Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:39])([CH3:38])/[CH:3]=[CH:4]/[C@H:5]1[O:10]C(C)(C)[O:8][C@@H:7]([C@@H:13]([O:35][CH3:36])[C:14]([NH:16][CH:17]2[CH2:23][N:22]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:21][CH2:20][NH:19][C:18]2=[O:34])=[O:15])[C@H:6]1[OH:37].Cl.[OH-].[Na+]>C1COCC1>[O:34]=[C:18]1[CH:17]([NH:16][C:14](=[O:15])[C@H:13]([O:35][CH3:36])[C@H:7]([OH:8])[C@@H:6]([OH:37])[C@H:5]([OH:10])/[CH:4]=[CH:3]/[C:2]([CH3:39])([CH3:1])[CH3:38])[CH2:23][N:22]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:21][CH2:20][NH:19]1
Reactant: CO[C@@H](C(=O)NC1CN(C(=O)OCc2ccccc2)CCNC1=O)[C@@H]1OC(C)(C)O[C@H](/C=C/C(C)(C)C)[C@@H]1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CO[C@@H](C(=O)NC1CN(C(=O)OCc2ccccc2)CCNC1=O)[C@H](O)[C@@H](O)[C@H](O)/C=C/C(C)(C)C
Reaction time: 5 h
Yield: 65.2 %

Procedure:
81 mg of 49 (148 μmol) are mixed with 0.75 ml of THF and 1.5 ml of 1N hydrochloric acid (750 μmol), with stirring and under argon. Stirring is continued for 5 hours at room temperature. The solution is then cooled to 0° C. and neutralized to pH 7.0 with 1N sodium hydroxide. The mixture is extracted twice with 2 ml of EtOAc. The organic phases are combined, dried over magnesium sulfate and filtered, and then evaporated to dryness. 49 mg of expected product Example 18 are obtained (yield=66%).
Reaction SMILES: [CH:1]1([CH:7]2[CH:16]3[CH2:17][CH2:18][CH2:19][O:20][CH:15]3[C:14]3[C:13]([N+:21]([O-])=O)=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CCO>[CH:1]1([CH:7]2[CH:16]3[CH2:17][CH2:18][CH2:19][O:20][CH:15]3[C:14]3[C:13]([NH2:21])=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1cccc2c1C1OCCCC1C(C1CCCCC1)N2
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc2c1C1OCCCC1C(C1CCCCC1)N2
Reaction time: 24 h
Yield: 26.3 %

Procedure:
A suspension of (4aSR*,5RS*,10bSR*)-5-cyclohexyl-10-nitro-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline (Example 12, obtained according to example 1 procedure) (90.0 mg, 0.284 mmol) and palladium on activated carbon (10 wt %, 34.5 mg, 0.031 mmol) in EtOH (10 mL) was purged with nitrogen followed by evacuation (three cycles) and then pressurized to 50 psi with hydrogen for 1 day while stirring. After the pressure was released, the reaction mixture was purged with nitrogen. The suspension was filtered over celite and the solvent removed under reduced pressure. The remaining residue was purified by Combiflash chromatography (SiO2, c-Hexane/AcOEt) to afford (4aSR*,5RS*,10bSR*)-5-cyclohexyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-10-amine (21.4 mg, 26%) as yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:4]=[C:5]([C:9]([C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)=O)[CH:6]=[CH:7][CH:8]=1.Cl.[NH2:19][OH:20]>N1C=CC=CC=1>[OH:20][N:19]=[C:9]([C:11]1[N:15]([CH3:16])[N:14]=[N:13][N:12]=1)[C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[N:2]([CH3:17])[CH3:1]
Reactant: NO
Reactant: CN(C)c1cccc(C(=O)c2nnnn2C)c1
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)c1cccc(C(=NO)c2nnnn2C)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 99.6 %

Procedure:
To a stirred solution of [3-(dimethylamino)phenyl](1-methyl-1H-tetrazol-5-yl)methanone (3.84 g, 17 mmol) in dry pyridine (30 mL) was added hydroxylamine hydrochloride (2.89 g, 42 mmol). The reaction mixture was stirred at 70° C. for 6 h, then concentrated in vacuo and diluted with ethyl acetate (100 mL) and water (50 mL). The organic layer was separated, washed with water (50 mL) and dried over MgSO4. Evaporation of the solvent in vacuo afforded 3-[(hydroxyimino)(1-methyl-1H-tetrazol-5-yl)methyl]-N,N-dimethylaniline as a yellow solid [4.48 g, yield 99.6%; HPLC/MS m/z=247 (M+H); logP(HCOOH)=1.17].
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH:17]([CH:18]=[CH:19][CH:20]([OH:27])[CH:21]([CH3:26])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:16][CH2:15][C:10]21OCC[O:11]2>Cl>[OH:27][CH:20]([CH:21]([CH3:26])[CH2:22][CH2:23][CH2:24][CH3:25])[CH:19]=[CH:18][CH:17]1[CH2:16][CH2:15][C:10](=[O:11])[CH:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1]
Reactant: CCCCC(C)C(O)C=CC1CCC2(OCCO2)C1CCCCCCCO
Agent: Cl
Product: CCCCC(C)C(O)C=CC1CCC(=O)C1CCCCCCCO
Temperature: 60 °C
Reaction time: 2 h
Yield: 33.9 %

Procedure:
A mixture of crude 6-(7-hydroxyheptyl)-7-(3-hydroxy-4-methyloct-1-enyl)-1,4-dioxaspiro[4,4]nonane (0.5 g.) and hydrochloric acid (50 ml; 2 N) was stirred at 60° C. for 2 hours, cooled to ambient temperature and then extracted with diethyl ether. The ether extract was washed with water and dried over magnesium sulphate. Removal of the solvent under reduced pressure gave a crude product (0.4 g.) which was purified by preparative thin layer chromatography on silica gel, using a mixture of diethyl ether, ethyl acetate and hexane (2:1:1 v/v) as eluant, to give 7-[2-(3-hydroxy-4-methyloct-1-enyl)-5-oxocyclopentyl]heptanol (0.15 g.), νmax 3400 cm-1, 1725 cm-1, 970 cm-1 ; Elemental analysis: Found C, 74.8; H, 11.7%; C21H38O3 requires C, 74.5; H, 11.53%; N.M.R. (approximately 10% solution in deuterochloroform): multiplets at 5.7-5.5δ, 3.98δ and 1.05-0.7δ, triplet at 3.6δ (J=6 cycles/sec.), broad singlet at 2.05δ.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[CH2:14][CH2:13][C@H:12]([NH:15][S:16]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[CH:24][CH:25]=4)[CH:20]=3)(=[O:18])=[O:17])[C:11]2=[O:31])[CH:6]=[CH:5][N:4]=1)#[N:2].[CH3:32]I>>[C:1]([C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[CH2:14][CH2:13][C@H:12]([N:15]([CH3:32])[S:16]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[CH:24][CH:25]=4)[CH:20]=3)(=[O:18])=[O:17])[C:11]2=[O:31])[CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccnc(C#N)c4)C3=O)cc2c1
Reactant: CI
Product: COc1ccc2ccc(S(=O)(=O)N(C)[C@H]3CCN(Cc4ccnc(C#N)c4)C3=O)cc2c1

Procedure:
The title compound is prepared from 7-methoxynaphthalene-2-sulfonic acid-[1-(2-cyanopyridin-4-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide as described in EXAMPLE 141, Part D using methyl iodide in place of benzyl bromide. The crude product is purified by column chromatography eluting with gradient of 20% EtOAc/CH2Cl2 to 40% EtOAc/CH2Cl2 to afford the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([CH:8]([C:16](=[O:18])[CH3:17])C(OC(C)(C)C)=O)=[O:7])=[C:4]([N+:21]([O-:23])=[O:22])[CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:20]=[CH:19][C:5]([C:6](=[O:7])[CH2:8][C:16](=[O:18])[CH3:17])=[C:4]([N+:21]([O-:23])=[O:22])[CH:3]=1
Reactant: CC(=O)C(C(=O)OC(C)(C)C)C(=O)c1ccc(Br)cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)CC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 73.6 %

Procedure:
Under a nitrogen atmosphere, to a solution of 4.95 g of tert-butyl 2-(4-bromo-2-nitrobenzoyl)-3-oxobutanoate in 30 mL of dichloromethane was added 20 mL of trifluoroacetic acid under ice-cooling. The mixture was warmed to room temperature and stirred for 2.5 hours, and then the solvent was evaporated under reduced pressure. To the residue was added ethyl acetate, and the solution was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 2.7 g of 1-(4-bromo-2-nitrophenyl)butane-1,3-dione.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Br[CH2:11][C:12]1[N:13]([CH3:28])[C:14]2[C:19]([N:20]=1)=[C:18]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[N:17]=[C:16]([Cl:27])[N:15]=2>>[Cl:27][C:16]1[N:15]=[C:14]2[C:19]([N:20]=[C:12]([CH2:11][N:6]3[CH2:7][CH2:8][CH:3]([N:2]([CH3:9])[CH3:1])[CH2:4][CH2:5]3)[N:13]2[CH3:28])=[C:18]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[N:17]=1
Reactant: Cn1c(CBr)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CN(C)C1CCNCC1
Product: CN(C)C1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3n2C)CC1
Yield: 45.8 %

Procedure:
N,N-dimethylpiperidin-4-amine (0.41 g) was reacted with 4-(8-(bromomethyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine (1.0 g) via General Procedure C to yield 1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)-N,N-dimethylpiperidin-4-amine (0.52 g) as a white solid. This intermediate was reacted with 1-(phenylsulfonyl)-1H-indol-3-ylboronic acid via General Procedure B to give intermediate N,N-dimethyl-1-((9-methyl-6-morpholino-2-(1-(phenylsulfonyl)-1H-indol-3-yl)-9H-purin-8-yl)methyl)piperidin-4-amine. The intermediate was suspended in MeOH (3 mL) whereupon 3N KOH (0.3 mL) was added and the reaction mixture was heated at 50° C. for several hours until the protecting group was removed. Reverse phase purification gave 110. MS (Q1) 475.3 (M)+. 1H NMR (400 MHz, DMSO) δ 11.46 (s, 1H), 8.66-8.51 (m, 1H), 8.13 (d, 1H), 7.48-7.36 (m, 1H), 7.19-7.08 (m, 2H), 4.26 (s, 4H), 3.93 (d, 3H), 3.83-3.75 (m, 4H), 3.70 (s, 2H), 2.84 (d, 2H), 2.15 (s, 6H), 2.11-1.94 (m, 3H), 1.72 (d, 2H), 1.36 (q, 2H)
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[C:7]([OH:20])(=[O:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]>C1(C)C=CC=CC=1>[OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[C:7]([O-:20])(=[O:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O-:18])=[O:17]
Reactant: O=C(O)CCCCCCCCC(=O)O
Solvent: Cc1ccccc1
Solvent: OCC(O)CO
Product: O=C([O-])CCCCCCCCC(=O)[O-]
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Glycerol (0.2 mol) was added to 30 ml of toluene containing sebacic acid (0.2 mol) dissolved therein, and then stirred in an argon atmosphere at 55° C. for one hour. After an enzyme B (5 wt %) was added as a catalyst, the mixture was allowed to react at 100° C. for 72 hours. Polycondensation was carried out using a dean-stark trap device. The resulting product was dried for 24 hours at reduced pressure.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)(C)C>[CH3:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)=[CH:11][CH:10]=1
Reactant: OC1CCNCC1
Reactant: Cc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1ccc(CN2CCC(O)CC2)cc1
Temperature: 25 °C
Yield: 51.6 %

Procedure:
Synthesis of this compound was accomplished according to Scheme 33. To 5.05 g (50 mmol) of 4-hydroxypiperidine and 7.08 g (50 mmol) of p-methylbenzyl chloride in 25 mL of tert-butanol was added excess solid potassium carbonate, and the mixture was heated on a steam bath for 3 h. The mixture was cooled to room temperature and partitioned between ether and water. The organic phase was extracted with cold dilute HCl, and the acidic aqueous phase was extracted with ether twice. The aqueous phase was made basic with ice and 50% aqueous NaOH and extracted with ether. The ether phase was washed with dilute aqueous sodium bicarbonate solution, brine, dried, and evaporated under vacuum to give 5.3 g (52%) of 1-(4-methylbenzyl)-4-hydroxypiperidine (123) as an oil. GC/MS showed 100% purity with a molecular ion of 205.
Reaction SMILES: [Br-:1].C1(C(C2C=CC=CC=2)(C)C(O[C@@H]2C3CC[N+](CC(=O)NC4C=CON=4)(CC3)C2)=O)C=CC=CC=1.[Br-].O[C@@H]1C2CC[N+](CC(=O)NC3C=CON=3)(CC2)C1.[Br-].[OH:56][C@@H:57]1[CH:62]2[CH2:63][CH2:64][N+:59]([CH2:65][C:66](=[O:74])[NH:67][C:68]3[CH:73]=[N:72][CH:71]=[CH:70][N:69]=3)([CH2:60][CH2:61]2)[CH2:58]1.[CH:75]1([C:80]([OH:90])([C:84]2[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=2)[C:81](O)=[O:82])[CH2:79][CH2:78][CH2:77][CH2:76]1>>[Br-:1].[CH:75]1([C:80]([OH:90])([C:84]2[CH:85]=[CH:86][CH:87]=[CH:88][CH:89]=2)[C:81]([O:56][C@@H:57]2[CH:62]3[CH2:63][CH2:64][N+:59]([CH2:65][C:66](=[O:74])[NH:67][C:68]4[CH:73]=[N:72][CH:71]=[CH:70][N:69]=4)([CH2:60][CH2:61]3)[CH2:58]2)=[O:82])[CH2:79][CH2:78][CH2:77][CH2:76]1
Reactant: O=C(O)C(O)(c1ccccc1)C1CCCC1
Reactant: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1cnccn1
Agent: CC(C(=O)O[C@H]1C[N+]2(CC(=O)Nc3ccon3)CCC1CC2)(c1ccccc1)c1ccccc1
Agent: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1ccon1
Agent: [Br-]
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)C1CCCC1)C2)Nc1cnccn1

Procedure:
This compound is prepared analogously to (R)-3-(2,2-Diphenyl-propionyloxy)-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide (Example 4), substituting (R)-3-hydroxy-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide (Intermediate A) with (R)-3-Hydroxy-1-(pyrazin-2-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide (Intermediate H) and by replacing 2,2′-diphenylpropionic acid with cyclopentyl-hydroxy-phenyl-acetic acid, yielding the titled compound as a diastereomeric mixture. (M+465.4)
Reaction SMILES: C[O:2][C:3](=[O:38])[CH:4]([CH2:13][CH2:14][C:15](=[O:37])[NH:16][O:17][C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[OH-].[Na+]>CO.O>[C:9]([O:8][C:6](=[O:7])[CH2:5][CH:4]([CH2:13][CH2:14][C:15](=[O:37])[NH:16][O:17][C:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:3]([OH:38])=[O:2])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(=O)C(CCC(=O)NOC(c1ccccc1)(c1ccccc1)c1ccccc1)CC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)CC(CCC(=O)NOC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the compound of example 65 (2.27 g, 4.39 mmol) in a mixture of methanol/water (4:1, 50 mL) was added a solution of sodium hydroxide (1N, 9 mL). The resulting mixture was stirred for 24 h at room temperature. The solvent was evaporated and the residue was partitioned between water and ether. The alkaline phase acidified using HCl (6N) and extracted with ethyl acetate followed by drying over sodium sulfate, filtration and evaporation. The product was converted to an off-white foam under high vacuum. 1H-NMR(CDCl3, 400 MH: 1.42(s, 9H); 1.59(m, 3H); 1.88–2.54(m, 4H); 7.33(m, 15H); 7.46(s, broad, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:10][CH2:9][O:8][CH2:7][CH:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].[I-].[Li+].[C-]#N.[Na+]>CN(C)C=O>[CH2:11]([CH:6]1[C:5]([CH2:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)=[CH:24][CH:23]=2)(=[O:21])=[O:20])([C:3]([OH:4])=[O:2])[CH2:10][CH2:9][O:8][CH2:7]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C1(CS(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CCOCC1Cc1ccccc1
Agent: [C-]#N
Agent: [I-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(O)C1(CS(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CCOCC1Cc1ccccc1
Temperature: 120 °C
Yield: 79.1 %

Procedure:
To a solution of 3-benzyl-4-[4-(4-chlorophenoxy)-phenylsulfonylmethyl]-tetrahydropyran-4-carboxylic acid methyl ester (410 mg, 0.80 mmol) in N,N-dimethylformamide (4 mL) was added lithium iodide (1.06 g, 7.96 mmol), followed by sodium cyanide (78 mg, 1.59 mmol). The mixture was heated to 120° C. for 8 hours, cooled to room temperature, the N,N-dimethylformamide solvent removed by heating under reduced pressure, and the residue partitioned between ethyl acetate (150 mL) and saturated aqueous sodium bisulfite (50 mL). The ethyl acetate layer was dried over magnesium sulfate, concentrated in vacuo, purified by preparative chromatography (20×40-1000 um plates), eluted with 8% methanol/methylene chloride) to afford 317 mg (80%) of 3-benzyl-4-[4-(4-chlorophenoxy)-phenylsulfonylmethyl]-tetrahydropyran-4-carboxylic acid 1HNMR (N,N-dimethylformamide contaminant, CDCl3) δ 1.74 (dm, J=13.5 Hz, 1H), 2.05-2.18 (m, 2H), 2.42 (dm, J=13.5 Hz, 1H), 3.22-3.26 (m, 2H), 3.48-3.58 (m, 2H), 3.78-4.18 (m, 5H), 6.83-6.88 (m, 4H), 6.93 (d, J=8.5 Hz, 2H), 7.08-7.13 (m, 3H), 7.36 (d, J=8.7 Hz, 2H), 7.62 (d, J=8.7 Hz, 2H); CIMS (NH3, M+ +NH4 +): 518.
Reaction SMILES: CC1(C)[O:6][CH:5]([C:7]2[CH:8]=[CH:9][C:10]3[C:19]4([N:20]5[CH2:25][CH2:24][O:23][CH2:22][CH2:21]5)[CH:15]([C:16]([C:26]5[O:30][N:29]=[C:28]([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=6)[C:27]=5[C:37]([F:40])([F:39])[F:38])=[N:17][O:18]4)[CH2:14][O:13][C:11]=3[CH:12]=2)[CH2:4][O:3]1.C(O)(C(F)(F)F)=O>>[O:23]1[CH2:24][CH2:25][N:20]([C:19]23[C:10]4[CH:9]=[CH:8][C:7]([CH:5]([OH:6])[CH2:4][OH:3])=[CH:12][C:11]=4[O:13][CH2:14][CH:15]2[C:16]([C:26]2[O:30][N:29]=[C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:27]=2[C:37]([F:40])([F:38])[F:39])=[N:17][O:18]3)[CH2:21][CH2:22]1
Reactant: CC1(C)OCC(c2ccc3c(c2)OCC2C(c4onc(-c5ccccc5)c4C(F)(F)F)=NOC32N2CCOCC2)O1
Solvent: O=C(O)C(F)(F)F
Product: OCC(O)c1ccc2c(c1)OCC1C(c3onc(-c4ccccc4)c3C(F)(F)F)=NOC21N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 7-(2,2-dimethyl-1,3-dioxolan-4-yl)-9b-morpholino-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,9b-dihydro-3aH-chromeno[3,4-d]isoxazole (Preparation 60D, 0.080 g, 0.140 mmol) and TFA (3.00 ml, 38.9 mmol) was stirred at room temperature for 60 min. The TFA was removed under reduced pressure, and the residue was diluted with dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded a quantitative yield of 1-(9b-morpholino-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,9b-dihydro-3aH-chromeno[3,4-d]isoxazol-7-yl)ethane-1,2-diol as a yellow oil. The product had an HPLC ret. time=2.63 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=532.0.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][CH:17]=[N:18][C:19]=2[NH2:23])([O:6]CC)=[O:5])C.Br[Si](C)(C)C>CN(C)C=O>[P:4]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][CH:17]=[N:18][C:19]=2[NH2:23])([OH:5])([OH:6])=[O:3]
Reactant: CCOP(=O)(CCCCOn1cnc2c(N)ncnc21)OCC
Agent: C[Si](C)(C)Br
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2OCCCCP(=O)(O)O
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 69.6 %

Procedure:
9-[4-(Diethoxyphosphoryl)butoxy]adenine (0.165 g, 0.48 mmol) and bromotrimethylsilane (0.62 ml, 4.8 mmol) were dissolved in dimethylformamide (5 ml) and the reaction mixture was stirred at 23° C. for 90 min. The solvent was evaporated and the residue dissolved in methanol-water solution (9:1). The material crystallised from the solution to give the title compound as colourless crystals (96 mg, 70%), m.p. 265°-268° C. 1H NMR: δH [CD3)2SO] 1.77 (6H, m, CH2CH2CH2P), 4.45 (2H, t, J=6 Hz, NOCH2), 7.46 (2H, br.s., D2O exchangeable, NH2), 8.24 (1H, s), 8.48 (1H, s).
Reaction SMILES: O.[C:2]1([C:8]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)O)=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]1[O:27][C:26]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=2[O:19]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl.C1(C)C(C)=CC=CC=1>[C:2]1([C:8]2[NH:23][C:22]3[C:24]([C:10]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:25][C:26]2[O:27][CH2:18][O:19][C:20]=2[CH:21]=3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1C
Product: c1ccc(-c2[nH]c3cc4c(cc3c2-c2ccccc2)OCO4)cc1

Procedure:
To a flask equipped with a stirrer and Dean-Stark water separator are charged 53g. of benzoin, 51g. of 3,4-methylenedioxyaniline, 2.5g. of p-toluenesulfonic acid and 300 ml. of xylene. The mixture is stirred and refluxed for 10 hours. After cooling to room temperature 1500 ml of chloroform are added and the organic layer is washed two times with 150 ml. of 10%, sulfuric acid. The organic layer is treated with charcoal, filtered and concentrated in vacuo to ca. 500 ml. On standing there is obtained 2,3-diphenyl- 5,6-methylenedioxyindole, m.p. 187°-188°C.
Reaction SMILES: O.[F:2][C:3]1[C:11](=[O:12])[NH:10][C:9](=[O:13])[NH:8][C:4]=1C(O)=O.O.C(=O)=O>COCCOCCOCCOC>[F:2][C:3]1[C:11](=[O:12])[NH:10][C:9](=[O:13])[NH:8][CH:4]=1
Reactant: O=C(O)c1[nH]c(=O)[nH]c(=O)c1F
Agent: O=C=O
Solvent: O
Solvent: COCCOCCOCCOC
Product: O=c1[nH]cc(F)c(=O)[nH]1
Temperature: 200 °C
Yield: 90 %

Procedure:
In the example, 20 g of crystals of 5-fluoro-orotic acid monohydrate obtained by the fluorination and the post-treatment of Example 1 was suspended in 80 ml of triethyleneglycol dimethyl ether and the mixture was heated under stirring whereby water was generated at higher than 130° C. and carbon dioxide was generated at higher than 190° C. The decarboxylation was completed by heating at 200° C. for about 20 minutes. After cooling the reaction mixture, the reaction product was separated by a filtration and recrystallized from water to obtain 12.2 g of 5-fluorouracil. The yield was 90% based on 5-fluoro-orotic acid monohydrate.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[C:23](=[O:24])[CH2:22][S:21][C:20]3=[O:25])[C:8]2=[N:7][CH:6]=1)=[O:4].[CH:28](=O)[CH2:29][CH2:30][CH3:31].N1CCCCC1>C(O)C>[CH:28](=[C:22]1[S:21][C:20](=[O:25])[N:19]([CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:13]2[C:8]3[N:9]([C:5]([C:3](=[O:4])[C:2]([F:1])([F:26])[F:27])=[CH:6][N:7]=3)[CH:10]=[CH:11][CH:12]=2)[C:23]1=[O:24])[CH2:29][CH2:30][CH3:31]
Reactant: O=C1CSC(=O)N1CCCCOc1cccn2c(C(=O)C(F)(F)F)cnc12
Reactant: CCCC=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCCCOc2cccn3c(C(=O)C(F)(F)F)cnc23)C1=O

Procedure:
To a solution of 271 mg (0.69 mmol) of 3-[4-(3-trifluoroacetylimidazo[1,2-a]pyridin-8-yloxy)butyl]thiazolidine-2,4-dione and 69 μl (0.69 mmol) of n-butyraldehyde in 5 ml of ethanol, 7 μl (0.07 mmol) of piperidine was added, followed by refluxing for 1 hour. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=2/1) to yield 250 mg (79.7%, light yellow oily substance) of the desired product.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH:10]([NH:16]C(=O)OCC1C=CC=CC=1)[CH2:11][C:12]([F:15])([F:14])[F:13].[ClH:27].C(OCC)C>CO.[Pd]>[ClH:27].[ClH:27].[F:13][C:12]([F:15])([F:14])[CH2:11][CH:10]([NH2:16])[CH2:9][NH2:8]
Reactant: NCC(CC(F)(F)F)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CCOCC
Product: NCC(N)CC(F)(F)F

Procedure:
130 mg of rac-benzyl (1-amino-4,4,4-trifluorobutan-2-yl)carbamate trifluoroacetate (Example 147 A, 0.33 mmol, 1 equivalent) were initially charged in 8.4 ml of methanol, under argon, 35 mg (0.03 mmol) of 10% palladium on activated carbon were added and the mixture was hydrogenated at RT and atmospheric pressure overnight. The mixture was then filtered through a Millipore® filter, 0.33 ml of 2 N hydrochloric acid in diethyl ether (0.66 mmol, 2 equivalents) was added and the mixture was concentrated. This gave 72 mg (100% of theory) of the title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.CCOCC>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][O:8]1
Reactant: OCCCCCBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: BrCCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-bromopentanol (8 g) was dissolved in dichloromethane (100 mL) and was chilled in an ice bath. Dihydropyran (9 g) was added dropwise followed by p-Toluene sulfonic acid monohydrate (1 g). The mixture was allowed to slowly warm to room temperature and stirred for 18 hours. The mixture was diluted with 200 mL ether, washed with 10% NaOH (100 mL) and dried over MgSO4 to give the title compound. δC (CDCl3, 62.9 MHz): 19.7, 25.0, 25.5, 28.9, 30.7, 32.6, 33.7, 62.4, 67.2 and 89.9.