Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Na].[CH2:13]([O:15][P:16]([CH2:21][OH:22])(=[O:20])[O:17][CH2:18][CH3:19])[CH3:14]>CN(C=O)C>[CH2:13]([O:15][P:16]([CH2:21][O:22][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])([O:17][CH2:18][CH3:19])=[O:20])[CH3:14]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CCOP(=O)(CO)OCC
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOP(=O)(COc1ccc(Br)cc1[N+](=O)[O-])OCC
Reaction time: 16 h

Procedure:
A solution of 2-fluoro-5-bromonitrobenzene (1 mmole) in DMF (5 mL) was cooled to 0° C., and treated with a solution of freshly prepared sodium salt of diethylhydroxymethylphosphonate (1.2 mmole) in DMF (5 mL). The mixture was stirred at room, temperature for 16 h. Evaporation, extraction and chromatography provided 2-diethylphosphonomethyloxy-5-bromonitrobenzene.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].Cl[C:6]1[S:7][C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([C:11](F)(F)F)[N:10]=1.[CH2:20]([OH:22])[CH3:21]>>[CH2:2]([O:1][C:6]1[S:7][C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([C:11]([O:17][CH2:18][CH3:19])([O:16][CH2:15][CH3:8])[O:22][CH2:20][CH3:21])[N:10]=1)[CH3:3]
Reactant: CCO
Reactant: CCOC(=O)c1sc(Cl)nc1C(F)(F)F
Reactant: CC[O-]
Agent: [Na+]
Product: CCOC(=O)c1sc(OCC)nc1C(OCC)(OCC)OCC
Reaction time: 4 h

Procedure:
To a warm solution of sodium ethoxide prepared from 2.0 g (0.0869 mole) of Na and 50 ml. of ethanol was added 5.2 g (0.02 mole) of ethyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate. The mixture was stirred for 4 hours. Ethanol was removed under reduced pressure. The residue was treated with water and extracted with ether. The ether solution was washed with saturated sodium bicarbonate, dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 2.2 g of the desired product as an oil, b.p. 115° C. at 0.1 mm; nD25 =1.4776.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([CH2:14]N3CCN(C(C(OCC)=O)CC(OCC)=O)CC3)[O:11][C:10]2=[O:33])=[CH:5][CH:4]=1)#[N:2].C(C1C=CC(N)=CC=1)#N.[O:43]1CC1CO.C(C1C=CC(NCC(O)CO)=CC=1)#N.C(=O)(OCC)OCC.CC(C)([O-])C>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:13][CH:12]([CH2:14][OH:43])[O:11][C:10]2=[O:33])=[CH:7][CH:8]=1)#[N:2]
Reactant: OCC1CO1
Reactant: CCOC(=O)CC(C(=O)OCC)N1CCN(CC2CN(c3ccc(C#N)cc3)C(=O)O2)CC1
Agent: CC(C)(C)[O-]
Agent: N#Cc1ccc(N)cc1
Agent: N#Cc1ccc(NCC(O)CO)cc1
Solvent: CCOC(=O)OCC
Product: N#Cc1ccc(N2CC(CO)OC2=O)cc1

Procedure:
1.3 g of 3-(4-cyanophenyl)-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl)oxazolidin-2-one [obtainable by reaction of 4-cyanoaniline with 2,3-epoxypropan-1-ol to give N-[4-cyanophenyl]-2,3-dihydroxypropylamine, reaction with diethyl carbonate in the presence of K tert-butoxide to give 3-(4-cyano-phenyl)-5-hydroxymethyloxazolidin-2-one, subsequent esterification with methanesulfonyl chloride and reaction with "B"] and 1.1 g of hydroxylamine hydrochloride are boiled for 2 hours in 125 ml of ethanol in the presence of 2.24 g of sodium ethoxide. The reaction mixture is then filtered and concentrated in vacuo. The residue is dissolved in water, the solution is adjusted to pH 3 using 2N hydrochloric acid and the resulting precipitate is filtered off with suction. After recrystallizing from water/glacial acetic acid, 3-[4-amino(hydroxyimino)methylphenyl]-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one, m.p. 186°, is obtained.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.[O:13]1[CH2:17][CH2:16][CH:15]([CH2:18]O)[CH2:14]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OCC)(=O)C.O>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH2:18][CH:15]2[CH2:16][CH2:17][O:13][CH2:14]2)[CH:3]=1
Reactant: OCC1CCOC1
Reactant: COC(=O)c1ccc(F)cc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(F)cc1OCC1CCOC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70 %

Procedure:
To a solution of 3 g of methyl 4-fluoro-2-hydroxybenzoate in 60 mL of tetrahydrofuran were added 1.98 g of tetrahydrofuran-3-ylmethanol and 4.28 g of tributylphosphine, followed by ice-cooling. To a mixture was gradually added 6.67 g of 1,1′-(azodicarbonyl)dipiperidine, followed by stirring for 20 minutes. The mixture was warmed to room temperature, stirred for 16 hours, and then poured into a mixture of water and ethyl acetate. The aqueous layer was separated, the organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 3.14 g of methyl 4-fluoro-2-(tetrahydrofuran-3-ylmethoxy)benzoate.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([S:7]([OH:9])=[O:8])=[CH:3][CH:2]=1.[CH:11]([C:13]([CH3:15])=[O:14])=[CH2:12].N.[CH2:17](O)[CH2:18][OH:19]>>[CH2:18]1[O:19][C:13]([CH2:11][CH2:12][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=2)(=[O:9])=[O:8])([CH3:15])[O:14][CH2:17]1
Reactant: OCCO
Reactant: Cc1ccc(S(=O)O)cc1
Reactant: C=CC(C)=O
Agent: N
Product: Cc1ccc(S(=O)(=O)CCC2(C)OCCO2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A stirred mixture of 4-toluenesulphinic acid (23.7 g, 0.15 mole) and ethylene glycol (30 ml) was treated over 10 minutes with methyl vinyl ketone (6.3 ml, 0.075 mole). The reaction was slightly exothermic and gave a clear solution. This was stirred at room temperature for 6 h, during which time a white precipitate formed. The mixture was poured into ice/water (600 ml) containing conc. ammonia solution (20 ml) and on vigorous stirring a white solid crystallised. This was filtered off, washed with water, dried and recrystallised from propan-2-ol/60-80 petrol to give the title compound (D25) as a white solid (15.2 g, 75%) m.p. 122-123° C. 1H-NMR (CDCl3) δ:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([CH3:33])=[CH:27]2>>[ClH:1].[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[NH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([CH3:33])=[CH:27]2
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Product: COc1cc2c(Nc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCCN1CCCC1
Product: Cl
Yield: 95.1 %

Procedure:
Using an analogous procedure to that described in Example 38, 4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (100 mg, 0.31 mmol), (prepared as described for the starting material in Example 9), was reacted with 5-amino-2-methylindole (50 mg, 0.34 mmol) to give 6-methoxy-4-(2-methylindol-5-ylamino)-7-(3-pyrrolidin-1-ylpropoxy)quinazoline hydrochloride (138 mg, 89%).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH2:22][CH2:23][C:24]([O:26]C)=[O:25])([CH2:16][CH2:17][C:18]([O:20]C)=[O:19])[C:4]=2[CH:3]=1.C1COCC1.CO.[OH-].[Na+]>O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[C:4]=2[CH:3]=1
Reactant: COC(=O)CCC1(CCC(=O)OC)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCC1(CCC(=O)O)c2cc(Br)ccc2-c2ccc(Br)cc21
Reaction time: 1 h
Yield: 81 %

Procedure:
Dimethyl 3,3′-(2,7-dibromo-9H-fluorene-9,9-diyl)dipropanoate (1.23 g, 2.5 mmol) is transferred to a small round bottom flask equipped with a Teflon-coated stirbar. A mixture of THF:MeOH:H2O, 3:2:1, (10 mL) is added and the mixture is stirred for 1 hr. Then a 1 mL portion of 1M NaOH (aq) is added and the mixture is stirred overnight. The next day the water layer is isolated and extracted with 20 mL portions diethyl ether three times. Next the water layer is acidified to ˜pH 2. The water layer is extracted three times with 20 mL portions of dichloromethane. The organic layers are combined and dried with Mg2SO4. The organic solution is filtered and the solvent evaporated to obtain the product as an off-white solid (948 mg, 90% yield).
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[O:22][CH2:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[F:31].[CH:32]1([C:35]#[C:36][C:37]([O:39][CH3:40])=[O:38])[CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:32]1([C:35]2[C:36]([C:37]([O:39][CH3:40])=[O:38])=[C:20]3[CH:19]=[C:18]([CH3:21])[CH:17]=[C:16]([O:22][CH2:23][C:24]4[C:25]([F:31])=[CH:26][CH:27]=[CH:28][C:29]=4[F:30])[N:15]3[N:14]=2)[CH2:34][CH2:33]1
Reactant: COC(=O)C#CC1CC1
Reactant: Cc1cc[n+](N)c(OCc2c(F)cccc2F)c1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(C2CC2)nn2c(OCc3c(F)cccc3F)cc(C)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.5 %

Procedure:
1.0 g (2.22 mmol) of 1-amino-2-[(2,6-difluorobenzyl)oxy]-4-methylpyridinium 2,4,6-trimethylbenzenesulphonate from Example 2A were dissolved in 7.2 ml of DMF, and 496 mg (4.00 mmol) of methyl 3-cyclopropylprop-2-ynoate were added. 552 mg (4.00 mmol) of potassium carbonate were added and the mixture was stirred at RT for 3 h. Subsequently, the mixture was poured onto 50 ml of water and stirred briefly, and the precipitated solids were filtered off, washed with water and dried. 384 mg of the title compound were obtained (46% of theory).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([CH2:20][C:21](=[O:31])[NH:22][C@H:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:24])[CH2:16][C:17](O)=[O:18])=[CH:11][CH:10]=1.ClC(OCC(C)C)=O>O1CCCC1>[C:25]1([C@@H:23]([NH:22][C:21](=[O:31])[CH2:20][C@H:15]([C:12]2[CH:11]=[CH:10][C:9]([F:8])=[CH:14][CH:13]=2)[CH2:16][CH2:17][OH:18])[CH3:24])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: C[C@H](NC(=O)C[C@@H](CC(=O)O)c1ccc(F)cc1)c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H](NC(=O)C[C@@H](CCO)c1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
3 mL of triethylamine was added to a solution of 5 g of compound 7a in 200 mL of tetrahydrofuran at room temperature. The solution was stirred for 60 min at room temperature and then was moved to a −78° C. dry ice acetone bath. To this solution was added dropwise 2.6 mL of iso-butyl chloroformate. The suspension was stirred from −78° C. to room temperature overnight. The mixture was filtered through a celite and silica gel pad, and washed with small amount tetrahydrofuran. To this solution in an ice bath was added 2.0 g of sodium borohydride, followed by dropwise addition of 10 mL of water. Carbon dioxide gas evolved violently. The reaction mixture was stirred for 2-4 hr, and was filtered through a celite pad. After the solvent evaporated, the aqueous layer was extracted several times with ethyl acetate. The organic layer was combined, washed with brine, dried over magnesium sulfate, and concentrated. The solid was recrystallized from ethyl acetate and hexanes to form the title compound as a colorless solid (80% yield, 95% de): mp 170.0-170.5° C.; [α]25D=−86.4 (c 1.0, CH3OH); 1H NMR (200 MHz, CDCl3) δ 7.40-7.10 (m, 7 H), 6.98 (t, J=8.7Hz, 2 H), 5.51 (br d, J=7.7 Hz, 1 H), 5.00 (quint, J=7.4 Hz, 1 H), 3.60-3.50 (m, 2 H), 3.33 (m, 1 H), 2.55 (dd, J=6.6, 14.2 Hz, 1 H), 2.38 (dd, J=8.6, 14.2 Hz, 1 H), 1.95-1.75 (m, 2 H), 1.27 (d, J=6.9 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 170.6, 161.6, 142.9, 139.6, 128.9, 128.6, 127.4, 126.1, 115.4, 60.1, 48.6, 44.0, 38.9, 38.4, 21.3. Anal. Calcd for C19H22FNO2: C, 72.36; H, 7.03; N, 4.44. Found: C, 72.35; H, 6.83; N, 4.33.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])[CH2:3][OH:4].C(N(CC)CC)C.[C:25](Cl)(Cl)=[S:26].O>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:17])[CH2:3][O:4][C:25](=[S:26])[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[CH2:5]1
Reactant: S=C(Cl)Cl
Reactant: CC(C)(CO)CNCc1ccccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC1(C)COC(=S)N(Cc2ccccc2[N+](=O)[O-])C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
2,2-Dimethyl-3-(2-nitrobenzylamino)-1-propanol (1.07 g, 4.50 mmol) was dissolved in chloroform (20 ml) and the reaction solution was cooled to 0° C. Then triethylamine (1.82 g, 18.0 mmol), thiophosgene (0.52 g, 4.50 mmol) was added thereto and stirred at a temperature as is for two hours and at room temperature for one hour. The reaction mixture was added with water, stirred at room temperature for one hour and then extracted with ethyl acetate. The organic layer was washed with a saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 5,5-dimethyl-3-(2-nitrobenzyl)-[1,3]-oxazinan-2-thione (1.12 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:11](=O)[CH2:12][CH2:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=O)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].C([O-])(=O)C.[NH4+:34].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:10]([C:11]2[NH:34][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:13][CH:12]=2)[CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: CSc1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ccccn2)cc1F
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CSc1ccc(C(CC2CCOCC2)c2ccc(-c3ccccn3)[nH]2)cc1F
Temperature: 110 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a solution of 5-[3-fluoro-4-(methylsulfanyl)phenyl]-1-(pyridin-2-yl)-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (127 mg) in acetic acid (2 mL) was added ammonium acetate (377% mg), and the mixture was stirred at 110° C. for 2 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (98.8 mg, yield 81%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:19])[CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:7]=1.[CH3:20][O:21][CH2:22][C@H:23](O)[CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([CH3:18])(=[O:16])=[O:17])=[CH:13][CH:14]=2)[CH:5]=[C:4]([O:19][C@@H:23]([CH3:24])[CH2:22][O:21][CH3:20])[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(O)cc(Br)c2)cc1
Reactant: COC[C@@H](C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC[C@H](C)Oc1cc(Br)cc(Oc2ccc(S(C)(=O)=O)cc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
3-Bromo-5-[4-(methylsulfonyl)phenoxy]phenol (4.86 g, 14.2 mmol) synthesized in Example (1c) was dissolved in toluene (100 mL), and (R)-(−)-1-methoxy-2-propanol (1.77 mL, 18.1 mmol) and triphenylphosphine (4.10 g, 15.6 mmol) were added, followed by cooling to 0° C. Under nitrogen atmosphere, diethyl azodicarboxylate (40% toluene solution, 7.75 mL, 17.1 mmol) was added dropwise over 10 minutes and stirring was carried out at 0° C. for 30 minutes, followed by raising the temperature naturally and stirring at room temperature overnight. Water (100 mL) and ethyl acetate (100 mL) were added, and the solution was separated. The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=20%-40%) to afford the desired compound (5.06 g, yield 86%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[NH:10][C@@H:11]1[CH2:19][CH2:18][CH2:17][C:16]2[N:15]([CH2:20][CH2:21][OH:22])[N:14]=[CH:13][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH2:1]([O:8][C:9]([NH:10][C@@H:11]1[CH2:19][CH2:18][CH2:17][C:16]2[N:15]([CH2:20][CH2:21][O:22][S:31]([CH3:30])(=[O:33])=[O:32])[N:14]=[CH:13][C:12]1=2)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(N[C@@H]1CCCc2c1cnn2CCO)OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCn1ncc2c1CCC[C@H]2NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.2 %

Procedure:
To a solution of (R)-[1-(2-hydroxy-ethyl)-4,5,6,7-tetrahydro-1H-indazol-4-yl]-carbamic acid benzyl ester (755 mg, 2.40 mmol) and pyridine (1.45 mL, 18.0 mmol) in dichloromethane was added methanesulfonyl chloride (1.40 mL, 18 mmol) dropwise at 0° C. The mixture was warmed to room temperature and stirred for 6 hours The resulting mixture was poured into ice (10 g). The organic layer was then separated and washed with 0.1 N hydrochloric acid and saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (10% methanol in dichloromethane) to afford methanesulfonic acid 2-((R)-4-benzyloxycarbonylamino-4,5,6,7-tetrahydroindazol-1-yl)-ethyl ester (880 mg, 90%) as a white solid. MS calcd. for C18H23N3O5S 393, obsd. (ESI+) [(M+H)+] 394.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=O)[CH2:2][CH3:3].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.B(F)(F)F.CCOCC.O>C1C=CC=CC=1>[C:5]1([C:1]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:2][CH3:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C1CCNC1
Reactant: CCC(=O)c1ccccc1
Agent: FB(F)F
Solvent: c1ccccc1
Solvent: O
Solvent: CCOCC
Product: CC=C(c1ccccc1)N1CCCC1
Yield: 78.9 %

Procedure:
In 50 ml of benzene, 9.38 g of propiophenone, 14.93 g of pyrrolidine and 0.99 g of boron trifluoride etherate were dissolved. The mixture was refluxed for 67 hours using a Cope water separator and molecular sieve 4A as the dehydrating agent. After having distilled out the solvent under a reduced pressure, the residue was subjected to a distillation under a reduced pressure to obtain 10.33 g of the desired enamine (yield: 79%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][N:18]([C:21]4[C:26]5[CH:27]=[CH:28][S:29][C:25]=5[CH:24]=[CH:23][N:22]=4)[CH2:17][CH2:16]3)=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.Cl[CH2:31][C:32]([NH2:34])=[O:33].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][N:18]([C:21]4[C:26]5[CH:27]=[CH:28][S:29][C:25]=5[CH:24]=[CH:23][N:22]=4)[CH2:17][CH2:16]3)=[CH:7][C:8](=[O:12])[N:9]2[CH2:31][C:32]([NH2:34])=[O:33])=[CH:4][CH:3]=1
Reactant: O=c1cc(CCN2CCN(c3nccc4sccc34)CC2)c2ccc(F)cc2[nH]1
Reactant: NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)Cn1c(=O)cc(CCN2CCN(c3nccc4sccc34)CC2)c2ccc(F)cc21
Temperature: 50 °C

Procedure:
66.9 kg of 7-fluoro-4-[2-[4-[thieno[3,2-c]pyridin-4-yl]piperazin-1-yl]ethyl]-quinolin-2(1H)-one (V), 18.4 kg of 2-chloroacetamide (1.2 eq.), 51.5 kg of potassium carbonate (2 eq.) and 335 l of DMF are introduced into a reactor. The mixture is stirred at 50° C. for twenty hours and then cooled to 25° C. and 1000 l of water are added. The suspension obtained is filtered and washed with water and a paste is re-formed in 307 l of ethanol. The solid is filtered off. 60.7 kg, estimated on a dry basis, of a white solid (II) are obtained.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.O.[OH-].[NH4+].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>C(#N)C>[ClH:1].[CH2:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][CH:3]1[NH:2][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NC1Cc2ccccc2C1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)CNC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
Acetonitrile (800 ml) is added to 2-aminoindan hydrochloride (50 g, 0.295 mole) followed by the addition of water (100 ml) and concentrated ammonium hydroxide (100 ml). To the resulting stirring solution tert-butyl bromoacetate (60 g, 0.308 mole) in acetonitrile (150 ml is added dropwise at room temperature and the resulting mixture stirred overnight at room temperature. The acetonitrile is evaporated on a rotary evaporator, water added to the residue and the product extracted several times into methylene chloride. The combined methylene chloride extract is washed twice with water, dried over magnesium sulfate, filtered and evaporated to afford the crude product as a tan oil. The crude product is purified further by silica-gel chromatography (chloroform). The desired fractions are concentrated and the hydrochloride prepared with ether-hydrochloric acid to afford tert-butyl N-(2,3-dihydro-1H-inden-2-yl)glycinate hydrochloride as a colorless solid (60 g, 72%); m.p. 175°; mass spectra (CI): 248(m+1, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:22])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH:19]([CH3:21])[CH3:20])[CH:13]=1)[C:5](O)=[O:6].B([O-])[O-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C(Br)C.Cl>C(Cl)Cl.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:22])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH:19]([CH3:20])[CH3:21])[CH:13]=1)[CH2:5][OH:6]
Reactant: CC(C)c1cc(Oc2c(Br)cc(C(=O)O)cc2Br)ccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [O-]B[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCBr
Product: CC(C)c1cc(Oc2c(Br)cc(CO)cc2Br)ccc1O
Temperature: 25 °C

Procedure:
A mixture of 3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoic acid (Example 1(c) (1.0 g, 3.3 mmol), tetrabutylammonium boronate (2.6 g, 9.9 mmol) and ethylbromide (1.0 ml, 13.2 mmol) in 25 ml of CH2Cl2 and 10 ml of tetrahydrofuran was stirred at room temperature over night. The reaction mixture was treated with 1M HCl and extracted several times with EtOAc. The combined organic phases were washed once with water followed by a saturated solution of NaCl. After drying over MgSO4, filtration and evaporation, the residue was purified by column chromathography (silica gel, 7:3 p-ether/EtOAc). This gave 0.922 g (98%) of 3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy) benzyl-alcohol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1.[OH-].[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(N2CCNCC2)nc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
A solution of t-butyl 4-(pyridin-2-yl)piperazine-1-carboxylate (500 mg, 1.90 mmol, 1.00 equiv) in DCM/CF3COOH (10/3 mL) was placed in a 50-mL round bottom flask and stirred for 1 h at 30° C. in an oil bath. The pH value of the solution was adjusted to 9 with aqueous sodium hydroxide (1M), then extracted with 3×10 mL of dichloromethane. The organic layers combined, dried over anhydrous sodium sulfate, and filtered to remove solids. The resulting solution was concentrated under vacuum, yielding 300 mg (97%) of 1-(pyridin-2-yl)piperazine as yellow oil.