Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[NH:10][CH2:11][CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C>ClCCl.CS(C)=O>[CH2:1]([O:8][C:9](=[O:14])[NH:10][CH2:11][CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCO)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a stirred solution of (2-hydroxyethyl)-carbamic acid benzyl ester (1.0 g, 5.1 mmol) and N,N-diisopropylethylamine (1.78 mL, 10.2 mmol) in dichloromethane (15 mL) was added a solution of sulfur trioxide-pyridine complex (1.63 g, 10.2 mmol) in dimethyl sulfoxide (15 mL) at −20° C. After 1 h, the reaction was warmed to room temperature, diluted with dichloromethane (50 mL) and washed with 1.0 N HCl (50 mL) and brine. The organics were separated, dried with anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography, eluting with ethyl acetate in hexanes (0% to 80% gradient) to give the title product (810 mg, 82%). 1H NMR (CDCl3, 300 MHz) δ (ppm): 9.5 (s, 1H) 7.4-7.2 (m, 5H), 5.1 (s, 2H), 3.9 (d, J=5.8 Hz, 2H), 2.9-3.3 (br, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.Br[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCCN1CCN(c2ccc(N)cc2)CC1

Procedure:
1-(4-Nitrophenyl)piperazine and ethyl 4—bromobutanoate were allowed to undergo the reaction under heating in 1-methyl-2-pyrrolidone in the presence of potassium carbonate. The resulting compound was subjected to catalytic hydrogenation in the same manner as shown in Reference Example 3 to obtain ethyl 4-[4-(4-aminophenyl)-piperazin -1-yl]butanoate. F: 264.
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[N:23]([O-])=[O:24].[Na+]>C(OC(=O)C)(=O)C>[N:23]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:11])=[O:10])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)N(Cc2ccccc2)N=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
To a solution of N-benzyl-p-toluenesulphonamide (21 g, 80 mmol) and acetic acid (100 ml) in acetic anhydride (400 ml) was added solid sodium nitrite (120 g, 1.7 mol) in portions over a period of 12 hours at 5° C. The temperature was kept below 10° C. all the time. After the addition was finished the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was poured over an excess of ice water and stirred for 1 hour. The pale yellow precipitate was filtered and washed several times with water. The crude product was recrystallized from ethanol to give the title compound as a tiny yellow needles (19.1 g, 82% yield, m.p. 92°-93° C., (Lit.1 89°-90° C.). δH (CDCl3): 7.80(2H,m); 7.25(7H,m); 4.95(2H,s); 2.40(3H,s)ppm.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([N+:16]([O-:18])=[O:17])=[C:12]([S:14][CH3:15])[CH:13]=1.CO.[O:21]1CCCC1>O.C(OCC)C>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([N+:16]([O-:18])=[O:17])=[C:12]([S:14]([CH3:15])=[O:21])[CH:13]=1
Reactant: CSc1cc(Br)ccc1[N+](=O)[O-]
Reactant: C1CCOC1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: CS(=O)c1cc(Br)ccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
Sodium periodate (4.2 g, 16.34 mmol) in water (8 mL) was added to the solution of the product of Example 14A (4.01 g, 16.34 mmol) in 2/1 methanol/tetrahydrofuran (60 mL) and the mixture stirred for 1 hour. The mixture was diluted with ethyl ether, washed with water and saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 3/1 ether/ethyl acetate to provide the title compound.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37](O)=[O:38])=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=2)[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])=[O:38])=[CH:29][CH:28]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(Cl)c1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol (300 mg, 0.79 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (151 mg, 0.79 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (228 mg, 1.19 mmol) and 1-hydroxybenzotriazole hydrate (122 mg, 0.79 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-ethyl acetate). Recrystallization from ethyl acetate-hexane gave the objective substance (163 mg, 37%).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]2[C@@:20]3([C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][C:21]3=[O:29])[CH2:19]2)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C@H:18]2[C@@:20]3([C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]([CH2:3][CH2:4][N:5]4[CH2:10][CH2:9][O:8][CH2:7][CH2:6]4)[C:21]3=[O:29])[CH2:19]2)=[CH:16][CH:17]=1
Reactant: ClCCN1CCOCC1
Reactant: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc(Cl)cc1
Agent: Cl
Product: O=C1N(CCN2CCOCC2)c2ccccc2[C@]12C[C@H]2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to Example 70 starting from 4-(2-chloroethyl)morpholine hydrochloride (commercially available), (1S,2R) and (1R,2S)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C22H23ClN2O2: 382, observed (M+H)+: 383.1 1H NMR (400 MHz, MeOD-d4) δppm 2.21-2.29 (m, 2 H) 3.30 (t, J=8.72 Hz, 1 H) 3.54-3.69 (m, 2 H) 3.97 (br. s., 8 H) 4.21-4.32 (m, 1 H) 4.36-4.48 (m, 1 H) 6.15 (d, J=7.33 Hz, 1 H) 6.83 (t, J=7.20 Hz, 1 H) 7.14-7.21 (m, 1 H) 7.22-7.30 (m, 3 H) 7.31-7.39 (m, 2 H).
Reaction SMILES: CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH3:12][N:13]([C:15](=[N:43][S:44]([CH3:47])(=[O:46])=[O:45])[C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][C:25]3[C:28]([C:39]([NH2:41])=O)=[N:29][N:30]([C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=4)[C:24]=3[C:23]2=[O:42])=[CH:18][CH:17]=1)[CH3:14].N1C=CC=CC=1>C(#N)C>[C:39]([C:28]1[C:25]2[CH2:26][CH2:27][N:22]([C:19]3[CH:20]=[CH:21][C:16]([C:15]([N:13]([CH3:14])[CH3:12])=[N:43][S:44]([CH3:47])(=[O:46])=[O:45])=[CH:17][CH:18]=3)[C:23](=[O:42])[C:24]=2[N:30]([C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[N:29]=1)#[N:41]
Reactant: COc1ccc(-n2nc(C(N)=O)c3c2C(=O)N(c2ccc(C(=NS(C)(=O)=O)N(C)C)cc2)CC3)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1ccc(-n2nc(C#N)c3c2C(=O)N(c2ccc(C(=NS(C)(=O)=O)N(C)C)cc2)CC3)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 72.9 %

Procedure:
N,N-Dimethylformamide (0.1 mL) was added to acetonitrile (10 mL) and cooled to 0° C. Oxalyl chloride (0.113 mL, 1.29 mmol) was added to the reaction. Once gas evolution stopped, 6-[4-(dimethylamino-methanesulfonylimino-methyl)-phenyl]-1-(4-methoxy-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid amide (0.020 g, 0.039 mmol) was dissolved in acetonitrile (2 mL) and added to the reaction and stirred at 0° C. for 20 min. Pyridine (1 mL) was then added to the reaction, and it was warmed to rt and stirred overnight. The reaction was quenched with 1N hydrogen chloride (50 mL), extracted with ether 3×50 mL), washed with brine (1×50 mL), dried with MgSO4, and concentrated. Purification by reverse phase HPLC and freeze-dried to afford the title compound (0.014 g, 72%): 1H NMR (CHCl3) δ 7.45 (d, j=8.8 Hz, 2H), 7.40 (d, j=1.1 Hz, 4H), 6.95 (d, j=8.7 Hz, 2H), 4.21 (t, j=6.6 Hz, 2H), 3.83 (s, 3H), 3.19 (s, 3H), 3.17 (t, j=6.1 Hz, 2H), 2.94 (s, 3H), 2.81 (s, 3H) ppm; Mass Spec 493.5 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:14][OH:15])[CH2:3][N:4]([CH2:9][CH:10]([OH:13])[CH2:11][OH:12])[CH2:5][CH2:6][CH2:7][NH2:8].[CH2:16]1[O:18][CH:17]1[CH2:19][OH:20]>CO>[OH:1][CH:2]([CH2:14][OH:15])[CH2:3][N:4]([CH2:9][CH:10]([OH:13])[CH2:11][OH:12])[CH2:5][CH2:6][CH2:7][NH:8][CH2:16][CH:17]([OH:18])[CH2:19][OH:20]
Reactant: NCCCN(CC(O)CO)CC(O)CO
Reactant: OCC1CO1
Solvent: CO
Product: OCC(O)CNCCCN(CC(O)CO)CC(O)CO

Procedure:
N,N-di-(2,3-dihydroxypropyl)trimethylenediamine (11.1 g., 0.05 mole) is dissolved in 125 ml. of methanol and heated under reflux with agitation. Glycidol (3.7 g., 0.05 mole) is added dropwise over a period of 1.5 hour and the solution mixed an additional hour at 60° C.-80° C. The methyl alcohol and other volatiles are removed by stripping under reduced pressure to leave the product suitable for use in the next steps.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].CO[C:13](OC)([CH3:15])[CH3:14].[CH3:18]C(C)=O>CO>[CH3:18][O:1][CH:2]1[C@@H:3]2[O:4][C:13]([CH3:15])([CH3:14])[O:6][C@@H:5]2[C@@H:7]([CH2:9][OH:10])[O:8]1
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(C)=O
Reactant: COC(C)(C)OC
Solvent: CO
Product: COC1O[C@H](CO)[C@H]2OC(C)(C)O[C@@H]12

Procedure:
In the first part of the transformation the glycol group of ribose is protected using 2,2-dimethoxy propane and/or acetone in methanol in the presence of catalytic amounts of acid. The intermediate ((3aR,4R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-methanol (B) is not isolated in a pure state, but the reaction is treated by a base, preferably selected from the base used in the next step, most preferably pyridine. Most of volatile compounds solvents are then removed, the residue is extracted by an organic solvent selected from chlorinated hydrocarbons, esters or ethers, preferably by methyl tert-butyl ether, the extract is optionally dried and solution is concentrated and diluted by a pyridine type solvent, selected from pyridine, picolines or lutidine, preferably by pyridine. The obtained mixture is sulfonated by an addition of a chloride or anhydride of a sulfonic acid selected from unsubstituted or fluoro substituted C1-C4-alkanesulfonic acids, or unsubstituted or methyl, methoxy, bromo, nitro substituted, preferably para substituted benzenesulfonic acids, or camphor-10-sulfonic acid, followed by demoisturing with drying agent such as sodium or magnesium sulfate and removal of solvent under reduced pressure. The sulfonates of formula C, such as ((3aR,4R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 4-methylbenzenesulfonate (C′, compound C, R′=p-tolyl) or ((3aR,4R,6aR)-6-methoxy-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl methanesulfonate (C″, compound C, R′=Me) are solid crystalline materials, which are optionally purified by recrystallization from appropriate solvent such as 2-propanol to give very pure compounds.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[C:15]([N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].CC(O)=O.C([O-])(O)=O.[Na+]>ClC(Cl)C>[N+:11]([C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:14])([CH3:1])[CH2:3][N:4]2[CH2:28][CH:25]2[CH2:26][CH2:27][N:22]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:23][CH2:24]2)=[CH:9][CH:8]=1)([O-:13])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(CN2CC(C)(C)c3ccc([N+](=O)[O-])cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,3-Dimethyl-6-nitroindoline (450 mg) was dissolved in 20 mL of dichloroethane, N-boc-4-formylpiperidine (750 mg) was added to the mixture, followed by 2 g NaHB(OAc)3 and 1 mL of glacial AcOH. The mixture was stirred at RT overnight. Saturated NaHCO3 solution (20 mL) was added to the reaction mixture and stirred for 1 h. The resulting mixture was separated by separation funnel, the organic layer was extracted once with saturated NaHCO3 solution and once with brine. The resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 9:1 Hexane:EtOAc to afford an orange oil. MS: 290 (M−99). Calc'd. for C21H31N3O4—389.5.
Reaction SMILES: [CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)[C:2]#[CH:3].[CH2:20]=O.[CH2:22]([N:24]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1)[CH2:25][CH3:26])[CH3:23]>>[CH2:22]([N:24]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH2:20][C:3]#[C:2][CH2:1][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)[CH2:25][CH3:26])[CH3:23]
Reactant: C=O
Reactant: CCN(CC)CC1CCCCN1
Reactant: C#CCN1c2ccccc2C(=O)Nc2cccnc21
Product: CCN(CC)CC1CCCCN1CC#CCN1c2ccccc2C(=O)Nc2cccnc21
Yield: 28 %

Procedure:
Prepared analogously to Example (1b) from 5,11-dihydro-11-(prop-2-ynyl)-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, paraformaldehyde and 2-[(diethylamino)methyl]piperidine in a yield of 28% of theory. Colourless crystals, m.p. 132°-134° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][N:17]([C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=1)[CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][N:17]([C:20]1[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=1)[CH2:18][CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(N(CC)CCc2ccccc2OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CCc1ccccc1OCc1ccccc1)c1ccc(C(=O)O)cc1

Procedure:
Ethyl 4-[N-(2-(2-benzyloxyphenyl)ethyl)-N-ethylamino]benzoate was dissolved in a solution of methanol (20 ml) and tetrahydrofuran (20 ml). To this solution was added aqueous 2N sodium hydroxide (10.5 ml) and the mixture heated at reflux for 24 hours; cooled and the volume reduced by evaporation to half the original volume. Water (20 ml) was added and the mixture acidified with acetic acid. The resulting solid was filtered and dried under vacuum at 60° C. to give the title product (950 mg) m.p. 175° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[Cl-].[CH3:9][N+:10](=[CH2:12])[CH3:11].C([Cl:16])(=O)C>C(#N)C>[ClH:16].[CH3:9][N:10]([CH2:12][CH:3]1[C:4](=[O:7])[CH2:5][CH2:6][O:1][CH2:2]1)[CH3:11]
Reactant: C=[N+](C)C
Reactant: O=C1CCOCC1
Reactant: CC(=O)Cl
Agent: [Cl-]
Solvent: CC#N
Product: CN(C)CC1COCCC1=O
Product: Cl
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
9.6 g tetrahydropyran-4-one were dissolved in 29 ml acetonitrile, and 9.69 g N,N-dimethyl-methylenammonium chloride, followed by 100 μl acetyl chloride, were added. After the mixture had been stirred at a bath temperature of 60° C. for 45 minutes, it was stirred at room temperature for 60 hours and the precipitate formed was filtered off with suction and dried. 16.4 g 3-dimethylaminomethyltetrahydropyran-4-one hydrochloride were obtained. The corresponding base was liberated from this with methylene chloride and sodium hydroxide solution (32 percent strength by weight).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:23]([C:24](OCC)=[O:25])=[C:22]([CH:29]([CH3:31])[CH3:30])[N:21]=[C:20]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:19]=2)=[CH:14][CH:13]=1>O1CCCC1.CCCCCC>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]2[C:23](=[CH:24][OH:25])[C:22]([CH:29]([CH3:31])[CH3:30])=[N:21][C:20]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[N:19]2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)nc(-c2ccccc2)nc1C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)C1=NC(c2ccccc2)=NC(c2ccc(F)cc2)C1=CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
Diisobutylaluminum hydride (DIBAL-H) (1M in tetrahydrofuran (THF) (55 ml, 55 mmol) was added dropwise to a 0° C. solution of 4-(4-fluorophenyl)-6-(1-methylethyl)-2-phenyl-5-ethoxycarbonyl-pyrimidine obtained in step (ii) above (4.000 gm, 11 mmol) in THF (50 ml). The solution was then allowed to warm to room temperature and the mixture stirred for 3 hours. The solution was then cooled to 0° C. and quenched with saturated NH4Cl (55 ml). The solution was diluted with ether (100 ml) and the mixture was filtered through a celite pad and washed with ether. The filtrate was entirely organic and was dried over MgSO4, filtered and concentrated to give a yellow oil. The oil was dissolved in hot hexane and cooled to afford the title compound as a white solid (2.686 gm, 76%) (mp 183°-184° C.).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:8]1[C:12]2([CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[O:11][CH2:10][CH2:9]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:15]2[CH2:16][CH2:17][C:12]3([O:11][CH2:10][CH2:9][O:8]3)[CH2:13][CH2:14]2)[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1CCN(C2CCC3(CC2)OCCO3)CC1
Temperature: 25 °C
Yield: 99.2 %

Procedure:
1-Methyl-piperazine (128.27 g, 105.90 ml, 1.28 mol) was added in one portion to a stirred and cooled (3° C.) solution of 1,4-dioxaspiro[4.5]decan-8-one (200.00 g, 1.28 mol) in 1,2-dichloroethane (2.0 L). Then glacial acetic acid (76.90 g, 73.31 ml, 1.28 mol) was added in one portion followed by solid NaBH(OAc)3 (379.97 g, 1.79 mol) portionwise over 20 min. The reaction was slowly allowed to warm to RT and was stirred overnight. The reaction was quenched by addition of 10% aqueous NaOH (3×450 mL) with stirring over a period of 25 min. An exotherm of ca. 10° C. was observed. The mixture was stirred for 30 min. The organic layer was separated. Aqueous layer was further extracted with CH2Cl2 (3×1 L). Brine (1000 mL) was added to the aqueous layer and extracted with EtOAc (2×1000 mL). The combined organic solutions were dried (MgSO4) and concentrated to afford 4 (305.00 g, 1.27 mol, 99.10% yield) as brown/orange oil. 1H NMR (400 MHz, CDCl3) δ 1.45-1.68 (m, 4H), 1.72-1.90 (m, 4H), 1.99 (s, 3H), 2.45 (s, 2H), 2.56-2.67 (m, 1H), 2.87 (bs, 6H), 3.86-3.95 (m, 4H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:32]=[CH:31][C:12]([O:13][C:14]3[N:22](COCC[Si](C)(C)C)[C:17]4=[N:18][CH:19]=[CH:20][CH:21]=[C:16]4[N:15]=3)=[CH:11][CH:10]=2)O1.Br[C:35]1[C:39]2=[N:40][CH:41]=[CH:42][CH:43]=[C:38]2[N:37]([CH2:44][CH3:45])[N:36]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:44]([N:37]1[C:38]2[C:39](=[N:40][CH:41]=[CH:42][CH:43]=2)[C:35]([C:9]2[CH:10]=[CH:11][C:12]([O:13][C:14]3[NH:22][C:17]4=[N:18][CH:19]=[CH:20][CH:21]=[C:16]4[N:15]=3)=[CH:31][CH:32]=2)=[N:36]1)[CH3:45]
Reactant: CCn1nc(Br)c2ncccc21
Reactant: CC1(C)OB(c2ccc(Oc3nc4cccnc4n3COCC[Si](C)(C)C)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCn1nc(-c2ccc(Oc3nc4cccnc4[nH]3)cc2)c2ncccc21
Yield: 118 %

Procedure:
A mixture of 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-3-{[2-(trimethylsilyl)ethoxy]methyl}-3H-imidazo[4,5-b]pyridine (100 mg), 3-bromo-1-ethyl-1H-pyrazolo[4,3-b]pyridine (140 mg), Pd(PPh3)4 (7 mg), Na2CO3 (79 mg), DME (5 mL), and water (1 mL) was refluxed overnight under Ar atmosphere. The mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) and recrystallized from AcOEt/hexane to give the title compound (90 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([O:18][CH2:19][CH:20]4[CH2:24][CH2:23][CH2:22][NH:21]4)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:38][O:39][C:40](=[O:44])[CH2:41][CH2:42]Br>C1COCC1.ClCCl>[CH3:38][O:39][C:40](=[O:44])[CH2:41][CH2:42][N:21]1[CH2:22][CH2:23][CH2:24][CH:20]1[CH2:19][O:18][C:16]1[C:17]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[C:10]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:11][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: COC(=O)CCBr
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC4CCCN4)c23)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CCN1CCCC1COc1ncnc2oc(-c3ccccc3)c(-c3ccc(OC)cc3)c12
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Dissolve 160 mg (0.4 mmol) of (+/−)-5-(4-methoxyphenyl)-6-phenyl-4-(pyrrolidin-2-ylmethoxy)-furo[2,3-d]pyrimidine (Example 38A) in 0.8 ml of THF and add 110 μl (0.8 mmol) of triethylamine and 87 μl (0.8 mmol) of 3-bromopropionic acid methyl ester. Stir the mixture at 20-40° C. overnight, then dilute with dichloromethane and wash with saturated sodium hydrogencarbonate solution. Concentrate the solution under reduced pressure and purify the resulting oil by preparative RP-HPLC (eluent: acetonitrile/water gradient). 90 mg (44% of theory) of the target product are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C@:15]34[CH2:17][CH2:18][NH:19][C@@H:9]([C@@H:10]3[CH2:11][CH2:12][C:13](=[O:20])[CH2:14]4)[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:27](Br)[CH:28]=[CH2:29]>CN(C=O)C>[CH2:29]([N:19]1[CH2:18][CH2:17][C@@:15]23[C:16]4[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=4[CH2:8][C@@H:9]1[C@@H:10]2[CH2:11][CH2:12][C:13](=[O:20])[CH2:14]3)[CH:28]=[CH2:27]
Reactant: COc1cccc2c1[C@]13CCN[C@H](C2)[C@@H]1CCC(=O)C3
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCN1CC[C@]23CC(=O)CC[C@H]2[C@H]1Cc1cccc(OC)c13
Temperature: 25 °C
Yield: 92.1 %

Procedure:
A mixture of 700 mg (2.44 mmol) 4-methoxymorphinan-6-one.1H2O, 900 mg (6.51 mmol) anhydrous K2CO3 and 310 mg (2.56 mmol) allyl bromide in 20 ml dry DMF was stirred at 80° C. for 30 min. Then the mixture was cooled to room temperature, filtered, and the filtrate evaporated in vacuo. The resulting oil was partitioned between water and ether, the organic layer washed with brine, dried and evaporated to give an oil which was crystallized with u-hexanes. To 700 mg (93%) N-allyl-4-methoxymorphinan-6-one, m.p. 84°-86°, [α]D26 -114.6° (c 0.79, CHCl3), were obtained.