added the product of Example 33, Step B, O-(2,2-dimethyl-[1,3]dioxan-5-yl)-hydroxylamine (0.287 g, 1.951 mmol), triethylamine (0.41 mL, 2.927 mmol), and benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (1.02 g, 1.951 mmol) and allowed to stir at ambient temperature for 75 minutes. The reaction mixture was concentrated in vacuo and the affording residue was partitioned between ethyl acetate and water. The organic layers were washed twice with saturated sodium carbonate solution and twice with brine. The organic layer was collected, dried over sodium sulfate, filtered and concentrated in vacuo. N-(2,2-Dimethyl-[1,3]dioxan-5-yloxy)-2-(4-ethyl-2-fluoro-phenylamino)-3,4-difluoro-benzamide was isolated via silica column chromatography in 4:1 hexanes/ethyl acetate affording a white foam (0.423 g, 61.4%).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([CH2:22][CH2:23]O)[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([CH2:22][CH2:23][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCc1cc(NC2CCCC2)c2[nH]c(-c3ccccc3)cc2c1
Reactant: C1CCNC1
Product: c1ccc(-c2cc3cc(CCN4CCCC4)cc(NC4CCCC4)c3[nH]2)cc1

Procedure:
2-[7-Cyclopentylamino-2-phenyl-1H-indol-5-yl]-ethanol prepared in Example 32 and pyrrolidine were reacted according to the same procedures as Steps A and B of Example 36 to give the title compound.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].O[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[C:27]#[N:28])=[CH:19][CH:18]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>ClCCl.C1(C)C=CC=CC=1>[C:12]([C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH:23]([O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=3)[C:27]#[N:28])=[CH:21][CH:22]=2)=[C:7]([CH2:8][CH2:9][CH3:10])[C:2]=1[OH:1])(=[O:14])[CH3:13]
Reactant: N#Cc1cccc(C(OC2CCCCO2)c2ccc(CO)cc2)c1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCc1c(OCc2ccc(C(OC3CCCCO3)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
Stir a solution of 1-(2,4-dihydroxy-3-propyl-phenyl)-ethanone (1.75 g, 9 mmol), 3-[(4-hydroxymethyl-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile (2.9 g, 9 mmol), toluene (10 mL), and dichloromethane (10 mL) at −20° C. Add 1,1′-(azodicarbonyl)dipiperidine (4.5 g, 18 mmol) followed by tributylphosphine (4.5 mL, 18 mmol) and allow the resulting yellow solution to stir at room temperature overnight. Concentrate the resulting thick reaction mixture and dilute with ether (50 mL). Cool the slurry to 0° C. with stirring, for 30 minutes. Filter the reaction mixture, concentrate, and purify via silica chromatography eluting with 1:1 hexanes:(5:4:1 hexanes:dichloromethane:ethyl acetate) to give the title compound (3 g, 67%), as an orange thick oil. LCMS (m/z) 498-M−1.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[CH3:12][N:13]([CH3:26])[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O.[OH-].[K+]>C(O)C>[CH3:26][N:13]([CH3:12])[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=[C:11]1[CH2:1][CH2:2][C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:9]1=[O:10]
Reactant: O=C1CCCc2ccccc21
Reactant: CN(C)CCCOc1ccccc1C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CCCOc1ccccc1C=C1CCc2ccccc2C1=O
Yield: 110.9 %

Procedure:
α-Tetralone (26.4 g) and 40 g of 2-[3-(dimethylamino)-propoxy]benzaldehyde are reacted in 180 ml of ethanol in the presence of 1.2 g of potassium hydroxide following the procedure in Example 1A. The product is extracted with ether and the solvent is evaporated to give a viscous residue (67.2 g), which begins to solidify on standing. It is crystallized from a mixture of 120 ml of warm diisopropylether and 120 ml of hexane to give 45.7 g of crystals, melting point 67°-69° C.
Reaction SMILES: C(O[CH:4]([O:15]CC)[C:5]1[CH:10]=[CH:9][C:8]([CH:11](O)[CH:12]=[CH2:13])=[CH:7][CH:6]=1)C.[C:18]([OH:22])(=[O:21])[CH2:19]C>>[CH:4]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[CH:12][CH2:13][CH2:19][C:18]([OH:22])=[O:21])=[CH:9][CH:10]=1)=[O:15]
Reactant: C=CC(O)c1ccc(C(OCC)OCC)cc1
Reactant: CCC(=O)O
Product: O=Cc1ccc(C=CCCC(=O)O)cc1
Temperature: 140 °C

Procedure:
1-(4-Diethoxymethylphenyl)prop-2-en-1-ol (9.90 g, 42 mmol) was dissolved in triethyl ortho formiate (50 ml), and propionic acid (1.0 ml) was added. The solution was heated to 140° C. for 48 hours. Solvent was removed by rotary evaporation, and the orange oil was re-suspended in aqueous HCl (200 ml, 2 N). The mixture was heated to reflux for 4 hours, then cooled on an ice-bath for 30 min. Precipitated material was collected and washed twice with water and dried in a vacuum oven. Yield: 3.02 g (35%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]([NH:17][C:18](=[O:37])[C@@H:19]([NH:29]C(OC(C)(C)C)=O)[CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl.C1(OC)C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:16][C:9]([NH:17][C:18](=[O:37])[C@@H:19]([NH2:29])[CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:8])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)NC(C)(C)c1ccccc1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(NC(=O)[C@@H](N)COCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
15.09 g of trifluoroacetic acid were added to a solution of 9.0 g of (2S)-N-(α,α-dimethylbenzyl)-3-benzyloxy-2-(t-butoxycarbonylamino)propionamide (prepared as described in Preparation 4) in a mixture of 100 ml of methylene chloride and 2.4 g of anisole, and the whole mixture was stirred for 1 hour at room temperature. At the end of this time, the excess trifluoroacetic acid was distilled off. On adding diethyl ether, the residue gave 8.8 g of the title compound as needles melting at 148°-150° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][C:8]3([CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH2:10][CH2:9]3)[C:7](=[N:17]S(C(C)(C)C)=O)[C:6]=2[CH:24]=1.CCOCC>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][C:8]3([CH2:9][CH2:10][CH:11]([O:14][CH3:15])[CH2:12][CH2:13]3)[C:7](=[NH:17])[C:6]=2[CH:24]=1
Reactant: COC1CCC2(CC1)Oc1ccc(Br)cc1C2=NS(=O)C(C)(C)C
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC1CCC2(CC1)Oc1ccc(Br)cc1C2=N
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of N-(5-bromo-4′-methoxy-3H-spiro[benzofuran-2,1′-cyclohexane]-3-ylidene)-2-methylpropane-2-sulfinamide (Example 29 Step 1, 2 g, 4.83 mmol) in anhydrous 1,4-dioxane (40 mL) was added 4M HCl in1,4-dioxane (12.07 mL, 48.27 mmol) and the resulting mixture was stirred under a nitrogen atmosphere at rt overnight. Et2O (30 mL) was added and the precipitate was filtered off and washed with Et2O, then partitioned between DCM (40 mL) and sat. aq. NaHCO3 (40 mL). The phases were separated and the organic layer concentrated, yielding 1.37 g of the crude title compound which was used immediately in the next step: MS (EI) m/z 309 M+.
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)[CH:3]=1.C(S[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[N:30]=[CH:29][C:28]2[C:23](=[CH:24][C:25]([C:31]([F:34])([F:33])[F:32])=[CH:26][CH:27]=2)[N:22]=1)C.[S:35]([O-:39])([O-])(=[O:37])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:35]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[N:30]=[CH:29][C:28]2[C:23](=[CH:24][C:25]([C:31]([F:34])([F:33])[F:32])=[CH:26][CH:27]=2)[N:22]=1)(=[O:39])=[O:37])[CH3:3]
Reactant: CCSc1ccccc1-c1ncc2ccc(C(F)(F)F)cc2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1ccccc1-c1ncc2ccc(C(F)(F)F)cc2n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
117 mg of 3-chloroperbenzoic acid (purity of 65% or more) was added to a mixture of 175 mg of 2-(2-ethylsulfanylphenyl)-7-trifluoromethylquinazoline and 3 ml of chloroform, under ice cooling, and the mixture was stirred at room temperature for 6 hours. A 10% aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 87 mg of 2-(2-ethylsulfonylphenyl)-7-trifluoromethylquinazoline (Compound of Present Invention 12).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:5])[CH3:4].[C:6]1(=[O:13])C[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(OCC)=O>C(OCC)C>[OH:5]/[CH:3]=[C:4]1\[C:6](=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]\1
Reactant: CCO
Reactant: O=C1CCCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC=O
Solvent: CCOCC
Product: O=C1CCCCC/C1=C/O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 976.6 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 535 mg, 13.4 mmol) in diethyl ether (25 mL) at 0° C. was added ethanol (0.06 ml, 1.03 mmol) dropwise. The grey suspension was stirred at 0° C. for 20 min. A solution of cycloheptanone (1.58 ml, 13.4 mmol) and ethyl formate (1.63 ml, 20.1 mmol) in diethyl ether (3 mL) was added dropwise over 10 min. The pale yellow heterogeneous reaction mixture was stirred at 0° C. for 1 h then warmed to room temperature for 4 h. The reaction was carefully quenched with ethanol (2 mL) then water (25 mL) was added. The layers were separated and the aqueous phase was washed with diethyl ether. The organic layers were set aside and later discarded. The aqueous layer was acidified with 1M HCl until pH=2 and then extracted with diethyl ether (2×). The combined organic layers were dried over MgSO4 and concentrated to afford 1.41 g (75%) of 2-[1-hydroxy-meth-(Z)-ylidene]-cycloheptanone as a yellow oil. 1H NMR (CDCl3, 400 MHz): δ (ppm) 14.69 (d, J=8.8 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 2.52-2.61 (m, 2H), 2.23-2.32 (m, 2H), 1.67-1.82 (m, 4H), 1.58-1.67 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]3[CH2:13][CH2:14][NH:15][CH2:16][CH2:17][C:9]3=[C:8]([CH3:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[Cl:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[ClH:19].[CH2:23]([O:22][C:20]([N:15]1[CH2:16][CH2:17][C:9]2[C:10](=[N:11][C:12]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[C:8]=2[CH3:18])[CH2:13][CH2:14]1)=[O:21])[CH3:24]
Reactant: CCOC(=O)Cl
Reactant: COc1cccc2c(C)c3c(nc12)CCNCC3
Product: CCOC(=O)N1CCc2nc3c(OC)cccc3c(C)c2CC1
Product: Cl
Yield: 49 %

Procedure:
1,2,4,5-Tetrahydro-7-methoxy-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester hydrochloride was prepared from 1,2,4,5-tetrahydro-7-methoxy-11-methyl-3H-azepino[4,5-b]quinoline and ethyl chloroformate analogous to Example 63.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[N+:6]([C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([N+]([O-])=O)[C:10]=1[C:11]#[N:12])([O-:8])=[O:7]>>[OH:4][CH2:3][CH2:2][CH2:1][O:5][C:13]1[CH:14]=[CH:15][CH:16]=[C:9]([N+:6]([O-:8])=[O:7])[C:10]=1[C:11]#[N:12]
Reactant: OCCCO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: N#Cc1c(OCCCO)cccc1[N+](=O)[O-]
Yield: 61 %

Procedure:
Prepared as in Example 215c from propane-1,3-diol and 2,6-dinitrobenzonitrile in 61% yield as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 1.89-1.93 (m, 2H), 3.56-3.61 (m, 2H), 4.30 (t, J=6.4 Hz, 2H), 4.61 (t, J=5.2 Hz, 1H), 7.71-7.74 (m, 1H), 7.85-7.91 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH2:50]O)[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:58])CC)C>ClCCl>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH2:50][F:58])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](CF)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 6.5 %

Procedure:
To a solution of {(1S,2S,3S,4R,5S)-2,3,4-Tris-benzyloxy-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6,8-dioxa-bicyclo[3.2.1]oct-1-yl}-methanol (616 mg, 0.871 mmol) in dichloromethane (3 mL) at 0 degrees Celsius was added diethylaminosulfur trifluoride (170 microL, 1.3 mmol) and the resulting mixture was slowly warmed to room temperature and stirred at this temperature for 16 hours. The mixture was diluted with dichloromethane and washed with a saturated solution of aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography over silica gel using a 40 g redisep silica cartridge (eluting with a gradient of 0 to 20% ethyl acetate in heptane) to afford (1S,2S,3S,4R,5S)-2,3,4-tris-benzyloxy-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-1-fluoromethyl-6,8-dioxa-bicyclo[3.2.1]octane as a colorless oil (40 mg, 7% yield). (LCMS) 753.4 (M+HCOO−: negative mode).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[N:7]1[CH:12]=[CH:11][C:10]([C:13]([NH:15][NH2:16])=[O:14])=[CH:9][CH:8]=1.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[C:23](Cl)=O)[CH3:18].O>CN1C(=O)CCC1>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([C:23]2[O:14][C:13]([C:10]3[CH:11]=[CH:12][N:7]=[CH:8][CH:9]=3)=[N:15][N:16]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[CH3:18]
Reactant: CCOc1ccc(C(=O)Cl)cc1OCC
Reactant: NNC(=O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOc1ccc(-c2nnc(-c3ccncc3)o2)cc1OCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 67 %

Procedure:
To a stirred solution of 3,4-diethoxybenzoic acid (0.71 mmol, 150 mg) in CH2Cl2 was added SOCl2 at room temperature; the reaction was refluxed for 1.5 h and the mixture concentrated under reduced pressure to yield 3,4-diethoxybenzoylchloride quantitatively. To a stirred suspension of Na2CO3 (1.42 mmol, 150.52 mg) and pyridine-4-carbohydrazide (0.71 mmol, 97 mg) in NMP (0.8 mL) was added a solution of the 3,4-diethoxybenzoylchloride in NMP (0.8 mL) and the reaction was stirred for 12 h at room temperature. The mixture was poured into 20 mL of cold H2O and filtered. The precipitated intermediate was dried in vacuum. The solid was added to POCl3 (5 mL) and heated to 70-72° C. for 6 h. The solution was poured into an ice-water container and neutralized with a solution of NaOH (2M). The precipitated product was filtered and purified by column chromatography using CH2Cl2:MeOH (9:1) to yield the product as white solid in 67% yield (150 mg). 1H NMR (400 MHz, CDCl3): δ 8.84 (bs, 2H), 7.99 (d, J=4.4 Hz, 2H), 7.67 (dd, J1=2.0, J2=8.4 Hz, 1H), 7.64 (d, J=2.0 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 4.18 (q, J=7.2 Hz, 2H), 1.51 (t, J=7.2 Hz, 3H), 1.50 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ165.81, 162.46, 152.51, 150.84, 149.20, 131.52, 128.05, 120.97, 115.77, 112.78, 111.58, 65.05, 64.80, 14.92, 14.85. MS (EI) m/z: 312 (M+), HRMS (EI) for C17H17N3O3 (M+): calcd 312.1343. found 312.1350.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[N:17]([CH2:19][CH2:20][NH:21][CH3:22])[CH3:18])=[O:5].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34](Cl)=[O:35])[CH:29]=1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[N:17]([CH2:19][CH2:20][N:21]([CH3:22])[C:34]([C:30]1[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=1)=[O:35])[CH3:18])=[O:5]
Reactant: O=C(Cl)c1cccnc1
Reactant: CNCCN(C)c1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCN(C)c1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12)C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
A mixture of 8-(2,6-dichlorobenzoylamino)-4-[N-(2-methylaminoethyl)-N-methylamino]quinoline (130 mg), 3-pyridinecarbonyl chloride (60.3 mg) and triethylamine (97.9 mg) in dichloromethane (2 ml) was stirred at ambient temperature overnight. The mixture was diluted with dichloromethane, washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from ethanol and collected by filtration. The residue was washed with ethanol to give 8-(2,6-dichlorobenzoylamino)-4-[N-[2-(N-methyl-3-pyridinecarboxamido)ethyl]-N-methylamino]quinoline (150 mg).
Reaction SMILES: [CH2:1]([Zn]CC)C.C([Si]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:22])=[CH2:21])=[CH:16][CH:15]=1)(C)C)(C)(C)C.ICI.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>ClC(Cl)C>[CH3:1][C:20]1([C:17]2[CH:16]=[CH:15][C:14]([OH:13])=[CH:19][CH:18]=2)[CH2:21][CH2:22]1
Reactant: C=C(C)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Reactant: CC[Zn]CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ICI
Solvent: CC(Cl)Cl
Product: CC1(c2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
Diethylzinc (1.0 M in hexanes, 69 mL, 69 mmol) was added to a solution of tert-butyl-(4-isopropenyl-phenoxy)-dimethyl-silane (6.85 g, 27.6 mmol) in dichloroethane at 0° C. Diiodomethane (11.2 mL, 138 mmol) was then added dropwise to the solution and the resultant mixture was stirred at 0° C. for 0.5 h and allowed to warm to rt for 2 h. The opaque mixture was quenched with saturated aqueous NH4Cl. The aqueous phase was extracted with CH2Cl2 and the combined organic layers were washed with saturated aqueous NaHCO3. The organic layers were dried over sodium sulfate, filtered through celite, and concentrated. The crude TBS ether was dissolved in THF (50 mL) and TBAF (1.0 M in THF, 28 mL, 28 mmol) was added at rt. The solution was stirred for 2 h and then quenched with aqueous 1.0 M HCl. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with saturated NaHCO3. The organic layers were dried over sodium sulfate, filtered and concentrated. Purification by silica-gel chromatography (1% 2-propanol/12% ethyl acetate in hexanes) provided 4-(1-methyl-cyclopropyl)-phenol (2.77 g, 68%) as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)C>[CH2:13]1[CH:14]2[N:10]([CH2:2][CH:3]=[C:4]([C:3]3[C:4]4[C:9](=[CH:8][N:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[CH2:5]2)[CH2:11][CH2:12]1
Reactant: c1cc2cc[nH]c2cn1
Reactant: C1CCNC1
Solvent: CCO
Product: C1=C(c2c[nH]c3cnccc23)CC2CCCN2C1

Procedure:
from 6-azaindole (250 mg, 2.1 mmol), 1,2,3,5,6,8,8a-heptahydrohydro-7-oxo-indolizine (324 mg, 2.3 mmol) and pyrrolidine (1.2 g, 16.9 mmol) in ethanol (2 mL) heating at reflux for 6 hrs.
Reaction SMILES: [CH2:1]([P:3]([OH:5])[OH:4])[CH3:2].[CH2:6]([OH:9])[CH:7]=[CH2:8].[O-]S(OOS([O-])(=O)=O)(=O)=O.[Na+].[Na+]>O>[CH2:1]([P:3]([CH2:8][CH2:7][CH2:6][OH:9])(=[O:5])[OH:4])[CH3:2]
Reactant: CCP(O)O
Reactant: C=CCO
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCP(=O)(O)CCCO
Temperature: 100 °C
Yield: 89 %

Procedure:
564 g (6 mol) of ethylphosphonous acid (produced as in Example 1) are dissolved in 860 g of water and initially charged to a 5 l five-neck flask equipped with thermometer, reflux condenser, high-performance stirrer and dropping funnel. The reaction mixture is heated to 100° C. and 406 g (7 mol) of allyl alcohol and 500 g of a 5% sodium peroxodisulfate solution (1.5 mol % based on allyl alcohol) is added dropwise at atmospheric pressure over 1 h. Then, the water is distilled off in vacuo, and the residue is taken up in tetrahydrofuran and the insoluble salts are filtered off. The solvent of the filtrate is removed in vacuo to leave 812 g (89% of theory) of ethyl(3-hydroxypropyl)phosphinic acid as oil.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]([Cl:11])=[N:4][N:3]=1.[Br-].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][Zn+])=[CH:16][CH:15]=1>>[Cl:11][C:5]1[C:6]2[CH2:10][CH2:9][CH2:8][C:7]=2[C:2]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=2)=[N:3][N:4]=1
Reactant: Fc1ccc(C[Zn+])cc1
Reactant: Clc1nnc(Cl)c2c1CCC2
Agent: [Br-]
Product: Fc1ccc(Cc2nnc(Cl)c3c2CCC3)cc1

Procedure:
Compound 45 is prepared analogous to compound 44 starting from of 1,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyridazine (compound 39) and para-fluorobenzyl zinc bromide.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[S:32])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[N:12]=[CH:13][C:8]4[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=4[N:10]=3)[CH2:15][CH2:16]2)=[S:32])=[CH:26][CH:25]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4ccc(Cl)cc4)CC3)nc21

Procedure:
Pipemidic acid (58 mg, 0.191 mmol) and 4-chlorophenyl isothiocyanate (27 mg, 0.159 mmol) were used. Purification on silica yielded compound 28 in Table 1, below (50 mg, 67%). 1H NMR (300 MHz, CDCl3) δ 9.34 (s, 1H), 8.68 (s, 1H), 7.36-7.34 (m, 2H), 7.17 (d, J=8.70 Hz, 2H), 4.39-4.28 (m, 2H), 4.28-3.93 (m, 8H), 1.49 (t, J=6.68 Hz, 3H) ppm.