Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C@@:21]4([CH2:25][O:24][C:23]([NH2:26])=[N:22]4)[C:20]4[C:15](=[N:16][CH:17]=[C:18]([C:27]#[C:28][C:29]5([CH3:33])[CH2:32][O:31][CH2:30]5)[CH:19]=4)[O:14][C:11]3=[CH:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.O.[ClH:35].C(OCC)(=O)C>CC#N.C(=O)(O)[O-].[Na+]>[NH2:26][C:23]1[O:24][CH2:25][C@:21]2([C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:27]#[C:28][C:29]([CH2:32][Cl:35])([CH3:33])[CH2:30][OH:31])[CH:19]=3)[O:14][C:11]3[C:10]2=[CH:9][C:8]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:13][CH:12]=3)[N:22]=1
Reactant: Cl
Reactant: CC1(C#Cc2cnc3c(c2)[C@]2(COC(N)=N2)c2cc(-c4cccnc4F)ccc2O3)COC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CC(C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3F)ccc1O2)(CO)CCl
Temperature: 50 °C
Yield: 53.6 %

Procedure:
To a slurry of (S)-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (500 mg, 1.13 mmol, Example 78) in 10 mL of MeCN was added 10 mL of water followed by 1 mL of 6 N HCl. The resulting solution was heated at 50° C. overnight. The reaction was cooled to rt, diluted with saturated sodium bicarbonate (100 mL) and poured into a separatory funnel containing ethyl acetate (100 mL). The layers were separated and the aqueous layer was extracted with EtOAc (1×50 mL). The combined organic layers were washed with water and then brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a white solid that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (40 g), 0-100% DCM to 10:1 methanol in DCM with 0.1% ammonium hydroxide) to provide 4-((S)-2′-amino-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-3-yl)-2-(chloromethyl)-2-methylbut-3-yn-1-ol (290 mg, 0.606 mmol, 53.6% yield) as a white solid.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].[C:6]([O:10]O)([CH3:9])([CH3:8])[CH3:7].S(=O)(=O)(O)O>O>[C:1]([O:5][O:10][C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)O
Reactant: CC(C)(C)OO
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)(C)OOC(C)(C)C

Procedure:
In Unit 3, the dehydration stage, the mixture of tertiary butanol and tertiary butyl hydroperoxide is dehydrated with concentrated sulphuric acid to form di-tertiary butyl peroxide and water. The products of Unit 3, di-tertiary butyl peroxide and water, present as an aqueous solution of sulphuric acid, are immiscible and can conventiently be separated by decantation, the di-tertiary butyl peroxide layer being fed to Unit 4 for carbonylation and the aqueous layer containing sulphuric acid being fed to a concentrator Unit 6 prior to recycling to Unit 3. The dehydration step is typically carried out in the temperature range 20°-80° C. preferably 30°-60° C. and at a pressure of up to 150 psig. A typical dehydration process using sulphuric acid is described in U.S. Pat. No. 2,862,973.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C[Si]([C:16]#[CH:17])(C)C>C1(C)C=CC=CC=1.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.[Cu]I>[C:16]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1)#[CH:17]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1ccc(I)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C#Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 147.4 %

Procedure:
To a solution of methyl 4-iodobenzoate (1.5 g, 5.72 mmol) and trimethylsilylacetylene (Aldrich, 1.58 mL, 11.45 mmol) in toluene (12 mL) were added Pd(PPh3)4 (0.66 g, 0.57 mmol), CuI (0.16 g, 0.86 mmol), and TEA (6.4 mL, 45.80 mmol). The resulting reaction mixture was purged with nitrogen for 3 min and stirred at rt for 3 h. The reaction mixture was diluted with ethyl acetate and NH4Cl solution. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 10% EtOAc/hexane) to afford the title compound as a white solid (1.35 g, 96%). 1H NMR (CDCl3) δ 7.98 (d, J=8.6 Hz, 2H), 7.53 (d, J=8.6 Hz, 2H), 3.92 (s, 3H), 0.27 (s, 9H); MS(ESI+) m/z 233.1 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[OH:8])[CH:2]=1.C(Cl)Cl.C(#N)C.C[N+]1([O-])CCOCC1>CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O.CCOCC>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:8])[CH:2]=1
Reactant: OC(c1cccnc1)c1cccnc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC#N
Product: O=C(c1cccnc1)c1cccnc1
Temperature: 0 °C

Procedure:
To a solution of dipyridin-3-ylmethanol (9 g, 48 mmol) in 9:1 methylene chloride/acetonitrile (100 mL) was added powdered 4A molecular sieves (24 g) and NMO (8.5 g, 72 mmol). The resulting mixture was cooled in an ice bath and TPAP (0.85 g, 2.4 mmol) added carefully in 3 portions at 5 min intervals. After stirring for 15 min the ice bath was removed and stirring was continued at RT. After stirring for 3 days, the reaction mixture was filtered through Celite and the cake washed well with methylene chloride and then chloroform. The filtrate was concentrated to approximately ⅓ the original volume then silica gel was added. The remaining solvent was removed leaving the crude material adsorbed onto the silica gel as a dark green powder. This powder was layered on top of an equal volume of silica gel in a Buchner funnel and flushed with ether. These washings were discarded. The silica pad was then flushed repeatedly first with methylene chloride then with chloroform until no further product eluted. The dark red filtrate was concentrated to give a red brown solid. Trituration with ether gave dipyridin-3-ylmethanone as a white powder. The mother liquors were stripped and the residue chromatographed (eluting with 24:1 methylene chloride/methanol). The fractions enriched in product were combined, stripped, and the residue triturated with ether to give a second crop of pure ketone.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]=[CH2:24])[C:13]([OH:15])=[O:14].N1C=CC=CC=1.[CH3:31][Si:32]([CH3:37])([CH3:36])[CH2:33][CH2:34]O.Cl.CN(C)CCCN=C=NCC>O1CCCC1.C(OCC)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]=[CH2:24])[C:13]([O:15][CH2:34][CH2:33][Si:32]([CH3:37])([CH3:36])[CH3:31])=[O:14]
Reactant: C=Cc1ccccc1CC(C(=O)O)N1C(=O)c2ccccc2C1=O
Reactant: C[Si](C)(C)CCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=Cc1ccccc1CC(C(=O)OCC[Si](C)(C)C)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
Dissolve 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(2-vinyl-phenyl)-propionic acid (2.47 g, 7.69 mmol) in tetrahydrofuran (35 mL) and cool in an ice bath. Treat with pyridine (1.6 mL, 20 mmol) and 2-(trimethylsilyl)ethanol (2.3 mL, 16 mmol). Stir for 30 minutes and add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (2.21 g, 11.5 mmol). Stir for 22 hours at 5° C., then at room temperature for 1.5 hours. Cool to 0° C., add 0.6 times all reagents and stir at room temperature overnight. Dilute with ethyl acetate (150 mL), wash with 5% sulfuric acid (40 mL) and saturated sodium hydrogen carbonate (40 mL). Back extract with methylene chloride (100 mL), wash with brine (30 mL) and dry (Na2SO4). Evaporate the solvent in vacuo and purify by silica gel chromatography (2:1 hexane/ethyl acetate) to give 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(2-vinyl-phenyl)-propionic acid, 2-trimethylsilanyl-ethyl ester (2.61 g, 81%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:9]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCC1CCCCN1
Reactant: ClCc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: OCC1CCCCN1Cc1ccccc1
Yield: 52.8 %

Procedure:
A mixture of 12.9 g of 2-piperidine methanol, 13.2 g of benzyl chloride, 10.5 g of triethylamine and 50 ml of toluene was stirred at reflux for 4 hours. The reaction mixture was filtered, the filtrate was concentrated, and the concentrate was distilled under reduced pressure to obtain 11.3 g of 1-benzyl-2-piperidine methanol (yield: 52.9%). b.p.: 107° C./2 mmHg
Reaction SMILES: Cl[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:10][SH:11].[Na]>CS(C)=O>[F:8][C:2]([F:9])([S:11][CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(F)(F)Cl
Reactant: CS
Agent: [Na]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)SC
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
A solution of ethyl chlorodifluoroacetate (7.9 g, 50.0 mmol) in dimethyl sulfoxide (20 ml) was added dropwise to a solution of sodium methyl mercaptan (4.6 g, 65 mmol) in dimethyl sulfoxide (60 ml) under cooling with ice, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into ice water to conduct extraction with ether. The solvent was distilled out of the resultant extract under reduced pressure. The resultant residue was distilled under reduced pressure to obtain the intended product (3.7 g; yield: 43.2%) as a colorless oil.
Reaction SMILES: C([Si]([C:8]#[C:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[C:17]2[CH2:20][NH:21][C:22]([N:24]2[CH2:28][CH2:27][CH2:26][C@H:25]2[C:29]([OH:31])=[O:30])=[O:23])=[CH:12][CH:11]=1)(CC)CC)C>C1COCC1>[C:9]([C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[C:17]2[CH2:20][NH:21][C:22]([N:24]2[CH2:28][CH2:27][CH2:26][C@H:25]2[C:29]([OH:31])=[O:30])=[O:23])=[CH:12][CH:11]=1)#[CH:8]
Reactant: CC[Si](C#Cc1ccc2cccc(CNC(=O)N3CCC[C@H]3C(=O)O)c2c1)(CC)CC
Solvent: C1CCOC1
Product: C#Cc1ccc2cccc(CNC(=O)N3CCC[C@H]3C(=O)O)c2c1

Procedure:
A solution of 250 mg of (S)-1-[(7-Triethylsilanylethynyl-naphthalen-1-ylmethyl)-carbamoyl]-pyrrolidine-2-carboxylic acid in 14 ml of THF is stirred at rt for 1 hour. Solvent is evaporated and the residue obtained is purified by preparative HPLC (Waters Sun Fire C18 column, gradient water/acetonitrile 95/5 to 0/100) to yield the title compound.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][C:21]1([F:37])[CH2:26][CH2:25][N:24]([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)[CH2:23][CH2:22]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>O1CCCC1>[F:37][C:21]1([CH2:20][CH2:19][OH:18])[CH2:26][CH2:25][N:24]([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)[CH2:23][CH2:22]1
Reactant: CC(C)(C)[Si](OCCC1(F)CCN(c2ccc3ccccc3n2)CC1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: OCCC1(F)CCN(c2ccc3ccccc3n2)CC1
Reaction time: 4 h

Procedure:
0.40 g (1.26 mmol) of n-tetrabutylammonium fluoride trihydrate is added to a solution of 2.15 g (4.19 mmol) of 2-[4-(2-{[tert-butyldiphenylsilyl]oxy}ethyl)-4-fluoro-1-piperidyl]quinoline, obtained in step 12.5, in 20 ml of tetrahydrofuran. Stirring is continued at room temperature for 4 hours. The mixture is concentrated to dryness and the residue obtained is then purified by chromatography on silica gel, eluting with a 35/65 and then 40/60 mixture of ethyl acetate and cyclohexane.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:6][C:5](=O)[C:4](=O)[CH2:3]1.COP([CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])=O)(=O)OC.O.[NH2:27][NH2:28]>>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[N:28]=[N:27][C:4]2[CH2:3][C:2]([CH3:9])([CH3:1])[CH2:6][C:5]=2[CH:16]=1
Reactant: NN
Reactant: COP(=O)(CC(=O)c1ccccc1Cl)OC
Reactant: CC1(C)CC(=O)C(=O)C1
Solvent: O
Product: CC1(C)Cc2cc(-c3ccccc3Cl)nnc2C1

Procedure:
yellow viscous oil. MS (EI): 258.2 (M+). Prepared from 4,4-dimethyl-cyclopentane-1,2-dione, [2-(2-Chloro-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17](O)=[O:18])=[CH:9]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:8][CH:9]=2)=[O:18])[CH:3]=1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: Nc1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1c[nH]c2ccccc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
3-aminopyridine (290 mg, 3.1 mmol) and indole-3-carboxylic acid (500 mg, 3.1 mmol) was dissolved in DMF (20 ml), DCC (579 mg, 3.1 mmol) was added to the solution, and then the mixture was stirred at 60° C. for 8 hours. After the reaction was completed, the product was washed and filtered to yield a target compound as a white solid (300 mg, 42%) by chromatography (methanol:dichloromethane=1:20).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][O:10][C:9]2=[O:19])[CH:5]=[CH:4][N:3]=1.[CH:20]1([C@@H:23]([NH2:25])[CH3:24])[CH2:22][CH2:21]1>CN1C(=O)CCC1>[CH:20]1([C@@H:23]([NH:25][C:2]2[N:7]=[C:6]([N:8]3[C@H:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:11][O:10][C:9]3=[O:19])[CH:5]=[CH:4][N:3]=2)[CH3:24])[CH2:22][CH2:21]1
Reactant: O=C1OC[C@@H](c2ccccc2)N1c1ccnc(Cl)n1
Reactant: C[C@H](N)C1CC1
Solvent: CN1CCCC1=O
Product: C[C@H](Nc1nccc(N2C(=O)OC[C@H]2c2ccccc2)n1)C1CC1
Temperature: 180 °C
Yield: 13.6 %

Procedure:
A mixture of (R)-3-(2-chloropyrimidin-4-yl)-4-phenyloxazolidin-2-one (55.3 mg, 0.20 mmol), (S)-1-cyclopropylethylamine (40 μL, 0.26 mmol, 1.3 equiv) and iPr2Net (0.20 mL, 1.15 mmol, 5.7 equiv) in NMP (1 mL) was heated in the microwave at 180° C. for 20 min. The reaction mixture was filtered and purified by reverse phase HPLC to give (R)-3-(2-(((S)-1-cyclopropylethyl)amino)pyrimidin-4-yl)-4-phenyloxazolidin-2-one as a white solid (8.8 mg) in 10% yield. 1H NMR (400 MHz, CD3OD) δ 7.72 (d, J=6.26 Hz, 1H), 7.29-7.43 (m, 6H), 5.76 (dd, J=4.11, 8.80 Hz, 1H), 4.28 (dd, J=4.30, 8.61 Hz, 1H), 3.06-3.19 (m, 1H), 1.39 (dd, J=3.52, 6.65 Hz, 1H), 0.88-0.97 (m, 1H), 0.83 (br. s., 3H), 0.53-0.62 (m, 1H), 0.50 (dt, J=4.11, 8.51 Hz, 1H), 0.33 (qd, J=4.78, 9.54 Hz, 1H), 0.26 (td, J=4.60, 9.59 Hz, 1H); HRMS(A) m/z 325.1667 (M+H)+, Rt 1.54 min; UPLC 2.807 min.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[NH2:28][C:29]([CH3:33])([CH3:32])[CH2:30][OH:31]>>[CH3:32][C:29]([NH:28][C:23]([C:22]1[CH:26]=[CH:27][C:19]([C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:16][CH2:15]2)=[O:18])=[N:20][CH:21]=1)=[O:24])([CH3:33])[CH2:30][OH:31]
Reactant: CC(C)(N)CO
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NC(C)(C)CO)cn2)CC1
Yield: 74 %

Procedure:
By the same procedure as described in the example 1, synthesis was carried out starting with 6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid and using 2-amino-2-methyl-1-propanol. Then, the product was recrystallized with ethyl acetate and ether to give a desired compound.
Reaction SMILES: C(OC(=O)[C:5]([C:14](=[O:33])[C:15]1[CH:20]=[C:19]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])[C:18]([O:30][CH3:31])=[CH:17][C:16]=1F)=[CH:6][NH:7][C@H:8]([CH2:12][OH:13])[CH:9]([CH3:11])[CH3:10])C.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:28][C:24]1[C:23]([F:29])=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][C:19]1[CH:20]=[C:15]2[C:16](=[CH:17][C:18]=1[O:30][CH3:31])[N:7]([C@H:8]([CH2:12][OH:13])[CH:9]([CH3:10])[CH3:11])[CH:6]=[CH:5][C:14]2=[O:33]
Reactant: CCOC(=O)C(=CN[C@H](CO)C(C)C)C(=O)c1cc(Cc2cccc(Cl)c2F)c(OC)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1Cc1cccc(Cl)c1F)c(=O)ccn2[C@H](CO)C(C)C
Temperature: 25 °C

Procedure:
To a solution of 2-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl)-3-((S)-1-hydroxymethyl-2-methylpropylamino)acrylic acid ethyl ester prepared in Step IX or Step III in N,N-dimethylformamide was added anhydrous potassium carbonate (4.86 g) with stirring at room temperature. After stirring at 95-105° C. for 6 hr, N,N-dimethylformamide (10 ml) and water (50 ml) were successively added dropwise at 65-75° C. to allow crystallization. After stirring for 1 hr, the mixture was cooled to room temperature and further stirred for 1 hr. Water (20 ml) was further added and, after stirring for 1 hr, the mixture was filtered, and the residue was washed successively with 50% aqueous N,N-dimethylformamide solution (20 ml) and water (20 ml), and vacuum dried to give 6-(3-chloro-2-fluorobenzyl)-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline)-3-carboxylic acid ethyl ester (13.5 g)).
Reaction SMILES: Cl.[CH3:2][N:3]([CH:14]1[CH2:19][CH2:18][N:17](C(=O)C2C=CC=CC=2)[CH2:16][CH2:15]1)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH3:13])=[CH:8][CH:7]=1>C(O)C>[CH3:2][N:3]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([S:12][CH3:13])=[CH:10][CH:11]=1
Reactant: CSc1ccc(CCN(C)C2CCN(C(=O)c3ccccc3)CC2)cc1
Agent: Cl
Solvent: CCO
Product: CSc1ccc(CCN(C)C2CCNCC2)cc1
Yield: 88.9 %

Procedure:
60 ml of 5 N hydrochloric acid was added to a solution of 5.8 g of 4-{N-methyl-N-[2-(4-methylthiophenyl)ethyl]amino}-1-benzoylpiperidine in 20 ml of ethanol. The mixture was refluxed by heating, for 12 hours. To the reaction mixture was added 100 ml of ethanol, followed by concentration under reduced pressure. To the residue was added ice water. The mixture was made basic with a 25% aqueous sodium hydroxide solution and then extracted with chloroform. The extract was water-washed, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3.7 g of 4-{N-methyl-N-[2-(4-methylthiophenyl)ethyl]amino}piperidine as a light yellow oily substance.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:5]=[C:6]([C:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8]>C(O)(=O)C.O>[Br:1][C:10]1[C:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:6]([CH:5]=[C:4]([OH:3])[C:11]=1[OH:12])[CH:7]=[O:8]
Reactant: COC(=O)Cc1cc(O)c(O)cc1C=O
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)Cc1c(C=O)cc(O)c(O)c1Br
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
Bromine (192 μl) was added to a suspension of 3,4-dihydroxy-6-(methoxycarbonylmethyl)benzaldehyde (0.79 g) in acetic acid (15 ml). The reaction mixture was stirred at ambient temperature for 5-6 hours, diluted with water (30 ml) and extracted into ethyl acetate (200 ml). The organic phase was washed with NaHCO3, water (100 ml) and brine, dried and evaporated under reduced pressure to give a brown solid. This was purified by chromatography using aqueous acetonitrile mixtures to give 3-bromo-4,5-dihydroxy-2-(methoxycarbonylmethyl)benzaldehyde (300 mg); NMR (DMSO-d6) 3.61(s,3H); 4.24(s,2H); 7.24(s,1H); 9.8(s,1H): CI M/S (M+H)+ 291.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[O:7]2)[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[CH2:21](Br)[CH:22]=[CH2:23]>C(Cl)(Cl)Cl>[CH2:23]([N:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[O:7]2)[CH2:3][CH2:2]1)[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: C=CCN1CCC2(CC1)OC(=O)c1ccccc12

Procedure:
A mixture of 1.02 g. of 1,3-dihydrospiro[isobenzofuran-1,4'-piperidine]-3-one, 1.0 g. of sodium bicarbonate, 10 ml. of chloroform, and 0.60 g. of allyl bromide is stirred at room temperature for 24 hours and filtered. The filtrate is washed with water, dried over potassium carbonate, and concentrated to an oily solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6](O)[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.BrC1C=C2C(C(=O)CCO2)=CC=1.[BH4-].[Na+].C1(P([N:41]=[N+:42]=[N-:43])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C(O)C.C1(C)C=CC=CC=1>[N:41]([CH:6]1[C:5]2[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=2)[O:9][CH2:8][CH2:7]1)=[N+:42]=[N-:43]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OC1CCOc2cc(Br)ccc21
Agent: O=C1CCOc2cc(Br)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NC1CCOc2cc(Br)ccc21

Procedure:
In analogy to the procedures described fort he preparation of intermediates A-2 [B] and A-2 [C], (rac)-7-bromo-chroman-4-ol prepared from 7-bromo-chroman-4-one with sodium borohydride in ethanol at 60-70° C., was treated with diphenylphosphoryl azide, DBU in toluene to give (rac)-4-azido-7-bromo-chroman, which was subsequently reduced with triphenylphosphine in THF/water to yield the title compound as light yellow oil. MS: 227 (M+, 1Br).
Reaction SMILES: [C:1]([O:5][C:6]([N-:8][S:9](N1C=CC(=[N+](C)C)C=C1)(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:23]([N:22]([CH3:21])[S:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])(=[O:10])=[O:11])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C[N+](C)=c1ccn(S(=O)(=O)[N-]C(=O)OC(C)(C)C)cc1
Reactant: CNCc1ccccc1
Solvent: ClCCl
Product: CN(Cc1ccccc1)S(=O)(=O)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 61 %

Procedure:
N,N-dialkyl sulfamides were prepared according to the published procedures: Winum, J-Y; Toupet, L.; Barragan, V.; Dewynter, G.; Montero, J.-L. Org. Letters 2001, 3, 2241-2243 and Casini, A.; Winum, J.-Y.; Montero, J.-L.; Scozzafava, A.; Supuran, C. Bioorganic & Medicinal Chemistry Letters 2003, 13, 837-840. A flask was charged with N-tert-butoxycarbonyl-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]azanide (500 mg, 1.66 mmol) and methylbenzylamine (0.21 mL, 1.66 mmol) in 10 mL of CH2Cl2. After 2 h, the solution was concentrated in vacuo and purified by flash column chromatography (5-70% EtOAc/hexanes) to afford 304 mg of tert-butyl {[benzyl(methyl)amino]sulfonyl}carbamate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[CH:4][CH:3]=1.BrC[CH2:29][O:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH2:18][CH2:29][O:30][CH3:31])[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: COCCBr
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COCCn1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)ccc1=O

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-phenyl)-3-otolyl-propionyl]-1-methyl-1H-pyridin-2-one (example 162, step 3) was reacted with 2-bromoethylmethylether in the presence of potassium carbonate to give the title compound as a colorless foam, MS (ESI+): m/z=454.1 [M+H]+.