Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CS(C)=O.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[S:15][CH3:16].Cl[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[C:19]=1[N+:25]([O-:27])=[O:26]>O>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[C:19]=2[N+:25]([O-:27])=[O:26])=[CH:10][C:9]=1[S:15][CH3:16]
Reactant: CSc1cc(O)ccc1N
Reactant: Nc1nccc(Cl)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CSc1cc(Oc2ccnc(N)c2[N+](=O)[O-])ccc1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60.7 %

Procedure:
Method A2 Sodium hydride (148 mg) was added to dry DMSO (5.5 mL) and the mixture was stirred at RT for 20 minutes under Ar atmosphere. 4-amino-3-(methylthio)phenol (573 mg, 3.7 mmol) was added thereto, and the mixture stirred for 10 more minutes. Next, 4-Chloro-3-nitropyridin-2-amine (3.7 mmol) was added, and the mixture was heated to 100° C. and stirred for 3 hours. After cooling down, water was added, and the mixture extracted three times with EtOAc. The combined organic layers were washed first with a saturated aqueous sodium hydrogen carbonate solution then water, dried over MgSO4 and evaporated to afford the title compound (657 mg, 61%) was obtained after purification by chromatography on silica gel (EtOAc-DCM, 1:1) as a red brown solid (Rf 0.56, EtOAc-DCM, 1:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:17][C:18](Cl)=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][S:32][C:33]1[N:38]=[C:37]([Sn](CCCC)(CCCC)CCCC)[CH:36]=[CH:35][N:34]=1>O1CCOCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:17][C:18]([C:35]2[CH:36]=[CH:37][N:38]=[C:33]([S:32][CH3:31])[N:34]=2)=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Reactant: COc1ccc(Oc2nc(Cl)ncc2NC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(Oc2nc(-c3ccnc(SC)n3)ncc2NC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Yield: 50.2 %

Procedure:
To a teflon-lined septum-sealed Schlenk tube, a mixture of Compound 1e (213 mg; 0.49 mmol), 2-methylsulfanyl-4-tributylstannanyl-pyrimidine (Compound 7a) (305 mg; 0.735 mmol) and tetrakis-(triphenylphosphine)palladium(0) (57 mg; 0.049 mmol) in dioxane (1.0 mL) was irradiated in a Microwave reactor at 150° C. for 30 min. The resultant mixture was diluted with EtOAc, and washed with saturated NH4Cl(aq) and H2O. The organic phase was washed with H2O, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 7b (129 mg; 50% yield). 1H-NMR (400 MHz, CDCl3): δ 8.48-8.50 (m, 1H), 8.08-8.12 (m, 1H), 7.54-7.57 (m, 1H), 7.16-7.23 (m, 2H), 6.96-7.01 (m, 2H), 6.27 (br. s, 0.7H), 5.18 (br, 0.3H), 4.25-4.36 (m, 1H), 3.88 (s, 3H), 3.24-3.59 (m, 4H), 2.68 (s, 3H), 1.79-2.16 (m, 4H), 1.44-1.54 (m, 9H); MS: m/z 525.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[NH:11][C:12](=[O:14])[CH3:13].CC1(C)C(C)(C)OB([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)O1.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>[N+:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[C:3]=1[NH:11][C:12](=[O:14])[CH3:13])([O-:10])=[O:9]
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: CC(=O)Nc1c(Br)cccc1[N+](=O)[O-]
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: CC(=O)Nc1c(-c2ccncc2)cccc1[N+](=O)[O-]
Yield: 55.2 %

Procedure:
A degassed mixture of N-(2-bromo-6-nitrophenyl)acetamide (XCI) (2.59 g, 10 mmol, 1.0 eq), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (XCII) (2.05 g, 10 mmol, 1.3 eq), Na2CO3 (2.12 g, 20 mmol, 2 eq) and Pd(PPh3)4 (1.16 g, 1 mmol, 0.1 eq) in a mixed solvent of DME (30 mL) and H2O (10 mL) was heated to reflux under nitrogen overnight, the mixture was poured onto water (40 ml) and extracted with ethyl acetate (30 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo, purification the resultant residue was purified by column chromatography (EtOAc:PE=1:4→100% EtOAc) to afford N-(2-nitro-6-(pyridin-4-yl)phenyl)acetamide (XCIII) (1.42 g, 5.52 mmol, 55% yield) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ ppm 1.92 (s, 3H), 7.46 (d, J=5.6 Hz, 2H), 7.69 (t, J=8 Hz, 1H), 7.80 (dd, J=7.6 Hz, J=1.2 Hz, 1H), 8.06 (dd, J=8 Hz, J=1.6 Hz, 1H), 8.73 (d, J=6 Hz, 2H), 9.96 (s, 1H); ESIMS found for C13H11N3O3 m/z 258 (M+H).
Reaction SMILES: Br[CH2:2][C:3](=[O:5])[CH3:4].[NH2:6][C@@H:7]([CH3:10])[CH2:8][OH:9].O>C(Cl)Cl>[OH:9][CH2:8][C@@H:7]([NH:6][CH2:2][C:3](=[O:5])[CH3:4])[CH3:10]
Reactant: CC(=O)CBr
Reactant: C[C@H](N)CO
Solvent: ClCCl
Solvent: O
Product: CC(=O)CN[C@@H](C)CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 145.7 %

Procedure:
A solution of 1-bromopropan-2-one (7.8 mL, 102 mmol) in DCM (15 mL) was added dropwise to a solution of (S)-2-aminopropan-1-ol (18.2 g, 0.243 mol) and anhydrous DCM (150 mL) at 0° C. The reaction stirred at 0° C. for 2 h. Water (150 mL) was added, and the organic phase was separated. The aqueous was extracted with DCM (3×40 mL), and the combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to give the crude product 19.5 g, which was used directly in the following step. LCMS: 132 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH2:12]1CCN2C(=NCCC2)CC1.CI>C(#N)C>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: O=C(O)c1c(Cl)ccnc1Cl
Reactant: C1CCC2=NCCCN2CC1
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1c(Cl)ccnc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 48.5 %

Procedure:
To a solution of 2,4-dichloronicotinic acid (500 mg, 2.60 mmol) in acetonitrile (10 mL) cooled to 0° C. was added DBU (0.981 mL, 6.51 mmol) followed by methyl iodide (0.814 mL, 13.0 mmol). The reaction mixture was stirred at RT overnight (14 h). After the reaction completion, the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (10 mL) and washed with water (1×5 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc-hexane) to afford methyl 2,4-dichloronicotinate (260 mg, 1.262 mmol, 49% yield) as pale yellow oil. LC/MS, (ESI) m/z 206.1 [(M+H)+, calcd for C7H6Cl2NO2 205.97]; LC/MS retention time (method D): tR=0.85 min. 1H NMR (300 MHz, CD3OD) δ ppm 8.42 (d, J=5.4 Hz, 1H), 7.59 (d, J=5.4 Hz, 1H), 3.99 (s, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14].N1C=CC=CC=1>O1CCCC1>[C:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:7][CH:8]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc(-c2cccs2)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-c2cccs2)cc1
Reaction time: 1 h
Yield: 79.5 %

Procedure:
To a mixture of 4-(2-thienyl)phenol (1.00 g) and acetic anhydride (869 mg) in tetrahydrofuran (10 ml) was added pyridine (494 mg) with ice-cooling. The mixture was stirred for 1 hour at said temperature and 1 hour at ambient temperature. After concentration, the mixture was partitioned between AcOEt and H2O. The separated organic layer was washed with 1% aqueous citric acid, 3% aqueous NaHCO3 solution and brine, dried over sodium sulfate and concentrated. The residue was triturated with hexane to give 985 mg of 2-(4-acetoxyphenyl)thiophene as a powder.
Reaction SMILES: [C:1]([Si:5]([CH3:22])([CH3:21])[O:6][C@H:7]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@@H:9]([CH2:19][OH:20])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:26]>CN(C=O)C>[C:1]([Si:5]([CH3:22])([CH3:21])[O:6][C@H:7]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[C@@H:9]([CH2:19][O:20][CH3:26])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 20 °C

Procedure:
A solution of tert-butyl (2R,4R) 4-(tert-butyl-dimethyl-silyl)oxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (9.32 g) in DMF (15 ml) was added to a stirred suspension of sodium hydride (60% dispersion) (1.37 g) in DMF 100 ml) at −10° C. Iodomethane (2.13 ml) was added and the reaction allowed to warm to 20° C. The reaction mixture was quenched carefully with water and evaporated to dryness. The crude material was partitioned between ethyl acetate (250 ml) and water (100 ml). The organic layer was washed with brine (100 ml), dried over Magnesium sulphate, filtered and evaporated to give tert-butyl (2R,4R) 4-(tert-butyl-dimethyl-silyl)oxy-2-(methoxymethyl)pyrrolidine-1-carboxylate (6.68 g) as a colourless oil. NMR Spectrum: (DMSOd6) 0.02 (6H, s); 0.83-0.84 (9H, s); 1.36 (9H, s); 1.78 (1H, d); 1.99 (1H, s); 2.99 (1H, d); 3.19 (3H, d); 3.23-3.48 (3H, m); 3.80 (1H, s); 4.33 (1H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH:5]2[OH:12].[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22][N:21]=2)[CH2:16][CH2:15]1.[NH4+].[OH-].C(Cl)Cl>CO>[CH3:13][N:14]1[CH2:15][CH2:16][N:17]([C:20]2[N:21]=[CH:22][C:23]([C:2]3[CH:3]=[C:4]4[C:9](=[N:10][CH:11]=3)[NH:8][CH2:7][CH2:6][CH:5]4[OH:12])=[CH:24][CH:25]=2)[CH2:18][CH2:19]1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: OC1CCNc2ncc(Br)cc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(c2ccc(-c3cnc4c(c3)C(O)CCN4)cn2)CC1
Yield: 22 %

Procedure:
6-Bromo-1,2,3,4-tetrahydro-[1,8]naphthyridin-4-ol (89 mg) was reacted with 1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-piperazine (125 mg) as in General Procedure 13. Silica gel chromatography using a gradient of 0-10% (5% NH4OH in methanol)/methylene chloride as the eluting solvent gave the title compound as brown solids (22% yield). M.p. 124-128° C., LCMS: m/z=326 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.00 (m, 1H), 2.08 (s, 1H), 2.62 (t, J=5.0 Hz, 4H), 3.49 (m, 2H), 3.58 (m, 2H), 3.63 (t, J=5.0 Hz, 4H), 4.85 (t, J=4.0 Hz, 1H), 6.68 (s, 1H), 6.71 (s, 1H), 7.59 (dd, J=2.6, 8.8 Hz, 1H), 7.66 (d, J=2.2 Hz, 1H), 8.01 (d, J=2.3 Hz, 1H), 8.32 (d, J=2.5 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[N+:9]([O-:11])=[O:10].CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1>CC(O)=O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:14]=[CH:18][CH:17]=[CH:16]2)[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: COC1CCC(OC)O1
Reactant: Cc1ccnc(N)c1[N+](=O)[O-]
Solvent: CC(=O)O
Product: Cc1ccnc(-n2cccc2)c1[N+](=O)[O-]
Yield: 90.4 %

Procedure:
11.82 g (0.0581 mol; yield: 90.4%) of a yellow powder, which turns red in air, are obtained by carrying out the reaction in the same way as in Stage B of Example 92 but starting from 9.85 g (0.0643 mol) of 4-methyl-3nitro-2-aminopyridine and using 10.2 g (0.0772 mol; 1.2 eq) of 2,5-dimethoxytetrahydrofuran and 200 cm3 of glacial CH3CO2H, and bringing the solution to reflux for 3 h.
Reaction SMILES: C1([Li])C=CC=CC=1.[CH2:8]([C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[N:16][CH:17]=1)[CH2:9][CH2:10][CH3:11].[CH2:19]([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1)[CH3:20]>C1CCCCC1.C(OCC)C.C(OCC)C>[CH2:19]([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][CH2:18][C:15]2[CH:14]=[CH:13][C:12]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:17][N:16]=2)=[CH:24][CH:23]=1)[CH3:20]
Reactant: CCCCc1ccc(C)nc1
Reactant: CCOc1ccc(CCl)cc1
Agent: [Li]c1ccccc1
Solvent: CCOCC
Solvent: C1CCCCC1
Product: CCCCc1ccc(CCc2ccc(OCC)cc2)nc1
Reaction time: 1 h

Procedure:
46 ml of a 2.2 molar solution of phenyllithium in cyclohexane/diethyl ether (7:3) are added with ice cooling to a solution of 14.9 g of 5-butyl-2-picoline in 50 ml of diethyl ether. After 1 hour of stirring, 15.9 g of 4-ethoxybenzyl chloride in 50 ml of diethyl ether are then added at room temperature, and the ether starts to boil. The reaction mixture is poured onto ice after 1 hour, and the organic phase is worked up. Separation by column chromatography (silica gel, toluene) and recrystallization gives 2-(p-ethoxyphenylethyl)-5-butylpyridine.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([C@H:10]3[C@H:15]([OH:16])[C@@H:14]([OH:17])[C@H:13]([OH:18])[C@@H:12]([CH2:19][OH:20])[O:11]3)=[CH:6][C:5]=2[CH2:21][C:22]2[CH:31]=[CH:30][C:25]3[O:26][CH2:27][CH2:28][O:29][C:24]=3[CH:23]=2)[CH2:3][CH2:2]1.Cl[C:33]([O:35][CH3:36])=[O:34]>N1C(C)=CC(C)=CC=1C.C(Cl)Cl>[CH3:36][O:35][C:33](=[O:34])[O:20][CH2:19][C@@H:12]1[C@@H:13]([OH:18])[C@H:14]([OH:17])[C@@H:15]([OH:16])[C@H:10]([C:7]2[CH:8]=[CH:9][C:4]([CH:1]3[CH2:3][CH2:2]3)=[C:5]([CH2:21][C:22]3[CH:31]=[CH:30][C:25]4[O:26][CH2:27][CH2:28][O:29][C:24]=4[CH:23]=3)[CH:6]=2)[O:11]1
Reactant: COC(=O)Cl
Reactant: OC[C@H]1O[C@@H](c2ccc(C3CC3)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: COC(=O)OC[C@H]1O[C@@H](c2ccc(C3CC3)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 107.7 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Intermediate 3, 890 mg, 2.1 mmol) in collidine (7 ml) was added a solution of methyl chloroformate (0.21 ml, 2.5 mmol) in DCM (0.5 ml) at −40° C. After stirring for 1 h at same temperature, it was stirred at room temperature for 1.5 h. Reaction mixture was poured into ice cold 10% HCl solution and extracted with ethyl acetate (2×10 ml). Combined organic layers were washed with brine (10 ml), dried over sodium sulfate, concentrated and purified by silica gel column chromatography to give 1.1 g of carbonic acid (2R,3S,4R,5R,6S)-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester methyl ester as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@@H:8]([O:21][Si:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:9][N:10]([CH2:18][CH2:19][OH:20])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.O[C:30]1[CH:38]=[C:37]2[C:33]([C:34]([CH:46]3[CH2:48][CH2:47]3)=[N:35][N:36]2[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[CH:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C(=O)([O-])[O-]>C1(C)C=CC=CC=1.C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[C:4]([C@@H:8]([O:21][Si:22]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:27][CH3:28])[CH2:9][N:10]([C:11]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:17])[CH2:18][CH2:19][O:20][C:30]2[CH:38]=[C:37]3[C:33]([C:34]([CH:46]4[CH2:48][CH2:47]4)=[N:35][N:36]3[C:39]([O:41][C:42]([CH3:44])([CH3:45])[CH3:43])=[O:40])=[CH:32][CH:31]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[Si](CC)(CC)O[C@@H](CN(CCO)C(=O)OC(C)(C)C)c1cccc(N)c1
Reactant: CC(C)(C)OC(=O)n1nc(C2CC2)c2ccc(O)cc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=C([O-])[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC[Si](CC)(CC)O[C@@H](CN(CCOc1ccc2c(C3CC3)nn(C(=O)OC(C)(C)C)c2c1)C(=O)OC(C)(C)C)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
(R)-Tert-butyl 2-(3-aminophenyl)-2-(triethylsilyloxy)ethyl(2-hydroxyethyl)carbamate (1.6143 g) which can be prepared according to the method described in Reference example 59, etc. and tert-butyl 6-hydroxy-3-cyclopropylindazole-1-carboxylate (924 mg) which can be prepared according to the method described in Reference example 7, etc. and triphenylphosphine (1.1419 g; manufactured by Kanto Chemical Co., Inc.) were dissolved in dehydrated toluene (18 mL), added with DIAD (808 μL; manufactured by Sigma-Aldrich Co.), and stirred overnight at room temperature. The reaction solution was purified by column chromatography (“COLUMN-A”; n-hexane:ethyl acetate=82:18→61:39) to obtain a crude product (1.669 g), which was then dissolved in CH2Cl2 (20 mL). After adding MP-Carbonate [5.15 g (2.73 mol/g); manufactured by Argonaut] to the mixture, it was stirred overnight at room temperature. After filtering the reaction solution, the filtrate was concentrated under reduced pressure to obtain the title compound (1.0644 g).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[N:10]=[C:11]([CH2:14][OH:15])[O:12][CH:13]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:26][S:23]([O:15][CH2:14][C:11]1[O:12][CH:13]=[C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)[N:10]=1)(=[O:25])=[O:24]
Reactant: CC1(c2coc(CO)n2)OCCO1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(c2coc(COS(C)(=O)=O)n2)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (4-(2-methyl-[1,3]dioxolan-2-yl)-oxazol-2-yl)-methanol (230 mg, 1.24 mmol) in dry CH2Cl2 (10 mL) was treated at 0° C. with Et3N (0.23 mL, 1.64 mmol) followed by DMAP (15 mg, 0.12 mmol) and Ms-Cl (0.13 mL, 1.61 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (4-(2-methyl-[1,3]dioxolan-2-yl)oxazol-2-yl)methyl methanesulfonate as a colorless oil. The crude material was dissolved in dry DMF (6 mL) and treated with NaN3 (93 mg, 1.41 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 2-(azidomethyl)-4-(2-methyl-[1,3]dioxolan-2-yl)oxazole as a colorless oil. To a solution of the crude azide in THF (9 mL) were added polymer-supported Ph3P (1.4 eq.) and water (3 mL). The reaction mixture was stirred at 55° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. sat. NaHCO3 and the layers separated. The aq. layer was concentrated under reduced pressure, the residue triturated in EtOH and the solid filtered off. The filtrate was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as an orange oil. LC-MS-conditions 01: tR=0.22 min; [M+H]+=185.00.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([OH:17])=[CH:7][CH:8]=2)[N:3]=1.Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:17][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(N2CCCC2)c2ccc(O)cc2n1
Reactant: ClCCN1CCOCC1
Agent: Cl
Product: Cc1cc(N2CCCC2)c2ccc(OCCN3CCOCC3)cc2n1

Procedure:
In analogy to example 6 there was prepared: on reaction of 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with 4-(2-chloroethyl)-morpholine hydrochloride, whereby the product was isolated as free base, 2-methyl-7-(2-morpholin-4-yl-ethoxy)-4-pyrrolidin-1-yl-quinoline as a brown solid. ISP mass spectrum, m/e: 342.3 (M+1 calculated for C20H27N3O2: 342).
Reaction SMILES: [C:1](=[O:13])([S:11][CH3:12])[O:2][CH:3]([O:5][C:6](=[O:10])[CH:7]([CH3:9])[CH3:8])C.ClC(OCCl)=O.[CH:20]1(C(O)=O)[CH2:25]CCC[CH2:21]1>>[C:1](=[O:13])([S:11][CH3:12])[O:2][CH2:3][O:5][C:6]([CH:7]1[CH2:9][CH2:25][CH2:20][CH2:21][CH2:8]1)=[O:10]
Reactant: O=C(O)C1CCCCC1
Reactant: CSC(=O)OC(C)OC(=O)C(C)C
Agent: O=C(Cl)OCCl
Product: CSC(=O)OCOC(=O)C1CCCCC1

Procedure:
Following the procedures for synthesizing O-(1-isobutanoyloxyethyl) S-methyl thiocarbonate (2) and replacing 1-chloroethyl chloroformate with chloromethyl chloroformate in Step A and replacing isobutyric acid with cyclohexanecarboxylic acid in Step B affords O-(cyclohexanoyloxymethyl) S-methyl thiocarbonate (10) as an oil.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH2:31]([NH2:35])[CH:32]([CH3:34])[CH3:33]>>[ClH:1].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([NH:35][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:27])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Reactant: CC(C)CN
Agent: Cl
Product: CC(C)CNC(=O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 149) and 17.1 mg (0.23 mmol) of iso-butylamine are reacted together by general method E. 15.2 mg (26.9% of theory) of the title compound are obtained.
Reaction SMILES: Cl[CH:2]1[O:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[C:4](=[O:15])[C:3]1([CH3:17])[CH3:16].C(N(CC)CC)C.[O-:25][CH2:26][CH3:27].[Na+]>C(O)C>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][N:5]1[C:4](=[O:15])[C:3]([CH3:17])([CH3:16])[CH:2]([O:25][CH2:26][CH3:27])[O:6]1
Reactant: CC1(C)C(=O)N(Cc2ccccc2Cl)OC1Cl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC1ON(Cc2ccccc2Cl)C(=O)C1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.1 %

Procedure:
To a stirred solution of 3.0 grams (0.011 mole) of 5-chloro-2-[(2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone (Example 23 (A)) in 30 ml of absolute ethanol was added dropwise 1.2 grams (0.012 mole) of triethylamine. Upon completion of addition the reaction mixture was heated under reflux for 18 hours; thin layer chromatography of the reaction mixture indicated no reaction had taken place. The reaction mixture was cooled, 0.74 gram (1 equiv.) of sodium ethoxide was added, and the reaction mixture was stirred at ambient temperature for two hours; again thin layer chromatography on the reaction mixture indicated that no reaction had taken place. The reaction mixture was filtered and diluted with 150 ml of methylene chloride. The mixture was washed with two 100-ml portions of water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give an oil residue. The oil was distilled at 80°/3.3 Pa. using a short-path distilling system. Nuclear magnetic resonance spectroscopy indicated 83% of the distillate to be the desired product. The distillate was subjected to column chromatography on silica gel, using 20% ethyl acetate in heptane for elution. The appropriate fractions were combined and concentrated under reduced pressure to give 1.3 grams of 2-[(2-chlorophenyl)methyl]-5-ethoxy-4,4-dimethyl-3-isoxazolidinone as an oil.