Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.BrCC([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)=O.O.OS(O)(=O)=O.[CH2:30](O)[CH3:31]>[Fe]>[N:1]1[C:30]([NH:21][C:18]2[CH:17]=[CH:16][CH:15]=[CH:20][CH:19]=2)=[CH:31][N:6]2[C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[S:3][C:2]=12
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: CCO
Reactant: Nc1nc2ccccc2s1
Agent: [Fe]
Agent: O=S(=O)(O)O
Solvent: O
Product: c1ccc(Nc2cn3c(n2)sc2ccccc23)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 2-aminobenzothiazole (4.00 g, 26.6 mmol) and 2-bromo-4′-nitroacetophenone (7.32 g, 30.0 mmol) was refluxed in ethanol for 90 min and then the mixture was cooled to 0° C. The solid (about 2 g) was collected by filtration, washed with the minimum quantity of cold ethanol and then dissolved again in 150 ml of ethanol and added of iron powder (7.47 g, 133.75 mmol), water (30 ml) and H2SO4 12N (750 μl). The mixture was stirred at 90° C. for 1 h, then filtered on celite and washed with hot ethanol. The solvent was removed under reduced pressure and the crude material was treated with aqueous NaHCO3 (10%, 400 ml) and extracted with CH2Cl2 (3×150 ml). The organic phase was dried with anhydrous Na2SO4 and the solvent removed under reduced pressure to afford 4-[(imidazo[2,1-b]benzothiazol-2-yl)aniline.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][NH:53][CH2:54][C@@H:55]([C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=2)[OH:56])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][N:53]([CH2:54][C@@H:55]([C:57]2[CH:58]=[CH:59][C:60]([Cl:63])=[CH:61][CH:62]=2)[OH:56])[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNC[C@H](O)c2ccc(Cl)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(C[C@H](O)c2ccc(Cl)cc2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 52.1 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 95 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[(R)-2-(4-chloro-phenyl)-2-hydroxy-ethyl]-amine were added. After stirring for 24 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:6) to give 72 mg light yellow solid (50%). MS (ISP) 461.4 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[O:4].[C:12]12([C:22](O)=[O:23])[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:12]12([C:22]([CH:8]3[C:9](=[O:10])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:11])[C:6]3=[O:7])=[O:23])[CH2:19][CH:18]3[CH2:17][CH:16]([CH2:15][CH:14]([CH2:20]3)[CH2:13]1)[CH2:21]2
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN1C(=O)C(C(=O)C23CC4CC(CC(C4)C2)C3)C(=O)N(C)C1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
A mixture of 1,3-dimethylbarbituric acid (5.00 g, 32.05 mmol), 1-adamantanecarboxylic acid (8.65 g, 48.03 mmol), 4-dimethylaminopyridine (1.95 g, 16.01 mmol) in dry CH2Cl2 (30 ml) was cooled to 0° C. and 1,3-dicyclohexylcarbodiimide (7.26 g, 35.22 mmol) added. The reaction mixture was stirred at room temperature overnight and filtered. The solid was washed with CH2Cl2 (150 ml) and the combined solution was washed with 2 N HCl solution (40 ml). The organic phase was dried over MgSO4 and evaporated. The residue was crystallized from MeOH giving 5-(1-adamantanecarbonyl)-1,3-dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione 12 (7.10 g, 69%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25](Cl)[N:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>CC(O)C.CO>[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25]([NH:12][CH:10]([C:8]2[N:7]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[C:6]3[CH:19]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH3:11])[N:24]=[CH:23][N:22]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: CC(N)c1nc2ccc(F)cc2n1-c1ccncc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1ccncc1
Temperature: 90 °C
Yield: 25.5 %

Procedure:
A mixture of 1-(6-fluoro-1-pyridin-4-yl-1H-benzoimidazol-2-yl)ethylamine (55 mg, 0.22 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (33 mg, 0.22 mmol) and DIPEA (115 μL, 0.64 mmol) in IPA (1 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the crude mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a gradient 5-60%, 0.1% NH4OH in acetonitrile/water) to afford 296 as a pale beige solid (21 mg, 26%). LCMS (Method K): RT 3.00 min [M+H]+ 375.06. 1H NMR (DMSO-d6, 400 MHz): δ 8.75-8.71 (2H, m), 7.88 (1H, s), 7.79-7.72 (2H, m), 7.65-7.60 (2H, m), 7.24-7.12 (3H, m), 7.06 (1H, dd, J=8.98, 2.49 Hz), 5.65-7.56 (1H, m), 1.57 (3H, d, J=6.77 Hz)
Reaction SMILES: [CH3:1][C:2]([CH3:23])([O:4][C:5]([N:7]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]1[N:9]=[CH:10][C:11]([C:14]#[N:15])=[N:12][CH:13]=1)=[O:6])[CH3:3].Cl.[NH2:25][OH:26].N1CCCCC1>CS(C)=O>[CH3:21][C:19]([CH3:22])([O:18][C:16]([N:7]([C:5]([O:4][C:2]([CH3:23])([CH3:3])[CH3:1])=[O:6])[C:8]1[N:9]=[CH:10][C:11]([C:14](=[NH:15])[NH:25][OH:26])=[N:12][CH:13]=1)=[O:17])[CH3:20]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cnc(C#N)cn1
Reactant: NO
Agent: Cl
Solvent: C1CCNCC1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cnc(C(=N)NO)cn1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 55.2 %

Procedure:
A solution of 5-[[bis[(1,1-dimethylethoxy)carbonyl]]amino]-2-pyrazinecarbonitrile (305.7 mg, 0.954 mmol) in dimethyl sulfoxide (5.8 mL) was treated with hydroxylamine hydrochloride (333.8 mg, 4.804 mmol) and piperidine (0.50 mL, 5.050 mmol). The reaction was stirred at 25° C. for 50 min and then was partitioned between ethyl acetate (100 mL) and water (50 mL). The organic layer was washed with water (50 mL) and a saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 1/3 ethyl acetate/hexanes) afforded the 5-[[bis[(1,1-dimethylethoxy)carbonyl]]amino]-N-hydroxy-2-pyrazinecarboximidamide as a white solid (186.2 mg, 55%): mp 185–186° C.; (ES)+-HRMS m/e calcd for C15H23N5O5 (M+H)+ 354.1772, found 354.1775.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[OH-:13].[Na+].Cl.[NH2:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=1)=O>O.C(O)C.O1CCCC1>[NH2:16][C:17]1[C:18]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)=[N:7][C:8]2[C:4]([C:5]=1[C:6]([OH:11])=[O:13])=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2
Reactant: NCC(=O)c1ccc(Br)cc1
Reactant: [OH-]
Reactant: O=C1Nc2ccc(F)cc2C1=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Nc1c(-c2ccc(Br)cc2)nc2ccc(F)cc2c1C(=O)O
Temperature: 85 °C
Yield: 86.3 %

Procedure:
To a stirred suspension of 4.13 g of 5-fluoroisatin in 40 ml of water was added a solution of 5.62 g of sodium hydroxide in 20 ml of water. The solution was heated to 85° C. and a solution 8.8 g of 2-amino-1-(4-bromophenyl)ethanone hydrochloride in a mixture of 61 ml of ethanol and 15 ml of tetrahydrofuran and 61 ml of water was added dropwise over 2 hours. After the addition was complete, the solution was refluxed for an additional 30 minutes and then the ethanol and tetrahydrofuran were removed by distillation. The mixture was cooled to 20° C. and filtered through celite. The filtrate was acidified to pH 4 with acetic acid. The solid was filtered off, washed with water and dried, giving 7.8 g of the desired compound as a yellow solid, mp 231°-233° C.
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][C:8]([CH2:9][S:10][C:11]2[O:12][C:13]3[C:18]([C:19](=[O:29])[C:20]=2[CH2:21][O:22]C2CCCCO2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.O>O1CCCC1>[C:1]([C:5]1[CH:31]=[CH:30][C:8]([CH2:9][S:10][C:11]2[O:12][C:13]3[C:18]([C:19](=[O:29])[C:20]=2[CH2:21][OH:22])=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CSc2oc3ccccc3c(=O)c2COC2CCCCO2)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(CSc2oc3ccccc3c(=O)c2CO)cc1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
2-(4-Tertbutylbenzyl)thio-3-((2-tetrahydropyranyloxy)methyl) chromen-4-one (5.5 g, 12.55 mmol) is dissolved in tetrahydrofuran in a 50 mL round bottom flask. Acetic acid and water are then added such that the ratio of THF:Acetic acid:Water is 4:2:1 (28 mL). The flask is warmed to 45° C. and the mixture stirred for 3 hours. After cooling the flask the contents are poured into a separatory funnel and the aqueous layer extracted with ethyl acetate. The organic layer is then washed with water and brine and dried over sodium sulfate and filtered. The filtrate is concentrated in vacuo and the residue obtained is purified by silica gel flash chromatography (ethyl acetate:hexanes) to give the above-mentioned product.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][C:4]=1[C:16]1[CH:17]=[CH:18][C:19]([C:22]([NH:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:23])=[N:20][CH:21]=1.[Cl:32][C:33]1[CH:38]=[C:37]([NH2:39])[CH:36]=[CH:35][C:34]=1[C:40]1[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][C:41]=1[CH3:50].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:32][C:33]1[CH:38]=[C:37]([NH:39][CH2:2][C:3]2[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][C:4]=2[C:16]2[CH:17]=[CH:18][C:19]([C:22]([NH:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:23])=[N:20][CH:21]=2)[CH:36]=[CH:35][C:34]=1[C:40]1[CH:45]=[CH:44][C:43]([C:46]([F:47])([F:48])[F:49])=[CH:42][C:41]=1[CH3:50]
Reactant: Cc1cc(C(F)(F)F)ccc1-c1ccc(N)cc1Cl
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(C(C)C)c2CBr)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(C(C)C)c2CNc2ccc(-c3ccc(C(F)(F)F)cc3C)c(Cl)c2)cn1
Temperature: 100 °C

Procedure:
Ethyl 3-(5-(2-(bromomethyl)-3-isopropyl-5-(trifluoromethyl)phenyl)picolinamido)propanoate (27 mg, 0.05 mmol), 2-chloro-2′-methyl-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-amine (20 mg, 0.07 mmol) and iPr2NEt (27 μL, 0.16 mmol) were dissolved in toluene (3 mL) and the resulting mixture was heated at 100° C. After 16 h the resulting mixture was concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].Br[C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[CH2:24][CH:23]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:22]2>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:27]1[CH:26]=[C:25]2[C:21](=[CH:20][CH:19]=1)[CH2:22][CH:23]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:24]2
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(Br)cc2C1
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc2c(c1)CC(NC(=O)OC(C)(C)C)C2
Yield: 15 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (1.1 g, 3.6 mmol) was reacted with tert-butyl 5-bromo-2,3-dihydro-1H-inden-2-ylcarbamate (2.0 g, 5.6 mmol) to afford the desired product (250 mg, 15%) as a brown solid: ESI MS m/z 363 [C26H26N2O4S+H-100]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[OH-].[Na+].[CH3:19]O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([O:7][CH3:19])=[O:6]
Reactant: CO
Reactant: O=C(O)c1ccc(O)c(Br)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1ccc(O)c(Br)c1
Yield: 85 %

Procedure:
A solution of 3-bromo-4-hydroxybenzoic acid (50.4 g, 232 mmol) and conc. sulfuric acid (17 mL) in methanol (330 mL) was heated under reflux for 24 hrs. The reaction mixture was neutralized with aqueous sodium hydroxide solution. Methanol was removed under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crystals were washed with diethyl ether/hexane to give the title compound (45.5 g, yield 85%) as pale-pink crystals.
Reaction SMILES: N(OCC(C)C)=O.N[C:9]1[CH:32]=[C:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:30]=[CH:29][C:10]=1[O:11][C:12]1[C:21]([Cl:22])=[C:20]2[C:15]([CH:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:18][O:19]2)=[CH:14][C:13]=1[Cl:28].O>CN(C=O)C>[C:36]([O:35][C:33]([C:31]1[CH:32]=[CH:9][C:10]([O:11][C:12]2[C:21]([Cl:22])=[C:20]3[C:15]([CH:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:18][O:19]3)=[CH:14][C:13]=2[Cl:28])=[CH:29][CH:30]=1)=[O:34])([CH3:37])([CH3:38])[CH3:39]
Reactant: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)OC(C)(C)C)cc1N)c2Cl
Agent: CC(C)CON=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)OC(C)(C)C)cc1)c2Cl
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 92.8 %

Procedure:
To a 2 L four neck round bottomed flask equipped with a thermocouple, a condenser, and an addition funnel were added DMF (200 ml) and isobutyl nitrite (30.8 ml, 260 mmol). The mixture was heated to 70° C. To the preheated mixture was added a solution of ethyl 7-(2-amino-4-(tert-butoxycarbonyl)phenoxy)-6,8-dichlorochroman-4-carboxylate (50.2 g, 104 mmol) in DMF (200 ml) over a period of 15 minutes. The reaction was slightly exothermic and gas evolution was observed. The mixture was stirred at 70° C. for 1.5 hours and cooled to ambient temperature. The mixture was transferred to a separatory funnel containing 2 liters of water. The mixture was extracted with EtOAc (500 ml, 2×250 ml). The combined extracts were washed with water (500 ml, 2×250 ml) and brine (250 ml), dried over MgSO4, filtered, and concentrated. The residue was purified on silica gel (EtOAc in hexanes gradient) to provide 45.1 g of the title compound as a very viscous oil (93%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.[CH3:33][O:34][CH2:35][CH2:36][C:37](O)=[O:38].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C.C(OCC)(=O)C>[CH3:33][O:34][CH2:35][CH2:36][C:37]([O:20][CH2:19][C@H:17]1[O:16][N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:21]4[CH2:25][C@H:24]([CH2:26][N:27]5[CH:31]=[CH:30][N:29]=[N:28]5)[O:23][C:22]4=[O:32])=[CH:3][C:2]=3[F:1])=[CH:9][N:10]=2)[CH2:18]1)=[O:38]
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Reactant: COCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
(5R)-3-(3-Fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1, 0.25 g, 0.57 mmol), 3-methoxypropionic acid (0.15 ml, 1.6 mmol), 4-dimethylaminopyridine (0.02 g, 0.16 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.25 g, 1.30 mmol) were combined in DMF (4 ml). The suspension was allowed to stir for one hour at room temperature resulting in a clear solution. The mixture was then diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. The residue obtained upon filtration and evaporation was purified via chromatography (silica gel, 0.5 to 5% methanol in dichloromethane). Evaporation of the product containing fractions and trituration of the resulting solid with diethyl ether yielded the title compound as a white solid (0.255 g), melting point: 149° C.
Reaction SMILES: Cl.Cl.[C:3]1([C@H:13]([NH:15][C@@H:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)[CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Cl[C:22]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.C(OCC)(=O)C>[C:3]1([C@H:13]([NH:15][C@@H:16]2[CH2:20][CH2:19][N:18]([C:22]3[CH:31]=[C:30]([C:32]([F:33])([F:35])[F:34])[C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][N:23]=3)[CH2:17]2)[CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Reactant: C[C@@H](N[C@@H]1CCNC1)c1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(N2CC[C@@H](N[C@H](C)c3cccc4ccccc34)C2)cc1C(F)(F)F
Temperature: 100 °C
Reaction time: 24 h

Procedure:
To a solution of 157 mg of (R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidine dihydrochloride and 120 mg of methyl 6-chloro-4-(trifluoromethyl)-nicotinate in 5 ml of dioxane was added 346 mg of potassium carbonate, and the reaction solution was stirred at 100° C. for 1 day. Further, to the reaction mixture was irradiated at 140° C. for 1 hour by using a Microwave reaction system, and then, the reaction mixture was cooled to room temperature. To the mixture were added water and ethyl acetate, and the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20→50:50), and then, purified by NH thin layer silica gel column chromatography (hexane:ethyl acetate=67:33) to obtain methyl 6-[(R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]-4-trifluoromethylnicotinate (the following Table, Example, 12.001).
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([CH3:11])[CH:5]=[CH:6][CH2:7][CH:8]([CH3:10])[CH3:9].[I-:12].[Na+]>CC(CC(C)C)=O.CCOCC>[I:12][CH2:2][CH2:3][C@H:4]([CH3:11])/[CH:5]=[CH:6]\[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: [I-]
Reactant: CC(C)CC=C[C@@H](C)CCCl
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: CCOCC
Product: CC(C)C/C=C\[C@@H](C)CCI
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.5 %

Procedure:
A solution of 4.4 g of (S)-1-chloro-3,7-dimethyl-4-octene in 30 ml of isobutyl methyl ketone is stirred at 130° for 37 hours with 7.55 g of sodium iodide. A further 3.75 g of sodium iodide are added thereto and the mixture is stirred further for 4 hours. After cooling to room temperature, the mixture is diluted with ether, washed with water, dried and concentrated under reduced pressure. The residue is prepurified by adsorption on silicagel (elution agent: n-hexane), pure fractions are combined and distilled at 14 Torr and 130°. There are obtained 5.6 g (83.5%) of (S)-cis-1-iodo-3,7-dimethyl-4-octene as a colourless liquid. [α]D20 =+14.3° (2.21% in CHCl3).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]([C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:37])[CH2:33][CH2:34][CH2:35][Cl:36])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].C(=O)(O)[O-].[K+].[I-].[K+]>C1(C)C=CC=CC=1.O>[ClH:36].[C:22]([C:26]1[CH:27]=[CH:28][C:29]([C:32](=[O:37])[CH2:33][CH2:34][CH2:35][N:12]2[CH2:13][CH2:14][CH:9]([C:7]([OH:8])([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:10][CH2:11]2)=[CH:30][CH:31]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)c1ccc(C(=O)CCCCl)cc1
Reactant: Cc1ccc(C(O)(c2ccccc2)C2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C(O)(c2ccccc2)C2CCN(CCCC(=O)c3ccc(C(C)(C)C)cc3)CC2)cc1
Product: Cl
Reaction time: 88 h

Procedure:
A mixture of 29.0 g (0.1 mole) of α-phenyl-α-(p-tolyl)-4-piperidinemethanol, 32 g (0.12 mole) of 4'-tert-butyl-4-chlorobutyrophenone, 20 g of potassium bicarbonate, 0.1 g of potassium iodide, 300 ml of toluene and 50 ml of water is stirred on a steam bath for 88 hours. Upon cooling to room temperature the toluene layer is separated, and the aqueous layer is extracted with toluene. The combined toluene fractions are washed with water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to an oil. The oily residue is dissolved in dry ether and filtered. The filtrate is treated with ethereal HCl, and the resulting precipitate is collected and recrystallized from methanol-butanone to give 4'-tert-butyl-4-[4-[α-hydroxy-α-(p-tolyl)benzyl]-piperidino]butyrophenone hydrochloride, M.P. 194°-196.5°C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1B(O)O>COCCOC>[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: Cc1cccc(C)c1B(O)O
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: COCCOC
Product: Cc1cccc(C)c1-c1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
2-Chloro-5-nitropyridine (1.0 g, 6.31 mmol), 2,6-dimethylphenylboronic acid (1.42 g, 9.47 mmol) and bis(di-tert-butyl(4-dimethylaminophenylphosphine)dichloropalladium(II) (0.044 g, 0.062 mmol) were added to 1,2-dimethoxyethan (32 ml), degassed and purged with nitrogen three times under reduced pressure. Under nitrogen atmosphere the mixture was stirred at room temperature for 30 minutes, 1M aqueous sodium carbonate (12 ml) was poured in, and the temperature was raised to 80° C. After the reaction at 80° C. for 3 hours, the mixture was cooled to room temperature and extracted with addition of ethyl acetate and water. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography gave the title compound (1.41 g, 98.1%).