Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][N:11]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[C:33]2=[O:35])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](NCCNc2cccc(Cl)c2)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](N2CCN(c3cccc(Cl)c3)C2=O)C1
Reaction time: 1 h
Yield: 106 %

Procedure:
In ice bath and under N2 atmosphere, to a stirred solution of (R)-tert-butyl 3-(2-(3-chlorophenylamino)ethylamino)piperidine-1-carboxylate (398) (10.1 g, 28.37 mmol) and Et3N (3.01 g, 29.8 mmol) in anhydrous DCM (300 mL) was added a solution of triphosgene (2.95 g, 9.93 mmol) in DCM (100 mL) dropwise. The resulting mixture was stirred in ice bath for 1 hour, and quenched with NaHCO3 (aq.) (1M, 50 mL). The mixture was extracted with DCM (100 mL×3). The combined organic layer was washed with brine, dried, concentrated and subjected to silica flash column chromatography using 0 to 5% MeOH in DCM to isolate (R)-tert-butyl 3-(3-(3-chlorophenyl)-2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (399) (4 g, 37%) as a white solid. It was treated with 40 mL commercial 4N HCl in dioxane to give (R)-1-(3-chlorophenyl)-3-(piperidin-3-yl)imidazolidin-2-one hydrochloride (400) (3.3 g, quant.) as a white solid. Proton NMR (DMSO-d6): δ 9.26 (1H, s), 8.93 (1H, s), 7.77 (1H, t, J=2.0 Hz), 7.47-7.40 (1H, m), 7.35 (1H, t, J=8.1 Hz), 7.06 (1H, dd, J=7.9, 1.1 Hz), 4.10-3.94 (1H, m), 3.89-3.76 (2H, m), 3.48 (2H, t, J=8.5 Hz), 3.25-3.14 (2H, m), 3.06-2.97 (1H, m), 2.82-2.72 (1H, m), 1.95-1.86 (1H, m), 1.83-1.68 (3H, m) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([CH2:13][OH:14])[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(Cl)Cl>[C:24]([O:14][CH2:13][CH:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:9]([O:11][CH3:12])=[O:10])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C(CO)C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(COC(C)=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 97.5 %

Procedure:
methyl 2-(tertbutoxycarbonyl)-3-hydroxypropanoate (29) (2.2 g, 10.0 mmol, 1.0 equiv.) was added to a 100 mL RBF followed by CH2Cl2 (40 mL). Next, DIEA (2.1 mL, 12.0 mmol, 1.2 equiv.) and acetic anhydride (1.2 mL, 13.0 mmol, 1.3 equiv.) were added to the reaction mixture and the solution was stirred at rt. The reaction solution was stirred for a total of 21 h. The solution was transferred to a separatory funnel with CH2Cl2 (75 mL), washed with 1% HCl (2×50 mL), and sat. NaCl (2×50 mL). The organic layers were dried over Na2SO4, concentrated on a rotary evaporator, and dried under vacuum to give 2.4 g (91%) of 30 as a clear oil which crystallized to a white solid upon standing. Rf=0.37 (25% EtOAc/hexanes); mp=61-62° C.; IR (KBr) 3327, 2985, 1742, 1683, 1533, 1348, 1241, 1166, 1071, 1038 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.33 (br d, J=8.0 Hz, 1H, carbamate-NH), 4.58 (m, 1H, Boc-NH—CH), 4.44 (dd, J=11.0, 3.5 Hz, 1H, CH—CH2), 4.33 (dd, J=11.0, 3.5 Hz, 1H, CH—CH2), 3.78 (s, 3H, OCH3), 2.06 (s, 3H, O═C—CH3), 1.46 (s, 9H, t-butyl-CH3); 13C NMR (125 MHz, CDCl3) δ 170.6, 170.5, 155.3, 80.5, 64.5, 53.0, 52.9, 28.4, 20.8; LRMS (ESI-MS m/z): Mass calcd for C11H19NNaO6 [M+Na]+, 284.26. Found 284.
Reaction SMILES: [OH:1][CH:2]([CH:4]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=O)[CH3:3].ON1C2C=CC=C[C:21]=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[NH2:46][CH:47]([C:49]1[C:50](=[O:64])[NH:51][C:52]([CH2:55][C:56]2[CH:61]=[CH:60][C:59](OC)=[CH:58][CH:57]=2)=[N:53][N:54]=1)[CH3:48]>>[OH:1][CH:2]([CH:4]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([NH:46][CH:47]([C:49]1[C:50](=[O:64])[NH:51][C:52]([CH2:55][C:56]2[CH:61]=[CH:60][C:59]([CH3:21])=[CH:58][CH:57]=2)=[N:53][N:54]=1)[CH3:48])=[O:7])[CH3:3]
Reactant: CC(O)C(CCCc1ccccc1)C(=O)O
Reactant: On1nnc2ccccc21
Reactant: COc1ccc(Cc2nnc(C(C)N)c(=O)[nH]2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Product: Cc1ccc(Cc2nnc(C(C)NC(=O)C(CCCc3ccccc3)C(C)O)c(=O)[nH]2)cc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
1.09 g (4.91 mmol) of 2-(1-hydroxyethyl)-5-phenylpentanoic acid are treated with 660 mg (4.61 mmol) of 1-hydroxy-1H-benzotriazole and 990 mg (9.82 mmol) of 4-methylmorpholine and the mixture is cooled to −20° C. After addition of 940 mg (4.61 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride, the mixture is stirred for 30 min. At the same time, the cooling bath is removed. Then, after again cooling to −20° C., 1.00 g (4.09 mmol) of 6-(1-aminoethyl)-3-(4-methoxybenzyl)-1,2,4-triazin-5(4H)-one is added and the mixture is stirred overnight while warming to room temperature. For work-up, the dichloromethane phase is washed with 1N potassium hydrogensulphate solution and then with saturated sodium hydrogencarbonate solution. The dried organic phase is concentrated and chromatographed using the eluent dichloromethane/methanol 100/1 to 30/1.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:18][C:19]([CH3:21])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[C:16]([NH:17][CH:19]([CH3:21])[CH3:18])=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Nc1cccnc1Nc1ccc2c(c1)OCO2
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)Nc1cccnc1Nc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.5 %

Procedure:
The N2-(benzo[d][1,3]dioxol-5-yl)pyridine-2,3-diamine (8.5 g, 37.1 mmol) was dissolved in dichloromethane (150 mL). Acetone (4.1 mL, 55.6 mmol), sodium triacetoxyborohydride (11.79 g, 55.6 mmol) and acetic acid (4.2 mL, 74.2 mmol) were added to it. This was stirred at ambient temperature for 18 h. The mixture was washed with 1N NaOH and then washed with water. The organic layer was concentrated in vacuo and chromatographed using a gradient of 0-10% ethyl acetate in dichloromethane to give N2-(benzo[d][1,3]dioxol-5-yl)-N3-isopropylpyridine-2,3-diamine (7.8 grams, 78%).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[NH2:15][CH:16]([CH2:22][SH:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(Cl)Cl>[CH:1]1([C:4]([NH:15][CH:16]([CH2:22][SH:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: CCOC(=O)C(N)CS
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CS)NC(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyclopropanecarbonyl chloride (3.1 mL) was added to a suspension of triethylamine (4.68 mL) and ethyl 2-amino-3-mercaptopropanoate hydrochloride (5.2 g) in DCM (200 mL) at 0° C. The resulting mixture was allowed to warm to RT and stirred overnight. The reaction was quenched with ethanol and the solvent evaporated. The residue was suspended in ethyl acetate (200 mL) and washed with saturated sodium bicarbonate solution (2×150 mL), aqueous HCl solution (2M, 2×150 mL) and brine (150 mL), then dried over magnesium sulphate, filtered and evaporated. The resulting white solid was purified by silica gel chromatography eluting with 4:1 isohexane:ethyl acetate to give the subtitled compound as a white solid. Yield 5 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]([OH:13])=O)[CH:7]=1.S(Cl)(Cl)=O.N1C=CC=CC=1.[NH2:24][C:25]1[C:26]([CH3:35])=[N:27][CH:28]=[C:29]([CH:34]=1)[C:30]([O:32][CH3:33])=[O:31]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]([NH:24][C:25]2[C:26]([CH3:35])=[N:27][CH:28]=[C:29]([CH:34]=2)[C:30]([O:32][CH3:33])=[O:31])=[O:13])[CH:7]=1
Reactant: COC(=O)c1cnc(C)c(N)c1
Reactant: O=C(O)c1cnn2cc(Br)ccc12
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1cnc(C)c(NC(=O)c2cnn3cc(Br)ccc23)c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
6-Bromopyrazolo[1,5-a]pyridine-3-carboxylic acid (7.71 g, 32.0 mmol) in toluene (80 ml) was treated with thionyl chloride (18.67 ml, 256 mmol) and was heated to 110° C. for 6 hr. The solvent was removed in vacuo and the residue was treated with pyridine (80 ml), methyl 5-amino-6-methylnicotinate (4.25 g, 25.6 mmol) and oven dried molecular sieves. The reaction mixture was stirred at RT overnight and then treated with MeOH (250 ml). The resulting suspension was removed by filtration. The filtrate was triturated with methanol and the solid produced was isolated to afford the title compound;
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:29])([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[C:32](Cl)(=O)[O:33]C1C=CC([N+]([O-])=O)=CC=1.[NH2:45][C:46]([CH3:50])([CH3:49])[CH2:47][OH:48]>ClCCl>[F:24][C:21]([F:22])([F:23])[C:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:10]2[CH2:9][CH2:8][CH:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:32](=[O:33])[O:48][CH2:47][C:46]([NH2:45])([CH3:50])[CH3:49])=[CH:31][CH:30]=3)[CH2:12][CH2:11]2)=[CH:15][CH:16]=1)([OH:29])[C:25]([F:28])([F:26])[F:27]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(N)CO
Reactant: Nc1ccc(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Solvent: ClCCl
Product: CC(C)(N)COC(=O)Nc1ccc(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.6 %

Procedure:
2-(4-((4-(4-Aminobenzyl)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.448 mmol, 200 mg) and 4-nitrophenyl carbonochloridate (0.448 mmol, 90 mg) were combined and stirred in dichloromethane at room temperature for 30 minutes. 2-Amino-2-methylpropan-1-ol (0.896 mmol, 114 μl, 80 mg) was added and the reaction stirred at room temperature overnight. The reaction mixture was concentrated and purified by basic prep-HPLC to give the title compound (94.7 mg).
Reaction SMILES: [CH:1]([N:4]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:7](=[O:21])[C:6]([C:22]([OH:24])=O)=[CH:5]1)([CH3:3])[CH3:2].[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[S:34]([CH3:37])(=[O:36])=[O:35])[CH2:29][NH2:30].CN1CCOCC1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(OCC)(=O)C>ClCCl>[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[S:34]([CH3:37])(=[O:36])=[O:35])[CH2:29][NH:30][C:22]([C:6]1[C:7](=[O:21])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[CH:12]=2)=[C:9]([CH3:10])[N:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)=[O:24]
Reactant: CS(=O)(=O)c1ccc(CN)cc1F
Reactant: Cc1c(-c2cccc(C(F)(F)F)c2)c(=O)c(C(=O)O)cn1C(C)C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1c(-c2cccc(C(F)(F)F)c2)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=O)c(F)c2)cn1C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carboxylic acid (preparation 3, 60 mg, 0.177 mmol), preparation 32b (72 mg, 0.354 mmol), N-methylmorpholine (0.10 mL, 0.910 mmol) in dichloromethane (1 mL) is added at 0° C. 1-propanephosphonic acid cyclic anhydride in ethyl acetate (0.31 mL, 50%, 0.53 mmol). The reaction mixture is stirred for 18 h at room temperature. The volatiles are evaporated under reduced pressure and the remaining residue is purified by preparative reversed-phase HPLC (Sunfire, gradient of acetonitrile in water, 0.1% TFA, 60° C.). Yield: 24 mg (26% of theory); ESI mass spectrum: [M+H]+=525; Retention time HPLC: 0.86 min (005_CA01).
Reaction SMILES: B1([O-])OO1.[OH2:5].[OH2:6].O.O.[Na+].[NH2:10][C:11]1[C:18]([F:19])=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[Cl:20]>C(O)(=O)C>[Cl:20][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:19])[C:11]=1[N+:10]([O-:6])=[O:5])[C:15]#[N:16]
Reactant: N#Cc1cc(F)c(N)c(Cl)c1
Reactant: O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Product: N#Cc1cc(F)c([N+](=O)[O-])c(Cl)c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
Sodium perborate tetrahydrate (131 g, 851 mmol) in acetic acid (200 mL) was heated to 60° C. A solution of 4-amino-3-chloro-5-fluorobenzonitrile (29.02 g, 170 mmol) in acetic acid (500 mL) was added dropwise and the reaction was stirred at 60° C. for 16 h. The LCMS the indicated the reaction showed ˜50% conversion. Additional sodium perborate tetrahydrate (14.4 g) was added and the reaction stirred at 70° C. for 2 h. Then additional sodium perborate tetrahydrate (70 g) was added and the reaction was stirred at 80° C. for 5 h, followed by RT for 2 days. The reaction was then poured into ice water and extracted with EtOAc (3×). The combined organic extracts were washed with H2O (2×), brine, dried over MgSO4 and concentrated. When most of the acetic acid was evaporated, water was added to the residue. The orange precipitate was collected by filtration, washed with H2O and air dried to give the crude product as an orange solid. NMR showed the product contaminated with ˜10% of starting material. This product was used without any further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]1[CH2:17][C:16](=[NH:18])[N:15]([C:19]2[C:24]([CH:25]([CH3:27])[CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=2[CH:28]([CH3:30])[CH3:29])[CH2:14]1)([CH3:3])[CH3:2].[Cl-:31].[Cl-].[Cl-].[CH:34]1([Ti+3:39])[CH:38]=[CH:37][CH:36]=[CH:35]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl-:31].[Cl-:31].[CH:34]1([Ti+2:39])[CH:38]=[CH:37][CH:36]=[CH:35]1.[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]1[CH2:17][C:16](=[NH:18])[N:15]([C:19]2[C:20]([CH:28]([CH3:30])[CH3:29])=[CH:21][CH:22]=[CH:23][C:24]=2[CH:25]([CH3:27])[CH3:26])[CH2:14]1)([CH3:3])[CH3:2]
Reactant: [Ti+3]C1C=CC=C1
Agent: CC(C)c1cccc(C(C)C)c1N1CC(=N)N(c2c(C(C)C)cccc2C(C)C)C1
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: [Ti+2]C1C=CC=C1
Reaction time: 2 h

Procedure:
To a suspension of 1,3-bis(2,6-diisopropylphenyl)-iminoimidazoline (1.02 g, 2.5 mmol) and cyclopentadienyltitanium trichloride (0.55 g, 2.5 mmol) in toluene (20 mL) was added triethylamine (0.25 g, 2.5 mmol) at ambient temperature. After stirring for 2 hours, the thick yellow-orange suspension was filtered, and the filtrate evaporated to dryness to afford 1.31 g (89% yield) of NMR-pure 1,3-bis(2,6-diisopropylphenyl)-iminoimidazoline cyclopentadienyltitanium dichloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[C@H:9]([N:19]([CH2:24][C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=2)[C:20]([O:22][CH3:23])=[O:21])[CH2:8][C@@H:7]1[CH3:39])=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:59](O)[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66].CN1CCNCC1NC(N=NC(NC1CNCCN1C)=O)=O>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([O:16][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH:14]=2)[C@H:9]([N:19]([CH2:24][C:25]2[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[C:27]([C:35]([F:36])([F:38])[F:37])[CH:26]=2)[C:20]([O:22][CH3:23])=[O:21])[CH2:8][C@@H:7]1[CH3:39])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2cc(O)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Reactant: CCCCCCCCO
Agent: CN1CCNCC1NC(=O)N=NC(=O)NC1CNCCN1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCCCCCCCOc1cc2c(cc1OC)[C@H](N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)OC)C[C@H](C)N2C(=O)OCC
Yield: 50.2 %

Procedure:
A solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-hydroxy-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (30 mg, 0.053 mmol), triphenylphosphine (28 mg, 0.11 mmol), 1-octanol (33 μL, 0.21 mmol), and bis-(N-methylpiperazinyl)-azodicarboxamide (30 mg, 0.11 mmol) in benzene (1 mL) was stirred at room temperature for 2 days. Purification of the solution directly by silica gel chromatography using 0-20% ethyl acetate/hexanes as eluent afforded the title compound (18 mg, 50%). MS m/z 695 (M++19), 376 (M+−300); 1H NMR (CDCl3) δ7.08 (C8, s, 1H), 6.40 (C5, s, 1H), 1.17 (C2-Me, d, 3H, J=6.1 Hz).
Reaction SMILES: [CH:1]([O:4][C:5]1C[CH:9]=[CH:8][CH2:7][CH:6]=1)([CH3:3])[CH3:2].[O:11]=[O+][O-].[CH3:14][OH:15]>>[OH:15][CH2:14][CH2:9]/[CH:8]=[CH:7]\[CH2:6][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:11]
Reactant: CO
Reactant: CC(C)OC1=CCC=CC1
Reactant: O=[O+][O-]
Product: CC(C)OC(=O)C/C=C\CCO
Temperature: -78 °C
Reaction time: 1.33 h

Procedure:
A mixture of 3.60 g. (26 mm.) of 1-isopropoxy-1,4-cyclohexadiene and 100 ml. of absolute methanol was treated with ozone (1.25 g., 26 mm.) at -78°C. The resulting mixture was flushed with nitrogen. The mixture was allowed to come to 0°C. and 2.42 g. (39 mm.) of dimethyl sulfide were added and the mixture stirred at this temperature for 80 minutes. After cooling to -78°C, a suspension of 1.47 g. (39 mm.) of sodium borohydride in 20 ml. of absolute ethanol was added dropwise. The resulting mixture was allowed to come up to room temperature and then stirred for 80 minutes. The methanol was removed under vacuum to produce 3.54 g. of product (80% of theory), b.p. 72° (0.2 mm., short path distillation).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:25][C:26]1[CH:27]=[C:28](CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=C[C:31]=1OC(C)C.CC1C=C(C)[N:55]2[N:59]=C(C=O)N=[C:54]2N=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[C:15]([CH2:28][C:27]3[C:26]([Cl:25])=[CH:31][N:55]([CH3:54])[N:59]=3)=[C:14]([OH:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Reactant: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3nn(C)cc3Cl)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared analogously to Example B(31), where 6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione was substituted in place of 6-[2-(3-Chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione and 4-chloro-1-methyl-1H-pyrazole-3-carbalehyde was substituted in place of 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde of that example.
Reaction SMILES: [H-].[Na+].COC1C=CC(C(C2C=CC(OC)=CC=2)[O:12][CH:13](C2C=CC=CC=2)[CH:14]2[O:18][CH:17]([N:19]3[CH:24]=[CH:23][C:22](=[O:25])[NH:21][C:20]3=[O:26])[CH:16]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:15]2[O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])=CC=1.[CH3:57][O:58][C:59]1[CH:66]=[CH:65][C:62]([CH2:63]Cl)=[CH:61][CH:60]=1.C1(S(O)(=O)=O)C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C>[Si:28]([O:27][C@@H:16]1[C@H:15]([O:35][Si:36]([C:39]([CH3:41])([CH3:42])[CH3:40])([CH3:37])[CH3:38])[C@@H:14]([CH2:13][OH:12])[O:18][C@H:17]1[N:19]1[CH:24]=[CH:23][C:22](=[O:25])[N:21]([CH2:63][C:62]2[CH:65]=[CH:66][C:59]([O:58][CH3:57])=[CH:60][CH:61]=2)[C:20]1=[O:26])([C:31]([CH3:33])([CH3:34])[CH3:32])([CH3:30])[CH3:29]
Reactant: COc1ccc(CCl)cc1
Reactant: COc1ccc(C(OC(c2ccccc2)C2OC(n3ccc(=O)[nH]c3=O)C(O[Si](C)(C)C(C)(C)C)C2O[Si](C)(C)C(C)(C)C)c2ccc(OC)cc2)cc1
Agent: O=S(=O)(O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3O[C@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 58.8 %

Procedure:
Following the procedure (Myers, A. G.; Gin, D. Y.; Rogers, D. H., J. Amer. Chem. Soc., 1994, 116, 4697-4718), a suspension of sodium hydride (1.55 g, 38.75 mmole, 60% oil dispersion) in anhydrous dimethylformamide (40 ml) was cooled at 0° C. under argon, and to this mixture was added a solution of 1-[5-[bis-(4-methoxy-phenyl)-phenyl-methoxymethyl]-3,4-bis-(tert-butyl-dimethyl-silanyloxy)-tetrahydro-furan-2-yl]-1H-pyrimidine-2,4-dione (20 g, 25.8 mmole, obtained from Reference Example 1) in anhydrous dimethylformamide (35 ml) over a period of 15 min. Neat p-methoxybenzyl chloride (7 ml, 51 mmole) was added to this solution. The resulting mixture was stirred at 0° C. for 15 h under argon, and diluted with ethyl acetate (700 ml). The organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness in vacuo. The oily residue was dissolved in chloroform (200 ml) and cooled at 0° C. under nitrogen. Benzenesulfonic acid (6 g, 37.93 mmole) was added portionwise, and the resulting red solution was stirred at 0° C. under nitrogen for 2 h. The mixture was diluted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness in vacuo. The residue was chromatographed (flash column, silica gel, methylene chloride:diethyl ether:methanol=95:3:2) to give 1-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(hydroxymethyl)tetrahydro-2-furanyl]-3-(4-methoxybenzyl)-2,4(1H,3H)-pyrimidinedione as white solid (9 g, 59%).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[C:5]1([S:11]([C:14]2[CH:23]=[CH:22][C:17]3[NH:18][CH2:19][CH2:20][O:21][C:16]=3[CH:15]=2)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C>ClCCl>[C:5]1([S:11]([C:14]2[CH:23]=[CH:22][C:17]3[N:18]([C:1]([Cl:4])=[O:2])[CH2:19][CH2:20][O:21][C:16]=3[CH:15]=2)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Cl
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(c1)OCCN2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cl)N1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C

Procedure:
To a solution of phosgene (1.44 mL of a 1.8 M solution in dichloromethane, 2.64 mmol) at 0° C. was added a solution of 7-benzenesulfonyl-3,4-dihydro-2H-benzo[1,4]oxazine (0.663 g., 2.4 mmol) in 3 mL dichloromethane followed by dropwise addition of triethylamine (0.361 mL, 2.6 mmol) over three minutes. The reaction was allowed to warm to room temperature and was stirred for an hour. The reaction mixture was then concentrated in vacuo, and then dissolved in 50 mL dichloromethane which was removed in vacuo. A suspension of the crude residue in 60 mL of 1:1 ethyl ether: hexanes was washed with 3 times with 50 mL of 6N aqueous hydrogen chloride. The organic fractions were dried over MgSO4 and concentrated in vacuo to give 7-benzenesulfonyl-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl chloride, which was used directly in the following step.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[O:11][C:10](=[O:22])[CH:9]=2)[CH2:3][CH2:2]1.[CH:23]1[C:28]([CH:29]=O)=[CH:27][C:26]2[O:31][CH2:32][O:33][C:25]=2[CH:24]=1>>[O:33]1[C:25]2[CH:24]=[CH:23][C:28]([CH2:29][N:1]3[CH2:2][CH2:3][CH:4]([NH:7][C:8]4[C:17]5[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:20])([F:19])[F:21])[CH:16]=5)[O:11][C:10](=[O:22])[CH:9]=4)[CH2:5][CH2:6]3)=[CH:27][C:26]=2[O:31][CH2:32]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: O=c1cc(NC2CCNCC2)c2cc(C(F)(F)F)ccc2o1
Product: O=c1cc(NC2CCN(Cc3ccc4c(c3)OCO4)CC2)c2cc(C(F)(F)F)ccc2o1
Yield: 43.8 %

Procedure:
4-(1-Benzo[1,3]dioxol-5-ylmethyl-piperidin-4-ylamino)-6-trifluoromethyl-chromen-2-one was prepared according to a reductive amination procedure using 4-(piperdin-4-ylamino)-6-trifluoromethyl-chromen-2-one (116 mg, 0.373 mmol) and piperonal (62 mg, 0.411 mmol) to provide the title product as a white solid (73 mg, 44%). MS (APCI) m/z 447 [M+H]+, 445 [M−H]+, 481 [M+Cl]+; 1H NMR (300 MHz, DMSO-D6) δ ppm 1.64 (m, 2H) 1.92 (m, J=9.83 Hz, 2H) 2.09 (m, 2H) 2.84 (m, J=11.53 Hz, 2H) 3.51 (m, 1H) 5.34 (s, 1H) 5.99 (s, 2H) 6.76 (d, J=6.44 Hz, 1H) 6.85 (d, J=8.82 Hz, 2H) 7.51 (t, J=9.32 Hz, 2H) 7.92 (dd, J=8.82, 1.70 Hz, 1H) 8.63 (s, 1H).