Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C@@H:8]([C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=1)[CH3:9])[C:4]([O:6][CH3:7])=[O:5].[C:17]1([S:23]([N:26]2[CH2:33][CH2:32][CH2:31][C@H:27]2[C:28](O)=[O:29])(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>>[C:17]1([S:23]([N:26]2[CH2:33][CH2:32][CH2:31][C@H:27]2[C:28]([C@@:3]([NH2:2])([C@@H:8]([C:10]2[CH:11]=[CH:12][C:13]([I:16])=[CH:14][CH:15]=2)[CH3:9])[C:4]([O:6][CH3:7])=[O:5])=[O:29])(=[O:24])=[O:25])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)[C@@H](N)[C@H](C)c1ccc(I)cc1
Reactant: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: COC(=O)[C@@](N)(C(=O)[C@@H]1CCCN1S(=O)(=O)c1ccccc1)[C@H](C)c1ccc(I)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To an ice cooled solution of 2(S)-amino-3(R)-(4-iodophenyl)-butyric acid, methyl ester hydrochloride (116 mg, 0.34 mmol), N-(benzenesulfonyl)-(L)-proline (128 mg, 0.50 mmol), HOBt (77 mg, 0.5 mmol) and N-methylmorpholine (55 μL, 0.5 mmol) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 99 mg, 0.5 mmol). After stirring overnight, the solvents were removed by rotoevaporation, and the residue was dissolved in methylene chloride and loaded onto a flash silica gel chromatography column. The product was eluted with 10% ethyl acetate in methylene chloride to yield 163 mg (85% yield) of the title compound.
Reaction SMILES: [CH:1]1([S:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[NH:16][C:17]4[C:22]([CH:23]=3)=[CH:21][C:20]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]3)=[O:25])=[CH:19][CH:18]=4)=[O:14])[CH2:9][CH2:8]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Cl:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>>[Cl:35][C:36]1[CH:41]=[C:40]([N:16]2[C:17]3[C:22](=[CH:21][C:20]([C:24]([N:26]4[CH2:27][CH2:28][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:30][CH2:31]4)=[O:25])=[CH:19][CH:18]=3)[CH:23]=[C:15]2[C:13]([N:10]2[CH2:9][CH2:8][N:7]([S:4]([CH:1]3[CH2:2][CH2:3]3)(=[O:5])=[O:6])[CH2:12][CH2:11]2)=[O:14])[CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(=O)(=O)C5CC5)CC4)cc3c2)CC1
Reactant: OB(O)c1cccc(Cl)c1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)C4CC4)CC2)n3-c2cccc(Cl)c2)CC1
Yield: 41 %

Procedure:
The title compound was synthesized in analogy to example 5, from (4-cyclopropanesulfonyl-piperazin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 33) and 3-chlorophenylboronic acid to afford the desired product as a light brown foam (41%). MS (ISP): 598.3 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].[NH:19]([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22]>C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([O:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][O:25][C:8](=[O:9])[C:7]1[CH:11]=[C:12]([C:15]([CH3:16])([CH3:17])[CH3:18])[C:13]([OH:14])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1)[C:8](=[O:9])[C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:13]([OH:14])=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:11]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCCNCCO
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(C(=O)OCCN(CCOC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O

Procedure:
One mole of 3,5-di-t-butyl-4-hydroxybenzoyl chloride in benzene was reactedwith two moles of diethanolamine in benzene to produce N,N-bis(3',5'-di-t-butyl-4'-hydroxybenzoyloxyethyl) 3,5-di-t-butyl-4-hydroxybenzamide; melting point 200°-202° C. When tested by the procedure of Example 2, the sample containing this compound lasted 1,300 hours, about 2.4 times as long as the control.
Reaction SMILES: Br[CH2:2][C:3]1[C:4](=[O:13])[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[OH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:26]2[S:27][CH:28]=[CH:29][N:30]=2)([O:24][CH3:25])[CH2:22][CH3:23])=[CH:17][C:16]=1[O:31][CH3:32]>>[CH3:25][O:24][C:21]([C:26]1[S:27][CH:28]=[CH:29][N:30]=1)([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:2][C:3]2[C:4](=[O:13])[NH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[C:16]([O:31][CH3:32])[CH:17]=1)[CH2:22][CH3:23]
Reactant: O=c1[nH]c2ccccc2cc1CBr
Reactant: CCC(OC)(c1ccc(O)c(OC)c1)c1nccs1
Product: CCC(OC)(c1ccc(OCc2cc3ccccc3[nH]c2=O)c(OC)c1)c1nccs1
Yield: 28 %

Procedure:
Using a similar procedure to that described in Example 1, 3-bromomethyl-1,2-dihydroquinolin-2-one was reacted with 2-[1-(4-hydroxy-3-methoxyphenyl)-1-methoxypropyl]thiazole to give 2-[1-methoxy-1-[3-methoxy-4-(1,2-dihydro-2-oxoquinolin-3-ylmethoxy)phenyl]propyl]thiazole in 28% yield, m.p. 170°-171° C. (recrystallised from a mixture of hexane and ethyl acetate).
Reaction SMILES: [OH-].[Na+].O.[CH3:4][C@H:5]1[CH2:10][C@@H:9]([CH3:11])[CH2:8][N:7]([S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([C:24]=2[Cl:25])[C:20]([O:22]C)=[O:21])(=[O:14])=[O:13])[CH2:6]1>CO>[CH3:4][C@H:5]1[CH2:10][C@@H:9]([CH3:11])[CH2:8][N:7]([S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([C:24]=2[Cl:25])[C:20]([OH:22])=[O:21])(=[O:13])=[O:14])[CH2:6]1
Reactant: COC(=O)c1cccc(S(=O)(=O)N2C[C@H](C)C[C@H](C)C2)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@@H]1C[C@H](C)CN(S(=O)(=O)c2cccc(C(=O)O)c2Cl)C1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
An aqueous solution of 4.2 g. (105 m moles) of sodium hydroxide in 130 ml. of water is added to 18 g. (52.5 m moles) of methyl 5-(cis-3,5-dimethylpiperidinosulfonyl)-6-chlorobenzoate in 130 ml. of methanol, and resulting reaction mixture allowed to stir at 40° C. for 1 hr. The solution is poured into ice water (1.5 l.) and extracted several times with benzene. The aqueous phase is separated, acidified with 12 N hydrochloric acid, and the precipitated product filtered and air dried, 17.3 g. Recrystallization from ethyl acetate-hexane gave the purified product, 16.4 g., m.p. 152.5°-153° C.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.C1COCC1>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)=[O:8])=[CH:5][CH:4]=1
Reactant: C1=COCCC1
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(OC1CCCCO1)c1ccc(CBr)cc1
Reaction time: 6 h
Yield: 57.5 %

Procedure:
In 70 ml of a mixed solvent of methylene chloride and THF were dissolved 5 g of p-bromomethylbenzoic acid, 10 g of dihydropyran and 585 mg of pyridinium p-toluenesulfonate, and reaction was carried out at room temperature for 6 hours. The reaction mixture was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, and was concentrated and recrystallized from an n-hexane/ethyl acetate/chloroform mixed solvent to obtain 4.0 g of tetrahydropyranyl p-bromomethylbenzoate. Then, 267 mg of sodium hydride washed with n-pentane was dissolved in 10 ml of DMF, and a solution of 2 g of tetrahydropyranyl p-bromomethylbenzoate and 1.86 g of p-hydroxyphenyl decylcarboxylate in 10 ml of DMF was dropped into the above solution in a nitrogen atmosphere. The mixture was stirred overnight, and the reaction liquid was put in an ice cooled 1N aqueous hydrochloric acid solution and extracted with chloroform. The extract was concentrated, the concentrate was diluted with ethanol, 170 mg of pyridinium p-toluenesulfonate was added to the dilution, and the mixture was stirred at 55° C. for 1 hour. The mixture was diluted with chloroform and the dilution was washed with a saturated aqueous sodium chloride solution concentrated and recrystallized from a mixed solvent of acetate and chloroform to obtain 1.2 g of p-decylcarboxyphenyl-p'-carboxybenzyl ether.
Reaction SMILES: Br[C:2]1[C:3]([C:22]([F:25])([F:24])[F:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[N:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O.O1CCOCC1>[N:26]1[CH:31]=[C:30]([C:2]2[C:3]([C:22]([F:25])([F:24])[F:23])=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])[CH:29]=[N:28][CH:27]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(C(F)(F)F)c(Br)c1
Reactant: OB(O)c1cncnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(C(F)(F)F)c(-c2cncnc2)c1
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
5-Bromo-N-(4-(trifluoromethoxy)phenyl)-6-(trifluoromethyl)nicotinamide (Stage 57.1, 125.7 mg, 0.293 mmol), pyrimidin-5-ylboronic acid (43.6 mg, 0.352 mmol), Cs2CO3 (191 mg, 0.586 mmol), PdCl2(dppf)-(CH2Cl2) (23.92 mg, 0.029 mmol), water (2 mL) and dioxane (8 mL) were added to a vial, which was sealed, evacuated/purged with argon and the RM was stirred at 70° C. for 2.5 h. The solvent was evaporated off under reduced pressure to give a residue which was treated with water and extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, 25 g, n-hexane/EtOAc) and recrystallized from n-hexane/EtOAc to give the title compound as a pink powder. UPLC-MS (Condition 2) tR=1.07 min, m/z=429 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:17])[C:6]([C:18]([O:20]C(C3C(=O)C4C(=C(OC)C(F)=CC=4)N(C4CC4)C=3)=O)=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.B(O)(O)O.[NH:44]1[CH2:47][CH:46]([NH:48][CH2:49][C@H:50]2[O:54][C:53](=[O:55])[N:52]([C:56]3[CH:57]=[CH:58][C:59]4[S:64][CH2:63][C:62](=[O:65])[NH:61][C:60]=4[CH:66]=3)[CH2:51]2)[CH2:45]1>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N:44]4[CH2:47][CH:46]([NH:48][CH2:49][C@H:50]5[O:54][C:53](=[O:55])[N:52]([C:56]6[CH:57]=[CH:58][C:59]7[S:64][CH2:63][C:62](=[O:65])[NH:61][C:60]=7[CH:66]=6)[CH2:51]5)[CH2:45]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: COc1c(F)ccc2c(=O)c(C(=O)OC(=O)c3cn(C4CC4)c4c(OC)c(F)ccc4c3=O)cn(C3CC3)c12
Reactant: O=C1CSc2ccc(N3C[C@@H](CNC4CNC4)OC3=O)cc2N1
Agent: OB(O)O
Solvent: CC(=O)O
Product: COc1c(N2CC(NC[C@@H]3CN(c4ccc5c(c4)NC(=O)CS5)C(=O)O3)C2)ccc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
The title compound was prepared in analogy to Example 2, starting from 1-cyclopropyl-7-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid anhydride with boric acid (1:1) and with acetic acid (1:2) (101 mg; prepared according to WO 2010/056633) and 6-[(5R)-5-[(3-azetidinylamino)-methyl]-2-oxo-3-oxazolidinyl]-2H-1,4-benzothiazin-3(4H)-one (prepared according to WO 2008/126034; 167 mg). At the end of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was taken up in MeOH and treated with 1N HCl in MeOH (3 ml) for 15 min. The reaction mixture was diluted with water (2 ml) and the solid was filtered off. The org. phase was concentrated under reduced pressure and purified by CC (DCM/MeOH 9:1 followed by DCM/MeOH 9:1+1% AcOH), affording after evaporation and stirring of the residue with MeOH/TBME a beige solid.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([O:15][CH3:16])([O:13][CH3:14])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[CH3:14][O:13][C:11]([C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:21]3[CH:22]=[CH:23][C:18]([F:17])=[C:19]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH:20]=3)=[CH:3][N:4]=[C:5]2[N:10]=1)([O:15][CH3:16])[CH3:12]
Reactant: OB(O)c1ccc(F)c(-c2cccnc2)c1
Reactant: COC(C)(OC)c1ccn2c(Br)cnc2n1
Product: COC(C)(OC)c1ccn2c(-c3ccc(F)c(-c4cccnc4)c3)cnc2n1

Procedure:
3-Bromo-7-(1,1-dimethoxyethyl)imidazo[1,2-α]pyrimidine was coupled with 4-fluoro-3-(pyridin-3-yl)benzeneboronic acid as described in Example 65 to give 7-(1,1-dimethoxyethyl)-3-[4-fluoro-3-(pyridin-3-yl)phenyl]imidazo[1,2-α]pyrimidine as an orange foam. This was dissolved in 2.5N hydrochloric acid and stirred at 50° C. for 15 h. After cooling to ambient temperature the reaction was neutralised by addition of solid sodium hydrogencarbonate and the resulting solid collected by filtration. The solid was dissolved in dichloromethane/methanol (1:1) and pre-adsorbed onto silica. Flash column chromatography on silica gel eluting with dichloromethane containing 1% ammonia and 5% methanol furnished 1-[3-(4-fluoro-3-(pyridin-3-yl)phenyl)imidazo[1,2-α]pyrimidin-7-yl]ethanone as a yellow solid: δH (360 MHz, d6-DMSO) 2.71 (3H, s), 7.54-7.63 (3H, m), 7.84-7.88 (1H, m), 8.01 (1H, dd, J 8 and 2), 8.10-8.13 (1H, m), 8.34 (1H, s), 8.66 (1H, dd, J 5 and 2), 8.90 (1H, s), 9.24 (1H, d, J 7).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][CH2:6][NH:7][C:8](=[O:34])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH:28]2[CH2:31][C:30]([CH3:33])([CH3:32])[CH2:29]2)[NH:16][C:17]2[C:26]([CH3:27])=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+].Cl>O1CCCC1.CO>[CH3:32][C:30]1([CH3:33])[CH2:31][CH:28]([CH:15]([NH:16][C:17]2[C:26]([CH3:27])=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[C:12]2[CH:13]=[CH:14][C:9]([C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:35])=[O:3])=[O:34])=[CH:10][CH:11]=2)[CH2:29]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(C(Nc2nc3ccccc3cc2C)C2CC(C)(C)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2ccccc2nc1NC(c1ccc(C(=O)NCCC(=O)O)cc1)C1CC(C)(C)C1
Yield: 120.5 %

Procedure:
(+/−)-3-{4-[(3,3-di methyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoylamino}-propionic acid ethyl ester (Intermediate 27) (36 mg, 0.076 mmol) was dissolved in tetrahydrofuran (3 mL) and methanol (1 mL), and 1.0 M sodium hydroxide (2 mL) was added. This was stirred as a solution at room temperature for 45 min before 1 N HCl was added to bring to pH 4.5. This was extracted twice with ethyl acetate and the combined organics dried over MgSO4. The solution was concentrated in vacuo to give (+/−)-3-{4-[(3,3-dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoylamino}-propionic acid (40.8 mg) as a white solid impure with ethyl acetate. MS (M+1): 446.3. HPLC: XBridge C18 150 mm×4.6 mm, 5 μm column, flow rate 1.50 mL/min, linear gradient of 5% acetonitrile/water (0.1% trifluoroacetic acid modifier) to 100% acetonitrile over 11 min, Retention time=7.046 min.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:30])=[C:11]([N:15]4[CH2:19][CH:18]([CH2:20][O:21]C(=O)C5C=CC=CC=5)[O:17][CH2:16]4)[C:12]=3[F:14])[C:7](=[O:31])[C:6]([C:32]([O:34]CC)=[O:33])=[CH:5]2)[CH2:3][CH2:2]1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:30])=[C:11]([N:15]4[CH2:19][CH:18]([CH2:20][OH:21])[O:17][CH2:16]4)[C:12]=3[F:14])[C:7](=[O:31])[C:6]([C:32]([OH:34])=[O:33])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3COC(COC(=O)c4ccccc4)C3)c(F)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3COC(CO)C3)c(F)cc2c1=O
Yield: 88.2 %

Procedure:
A mixture of 250 mg of ethyl 1-cyclopropyl-6,8-difluoro-7-(5-benzoyloxymethyl-3-oxazolidinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate, 2 ml of ethanol and 10 ml of 10% aq. sodium carbonate solution was stirred under reflux for 1 hour. The reaction mixture was allowed to cool down and then acidified with acetic acid. Crystals thus precipitated were collected by filtration. They were washed with water and ethanol and then dried, whereby 162 mg of the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH2:4][OH:5].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].Cl>C(OCC)(=O)C>[CH3:23][S:24]([O:5][CH2:4][C:3]1[CH:6]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:9][C:2]=1[CH3:1])(=[O:26])=[O:25]
Reactant: Cc1ccc(-c2ccccc2)cc1CO
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccccc2)cc1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
2.00 g (10.1 mmol) of 2-methyl-5-phenylbenzyl alcohol was dissolved in 100 ml of ethyl acetate, and to this solution was added 4.2 ml (30.3 mmol) of triethylamine and the mixture was cooled to 0° C. To the reaction mixture was slowly dropped 1.73 g (15.1 mmol) of methanesulfonyl chloride, and the reaction mixture was controlled to room temperature. After stirring for 1 hours at room temperature, the reaction mixture was made acidic by addition of 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution and saturated saline sequentially, dried over anhydrous magnesium sulfate, then, concentrated. The residue was subjected to silica gel column chromatography (eluant: hexane/ethyl acetate=4/1 (v/v)), to obtain 2.79 g of 2-methyl-5-phenylbenzyl methanesulfonate.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:9]([CH3:28])[CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([C:26]#[N:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1)[CH3:8]>O1CCCC1>[NH2:27][CH2:26][C:20]1([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][CH2:10][N:9]([CH2:7][CH3:8])[CH3:28])=[CH:15][CH:16]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: CCN(C)CCCOc1ccc(C2(C#N)CCOCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(C)CCCOc1ccc(C2(CN)CCOCC2)cc1
Temperature: 25 °C
Yield: 95.5 %

Procedure:
Lithium aluminium hydride (9.93 ml of a 1M solution in tetrahydrofuran, 9.93 mmol) was added to a solution of 4-(4-{3-[ethyl(methyl)amino]propoxy}phenyl)tetrahydro-2H-pyran-4-carbonitrile (2.0 g, 6.6 mmol) in tetrahydrofuran (10 ml) at 0° C. under N2. The reaction mixture was warmed to room temperature over 18 h and then quenched by the sequential addition of water (0.4 ml), 2M NaOH solution (0.4 ml) and water (0.4 ml). The mixture was filtered through arbocel and concentrated in vacuo to yield 3-{4-[4-(aminomethyl)tetrahydro-2H-pyran-4-yl]phenoxy}-N-ethyl-N-methylpropan-1-amine as a pale yellow oil (1.93 g, 6.3 mmol, 95%). 1H NMR (400 MHz CDCl3) δ 1.02-1.08 (t, 3H), 1.73-1.83 (m, 2H), 1.90-2.00 (m, 2H), 2.06-2.16 (m, 2H), 2.23 (s, 3H), 2.40-2.48 (q, 2H), 2.50-2.58 (t, 2H), 2.75 (s, 2H), 3.48-3.58 (m, 2H), 3.70-3.80 (m, 2H), 3.98-4.04 (t, 2H), 6.89 (d, 2H), 7.19 (d, 2H). LRMS APCI+ m/z 307 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[CH3:11][Mg]Cl.[NH4+].[Cl-]>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([OH:10])([CH3:11])[CH3:9]
Reactant: C[Mg]Cl
Reactant: CC(=O)c1ccccc1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccccc1C(C)(C)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.6 %

Procedure:
Under the protection by nitrogen, ortho-methylphenylethanone (134 g, 1.0 mol) is dissolved in 1000 ml of tetrahydrofuran and then cooled to −5° C., into which 2M methylmagnesium chloride in tetrahydrofuran (550 ml) is slowly added dropwise at below 0° C. After the addition, the reactant solution is stirred at room temperature for 4 hours under the detection by TLC. When the reaction is complete, 200 ml of saturated NH4Cl solution is slowly added dropwise into the reactant solution and stirred until no bubbling from the solution. The reactant solution is then extracted by dichloromethane (500 ml×3), the extracts are combined, dried by anhydrous sodium sulfate, absorbed by activated carbon, filtered and then the solvent is distilled using rotary evaporator to obtain 124 g of 2-ortho-methylphenyl-2-propanol as a light yellow sticky liquid, with a yield of 82.6%.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].C([O-])([O-])=O.[K+].[K+].I[CH2:24][CH2:25][CH3:26]>CC#N>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][N:14]([CH2:24][CH2:25][CH3:26])[CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(N2CCNCC2)c1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCN(c2cccc(S(C)(=O)=O)c2)CC1

Procedure:
A suspension of 1-(3-methanesulfonyl-phenyl)-piperazine (350 mg) and ground K2CO3 (403 mg) was stirred in CH3CN (25 mL) at room temperature. 1-Iodopropane (712 μL) was added. The mixture was refluxed overnight. The reaction mixture was filtered and the volatiles were evaporated in vacuum. The oily residue was chromatographed on a silica column with MeOH:CH2Cl2 (1:30 (v/v)) as eluent. Collection of the fractions containing pure product and evaporation of the solvent afforded pure 1-(3-methanesulfonyl-phenyl)-4-propyl-piperazine (220 mg). The amine was converted into the HCl salt and recrystallized from ethanol/diethylether: m.p. 233° C. MS m/z (relative intensity, 70 eV) 282 (M+, 30), 254 (15), 253 (bp), 210 (17), 70 (21).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]([CH2:12][C:13]#[N:14])=[N:3]1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>O1CCOCC1>[CH:9]1[CH:10]=[C:11]2[C:2]([NH:3]/[C:4](/[NH:5][C:6]2=[CH:7][CH:8]=1)=[C:12](/[C:25]([C:24]1[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:23]=1[Cl:22])=[O:26])\[C:13]#[N:14])=[O:1]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: N#CCc1nc(=O)c2ccccc2[nH]1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: N#C/C(C(=O)c1ccc(Cl)cc1Cl)=C1\NC(=O)c2ccccc2N1
Yield: 54.6 %

Procedure:
To solution of 2-(4-oxo-1.4-dihydroquinazolin-2-yl)acetonitrile (202 mg, 1.09 mmol) and triethylamine (167 μL, 1.20 mmol) in dioxane (8 mL) was added 2.4-dichlorobenzoyl chloride (152 μL, 1.09 mmol), and the resulting mixture was refluxed overnight with stirring. A solid precipitate formed upon cooling of the reaction mixture, which was recovered by vacuum filtration and washed sequentially with methanol, water, methanol, and dichloromethane. The solid was then dried to yield ciliobrevin A (1) (213 mg, 53%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.46-7.50 (m, 1H), 7.52 (d. 1=8.2 Hz, 1H), 7.56 (dd, J1=8.2, J2=1.9 Hz, 1H), 7.77 (d, J=2.0 Hz, 1H), 7.83-7.88 (m, 2H), 8.07 (d, J=8.1 Hz, 1H). 13C NMR (500 MHz, DMSO-d6) δ ppm 71.74, 117.43, 117.54, 118.71, 125.92, 126.68, 127.66, 129.21, 129.66, 130.49, 134.85, 135.85, 138.15, 139.25, 155.01, 158.3, 188.75. HRMS (m/z): [M+ calc. for C17H9N3O2Cl2Na, 379.9970; observed, 379.9967.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][CH:8]([F:30])[C:9]1[N:20](S(C2C=CC=CC=2)(=O)=O)[C:12]2=[N:13][CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=[C:11]2[CH:10]=1.C(OCC)(=O)C>CO.O>[F:30][CH:8]([F:7])[C:9]1[NH:20][C:12]2=[N:13][CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=[C:11]2[CH:10]=1
Reactant: O=[N+]([O-])c1cnc2c(c1)cc(C(F)F)n2S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=[N+]([O-])c1cnc2[nH]c(C(F)F)cc2c1
Temperature: 40 °C
Yield: 59.6 %

Procedure:
Potassium carbonate (0.25 g, 1.76 mmol) was added to a solution of 2-(difluoromethyl)-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.089 g, 0.252 mmol) in methanol (2.2 mL) and water (0.7 mL). The reaction mixture was heated at 40° C. for 30 minutes. The reaction mixture was then cooled down and treated with water and ethyl acetate. The layers were separated. The combined organic layers were washed twice with water, dried over sodium sulfate, filtered, and evaporated to afford 2-(difluoromethyl)-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.032 g, 49%).