Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][C@H:5](O)[C@H:4]([CH2:8][C:9]([OH:11])=[O:10])[C@H:3]1[CH:12]=[CH:13][C@H:14]([OH:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].CC(OC)(C)C.ClC(Cl)(Cl)C(O)=O>C(N(CC)CC)C>[OH:1][C@H:2]1[CH2:6][C@H:5]2[O:10][C:9](=[O:11])[CH2:8][C@H:4]2[C@@H:3]1/[CH:12]=[CH:13]/[C@H:14]([OH:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCC[C@@H](O)C=C[C@@H]1[C@@H](CC(=O)O)[C@@H](O)C[C@H]1O
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CCCCC[C@@H](O)/C=C/[C@H]1[C@@H]2CC(=O)O[C@@H]2C[C@@H]1O

Procedure:
2-[(1R, 2R, 3R, 5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-1-octenyl]cyclopentyl]acetic acid (XIX, EXAMPLE 11, 2.55 g) is stirred with MTBE (100 mL) and trichloroacetic acid (0.102 g). The slurry is heated to reflux for more than one hour. Then triethylamine (0.2 mL) is added. The mixture is cooled and washed once with water (50 mL) of water. The mixture is dried over anhydrous granular sodium sulfate and then concentrated under reduced pressure to give the title compound, NMR (CDCl3, 400 MHz) δ 5.58, 5.43, 4.88, 4.03, 3.92, 3.55, 2.8, 2.71, 2.3-2.5, 2.22, 1.9, 1.2-1.6 and 0.89; CMR (CDCl3, 100.6 MHz) δ 176.94, 136.79, 130.20, 82.41, 76.27, 72.78, 56.12, 42.34, 39.61, 37.05, 33.98, 31.60, 25.06, 22.52 and 13.94.
Reaction SMILES: [Cl-].[CH2:2]([O:4][CH:5]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:3].C1CCN2C(=NCCC2)CC1.[CH2:41]([O:48][C:49]1[C:54]2[CH:55]=[CH:56][O:57][C:53]=2[C:52]([CH:58]=O)=[CH:51][CH:50]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1COCC1>[CH2:9]([O:8][C:6](=[O:7])/[C:5](/[O:4][CH2:2][CH3:3])=[CH:58]/[C:52]1[C:53]2[O:57][CH:56]=[CH:55][C:54]=2[C:49]([O:48][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[CH:50][CH:51]=1)[CH3:10]
Reactant: O=Cc1ccc(OCc2ccccc2)c2ccoc12
Reactant: CCOC(=O)C(OCC)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)/C(=C/c1ccc(OCc2ccccc2)c2ccoc12)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.8 %

Procedure:
A suspension of (ethoxy-ethoxycarbonyl-methyl)-triphenyl-phosphonium chloride (2.04 g, 4.8 mmol) and DBU (0.8 g, 5.2 mmol) in THF (40 ml) was stirred for 10 min at ambient temperature under an argon atmosphere [for the preparation of (ethoxy-ethoxycarbonyl-methyl)-triphenyl-phosphonium chloride see: K. K. Bach, H. R. El-Seedi, H. M. Jensen, H. B. Nielsen, I. Thomson, K. B. G. Torssell, Tetrahedron 1994, 50, 7543-7556]. 4-Benzyloxy-benzofuran-7-carbaldehyde (0.8 g, 3.2 mmol) was added and the mixture was heated under reflux for 12 h. The solvent was concentrated at reduced pressure, the residue taken up with ethyl acetate, washed with saturated aqueous NH4Cl solution and two times with brine. The organic layer was dried over sodium sulfate, the solvent removed under reduced pressure and the residue purified by column chromatography (silica gel, hexane/AcOEt=9/1) to give 0.8 g (2.2 mmol, 69%) of the title compound as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:21])([CH2:15][O:16]S(C)(=O)=O)[CH2:10]OC(=O)C.[OH-].[K+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:21][CH2:10]1)[CH2:15][OH:16]
Reactant: CC(=O)OC[C@](O)(COS(C)(=O)=O)c1ccc(F)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: OC[C@@]1(c2ccc(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.2 %

Procedure:
In 250 ml of toluene was dissolved 50 g of (S)-2-(2,4-difluorophenyl)-1-acetoxy-3-methanesulfonyloxy-2-propanol and thereto was added 250 ml of 20% aqueous solution of potassium hydroxide and then the resulting liquid was stirred at room temperature for 12 hours. A toluene-layer was separated and the aqueous layer was extracted three times with 100 ml of ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate and the solvent was removed. The residue was purified by column chromatography on silica gel to give 21 g of (S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-propanol. The optical purity thereof was determined by HPLC analysis (column: CHIRALPAK AS made by Daicel Chemical Industries, Ltd., eluent: n-hexane/isopropanol=98/2, detection wavelength: 254 nm, flow rate: 1.2 ml/min).
Reaction SMILES: [NH2:1][C:2]1[N:6]2[C:7]3[C:12]([C:13](=[O:22])[N:14]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:5]2=[N:4][N:3]=1)=[CH:11][C:10]([Br:23])=[CH:9][CH:8]=3.CO[CH:26]1[CH2:30][CH2:29][CH:28](OC)O1>C(O)(=O)C>[CH2:15]([N:14]1[C:13](=[O:22])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:23])[CH:11]=2)[N:6]2[C:2]([N:1]3[CH:26]=[CH:30][CH:29]=[CH:28]3)=[N:3][N:4]=[C:5]12)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1nnc2n(Cc3ccccc3)c(=O)c3cc(Br)ccc3n12
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: O=c1c2cc(Br)ccc2n2c(-n3cccc3)nnc2n1Cc1ccccc1
Yield: 59.5 %

Procedure:
In a 25 ml balloon flask, we resuspend 0.7 g (1.8 mmol) of 1-amino-4-benzyl-7-bromo-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one (intermediate 10 compound of example 271) in 5 ml of acetic acid. We add 0.25 g (1.9 mmol) of 2.5-dimethoxytetrahydrofuran then heat the mixture by reflux for 1 hour. After cooling down and evaporation of acetic acid under vacuum, we obtain 0.8 g of highly colored solid which is purified by chromatography on silica column by elution with the mixture CH2Cl2/CH3OH (99,4/0,6 then 99/1). The solid obtained from pure fractions is recrystallized in ethanol to give 0.45 g of compound from example 217.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH:19]([C:20]2[N:25]=[C:24]([C:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=3)[CH:23]=[CH:22][CH:21]=2)[CH2:18][C:17]([C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])=[N:16]1.[CH3:39][N:40]([CH3:45])[S:41](Cl)(=[O:43])=[O:42]>>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH:19]([C:20]2[N:25]=[C:24]([C:26]3[CH2:27][CH2:28][N:29]([S:41](=[O:43])(=[O:42])[N:40]([CH3:45])[CH3:39])[CH2:30][CH:31]=3)[CH:23]=[CH:22][CH:21]=2)[CH2:18][C:17]([C:32]([F:38])([F:37])[C:33]([F:34])([F:36])[F:35])=[N:16]1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2cccc(C3=CCNCC3)n2)C1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)S(=O)(=O)N1CC=C(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)n2)CC1

Procedure:
The titled compound was prepared in accordance with the same procedures as in Step 2 of Example 158, except for using 1-(2-chloro-phenyl)-5-[2-(1,2,3,6-tetrahydropyridin-4-yl)-pyridin-6-yl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole trifluoroacetate prepared in Step 1 of Example 158; and using dimethylsulfamoyl chloride instead of methanesulfonyl chloride.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:17]=[C:16]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:26]([CH3:31])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[H][H]>CO>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:26]([CH3:31])[S:27]([CH3:30])(=[O:28])=[O:29])[CH:15]=[CH:14][N:13]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: [H][H]
Reactant: CN(c1ccccc1C#Cc1ccnc(Nc2ccc(S(C)(=O)=O)cc2)n1)S(C)(=O)=O
Solvent: CO
Product: CN(c1ccccc1CCc1ccnc(Nc2ccc(S(C)(=O)=O)cc2)n1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.6 %

Procedure:
100 mg of N-(2-{2-[2-(4-methanesulfonylphenylamino)pyrimidin-4-yl]ethynyl}-phenyl)-N-methylmethanesulfonamide are dissolved in 1 ml of methanol, and 100 mg of activated carbon (with 10% of Pd) are added. A hydrogen atmosphere is generated, and the suspension is stirred at room temperature for 3 h. The catalyst is subsequently filtered off, and the solvent is removed. The residue is chromatographed on silica gel, giving 50 mg of the title compound as colourless solid;
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[Mg].II.[CH2:13]([N:20]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:13]([N:20]1[CH2:24][CH2:23][C:22]([C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=2)([OH:25])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CCN(Cc2ccccc2)C1
Reactant: Fc1cc(F)cc(Br)c1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(c2cc(F)cc(F)c2)CCN(Cc2ccccc2)C1
Yield: 33.3 %

Procedure:
To a solution of 1-bromo-3,5-difluorobenzene (10 g, 57.14 mmol) in dry tetrahydrofuran (60 mL), under nitrogen, was added magnesium turnings (1.37 g, 57.14 mmol) and one crystal of Iodine. The mixture started to reflux spontaneously and when all magnesium was consumed, a solution of 1-benzylpyrrolidin-3-one (10 g, 57.14 mmol) in dry tetrahydrofuran (40 mL) was added drop wise. The resulting mixture was heated to 60° C. for 2 h after which aqueous saturated ammonium chloride solution (50 mL) was added. The mixture was extracted with ethyl acetate (2×50 mL) and the combined organic phase was dried (Na2SO4) and evaporated. Purification twice by flash chromatography on silica gel (isooctane/ethyl acetate, 1:1 and 6:4) gave the title compound (5.5 g). MS m/z (rel. intensity, 70 eV) 289 (M+, 9), 198 (61), 133 (51), 132 (41), 91 (bp).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][C:7]3[C:12]([CH2:13][N:4]2[CH2:3][C:2]1=[O:14])=[CH:11][CH:10]=[CH:9][CH:8]=3.C(O)(=O)C.[Br:19]Br>O>[Br:19][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]=[C:5]1[NH:1][C:2](=[O:14])[CH2:3][N:4]1[CH2:13]2
Reactant: O=C1CN2Cc3ccccc3N=C2N1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=C1CN2Cc3cc(Br)ccc3N=C2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a vigorously stirred solution of 1.87 g. (0.01 mole) of 1,2,3,5-tetrahydroimidazo[2,1-b]-quinazolin-2-one in 40 ml. of glacial acetic acid was added dropwise at room temperature 1.60 g. (0.01 mole) of bromine. The mixture was stirred at room temperature for one hour, water (50 ml.) was added and the volume concentrated (10-15 ml.) in vacuo. Additional water (50 ml.) was added, the solution made basic with ammonium hydroxide, warmed and the insoluble material filtered under suction. The colorless solid was washed with water, dried and crystallized from 50 ml. of 5% hydrochloric acid yielding 0.8 g. (30% yield) of a colorless solid: m.p. >275°. Purification was effected by crystallization from methanol/ether; m.p. 275° to yield the title product.
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:3].[CH2:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]CC.C[O-].[Na+]>C(O)C>[CH3:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:9][CH2:8][O:7][C:5]([CH:4]([N:2]([CH3:3])[CH3:1])[CH3:10])=[O:6]
Reactant: CCCCCCCCCCCCO
Reactant: CCOC(=O)C(C)N(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCOC(=O)C(C)N(C)C

Procedure:
A representative reaction scheme follows: ##STR6## The ethyl 2-(N,N-dimethylamino)-propionate is preferably refluxed for about 2 hours in the presence of 10 percent stoichiometric excess 1-dodecanol and a catalytic amount of sodium methoxide (predissolved in toluene). During this process, the ethanol formed is removed from the reaction medium by azeotropic distillation. Following the reaction phase, the solids of the remaining mixture are filtered off, resulting in a DDAIP filtrate.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][C:4]2[N:8]=[C:9]([CH3:12])[CH:10]=[CH:11][C:3]1=2.[C:13](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:14].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C1COCC1.C(OCC)(=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][NH:5][C:4]2[N:8]=[C:9]([CH2:12][CH2:13][OH:14])[CH:10]=[CH:11][C:3]1=2
Reactant: Cc1ccc2c(n1)NCCN2C
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCNc2nc(CCO)ccc21
Temperature: 25 °C
Yield: 118.3 %

Procedure:
A solution of 1,6-dimethyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (1.14 g, 7 mmol), di-tert-butyl dicarbonate (2.29 g, 10.5 mmol), DMAP (100 mg) and triethylamine (1.46 mL, 10.5 mmol) in 30 mL THF was refluxed 72 hours under N2. The reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate. The mixture was washed with brine, dried over Na2SO4. After filtration and concentration at reduced pressure, the crude mixture was purified by flash chromatography on silica gel (40% EA/Hex) to afford the desired product (1.6 g, 90% yield) as yellow oil. H NMR (400 MHz, CDCl3) δ 1.51 (s, 9H), 2.40 (s, 3H), 2.90 (s, 3H), 3.28 (t, 2H), 3.83 (m, 2H), 6.78 (d, 1H), 6.83(d, 2H). Step 6. Synthesis of tert-butyl 6-(2-ethoxy-2-oxoethyl)-1-methyl-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxylate.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)[CH:9]=[CH:10][CH:11]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:20][C:18]1[CH:17]=[CH:16][N:15]2[CH:21]=[C:12]([C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[CH:7]=3)[N:13]=[C:14]2[CH:19]=1
Reactant: Cc1ccn2cc(-c3cccc(OCCCCl)c3)nc2c1
Reactant: C1CCNCC1
Product: Cc1ccn2cc(-c3cccc(OCCCN4CCCCC4)c3)nc2c1
Temperature: 25 °C

Procedure:
The product of Step C (271 mg) and piperidine (2.0 mL) were heated at 100° C. for 2 hours. The reaction was cooled to ambient temperature and partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL). The aqueous portion was extracted with a fresh portion of ethyl acetate (10 mL) and the organic portions combined and washed with brine (10 mL). The organic portions were dried over magnesium sulfate, filtered and evaporated. The residue was purified via silica gel chromatography (dichloromethane/methanol) to give the title compound (193 mg). 1H-NMR (CD3OD) δ8.27 (d, J=7.0 Hz, 1H), 8.08 (s, 1H), 7.46 (m, 2H), 7.31 (m, 2H), 6.88 (m, 1H), 6.76 (m, 1H), 4.09 (t, J=6.0 Hz, 2H), 2.58 (m, 6H), 2.42 (s, 3H), 2.04 (m, 2H), 1.65 (m, 4H), 1.51 (m, 2H).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([C:7]1[S:31][C:10]2[N:11]=[CH:12][N:13]=[C:14]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[O:23][C@H:24]3[CH2:29][CH2:28][CH2:27][C@H:26]([OH:30])[CH2:25]3)[C:9]=2[C:8]=1[CH3:32])=[O:6].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:14]2[C:9]3[C:8]([CH3:32])=[C:7]([C:5]([OH:6])=[O:4])[S:31][C:10]=3[N:11]=[CH:12][N:13]=2)=[C:17]([O:23][C@H:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([OH:30])[CH2:25]2)[CH:18]=1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCC[C@H](O)C3)c2c1C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCC[C@H](O)C3)c12
Reaction time: 8 h

Procedure:
2.665 g lithium hydroxide were added to a mixture of 6.5 g racemic racemic 4-[4-fluoro-2-((trans)-3-hydroxy-cyclohexyloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methylester in 350 ml water and 70 ml water. The mixture was stirred overnight. Then the mixture was acidified by addition of citric acid (10% in water) and concentrated. Water was added and the mixture was filtered. The solid was washed with water and dried.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][O:18][C:19](=[O:46])[N:20]([C:43](=[O:45])[CH3:44])[CH2:21][C@@H:22]2[O:26][C:25](=[O:27])[N:24]([C:28]3[CH:33]=[CH:32][C:31]([CH:34]4[CH2:39][CH2:38][S:37](=[O:41])(=[O:40])[CH2:36][CH2:35]4)=[C:30]([F:42])[CH:29]=3)[CH2:23]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C1(OC)C=CC=CC=1.[ClH:55].CCOCC>O1CCCC1.O1CCOCC1>[ClH:55].[C:43]([N:20]([CH2:21][C@@H:22]1[O:26][C:25](=[O:27])[N:24]([C:28]2[CH:33]=[CH:32][C:31]([CH:34]3[CH2:39][CH2:38][S:37](=[O:40])(=[O:41])[CH2:36][CH2:35]3)=[C:30]([F:42])[CH:29]=2)[CH2:23]1)[C:19]([O:18][CH2:17][O:16][C:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15])=[O:46])(=[O:45])[CH3:44]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOCC
Solvent: COc1ccccc1
Solvent: C1COCCO1
Product: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)C1CCNCC1

Procedure:
(R)-Piperidine-1,4-dicarboxylic acid 4-[(acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-carbamoyloxy)-methyl] ester 1-tert-butyl ester (17) (588.5 mg, 0.88 mmol) and anisole (0.9 mL) are diluted with tetrahydrofuran (17 mL). Hydrochloric acid in dioxane (4 M, 6.6 mL) is added dropwise and the resultant mixture is stirred at RT overnight. Ether is added dropwise to the mixture while stirring, resulting in the formation of a solid. The solid is collected via filtration, rinsed with ether, and dried under vacuum to give the title compound in quantitative yield (530.8 mg, 0.88 mmol) 1H NMR (400 MHz, CD3OD): δ 7.51 (dd, 1H), 7.36 (t, 1H), 7.26 (dd, 1H), 5.92 (s, 2H), 4.15-422 (m, 2H), 4.05 (dd, 1H), 3.81 (dd, 1H), 3.36-3.43 (m, 4H), 3.23 (tt, 1H), 3.05-3.14 (m, 5H), 2.90 (tt, 1H), 2.52 (s, 3H), 2.35 (q, 2H), 2.13-2.26 (m, 4H), 1.92-2.00 (m, 2H). MS-APCI (m/z+): 570.
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[C:5]([O:6][C:7]2[C:12]([CH3:13])=[C:11]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=[C:9]([CH3:20])[N:8]=2)=[C:4]([CH3:24])[CH:3]=1.[CH3:25][C:26]([CH3:28])=[O:27]>C1COCC1>[CH2:16]([CH:15]([NH:14][C:11]1[CH:10]=[C:9]([CH3:20])[N:8]=[C:7]([O:6][C:5]2[C:21]([CH3:23])=[CH:22][C:2]([C:26]([OH:27])([CH3:28])[CH3:25])=[CH:3][C:4]=2[CH3:24])[C:12]=1[CH3:13])[CH2:18][CH3:19])[CH3:17]
Reactant: CC(C)=O
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1C
Solvent: C1CCOC1
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C(C)(C)O)cc2C)c1C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of [2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine in dry THF was added n-butylithium at −78° C. After stirring at −78° C. for 10 min, acetone was added and the resulting mixture was stirred at −78° C. for 30 min, the dry-ice bath was removed. After stirring for 5 min, the mixture was quenched with brine and extracted with ethyl acetate. The organic layer was separated, dried, and concentrated to dryness. The residue was purified through silica gel chromatography to give the title compound. 1H NMR(CDCl3) d 7.17(s, 2H), 6.08(s, 1H), 3.73(d, 1H), 3.33(m, 1H), 2.19(s, 3H), 2.15(s, 3H), 2.12(s, 6H), 1.4-1.7(m, 4H), 1.26(s, 6H), 0.96(t, 6H) ppm.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1OS(C1C=CC(C)=CC=1)(=O)=O)(=[O:3])[CH3:2].[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)#[CH:23]>CCCCCCC.CCOC(C)=O>[C:24]1([C:22]#[C:23][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:1](=[O:3])[CH3:2])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)Nc1ccccc1OS(=O)(=O)c1ccc(C)cc1
Reactant: C#Cc1ccccc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccccc1C#Cc1ccccc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 2-acetylamino-phenyl ester and ethynyl-benzene following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 9:1; yield (60 mg, 50%); 1H NMR δ (CDCl3): 8.39 (d, J=8.55 Hz, 1H), 7.9 (br s, 1H), 7.59-7.67 (m, 2H), 7.58-7.52 (m, 2H), 7.41-7.35 (m, 3H), 7.02 (t, J=7.22 Hz, 1H), 2.21 (s, 3H); LCMS m/z: 235.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[CH2:20][N:21]([CH3:43])[CH2:22][C:23]([C:25]1[CH:42]=[CH:41][C:28]([O:29][CH2:30][C:31]([O:33]CC2C=CC=CC=2)=[O:32])=[CH:27][CH:26]=1)=[O:24].CC#N.O>CO.[Pd]>[N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:1][C:2]=1[CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[CH2:20][N:21]([CH3:43])[CH2:22][C:23]([C:25]1[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:41][CH:42]=1)=[O:24]
Reactant: CN(CC(=O)c1ccc(OCC(=O)OCc2ccccc2)cc1)Cc1nc2ccccc2n1Cc1nc2ccccc2[nH]1
Agent: [Pd]
Solvent: CC#N
Solvent: O
Solvent: CO
Product: CN(CC(=O)c1ccc(OCC(=O)O)cc1)Cc1nc2ccccc2n1Cc1nc2ccccc2[nH]1
Reaction time: 1 h

Procedure:
A mixture of benzyl 4-[2-[[[1-[(benzimidazol-2-yl)methyl]benzimidazol-2-yl]methyl]methylamino]acetyl]phenoxyacetate (0.08 g, 0.18 mmol) and 5% Pd/C (0.11 g) in MeOH (15 m L) was shaken on a Parr apparatus under H2 (41 psi) for 1 h. The mixture was filtered through a bed of Celite®, and the filter pad was washed with glacial AcOH and MeOH. The filtrate was concentrated to give the crude product (0.07 g). Preparative HPLC (Hamilton PRP-1® column, step gradient, 10-30% CH3CN/H2O-0.1% TFA) afforded the title compound: MS (ES) m/e 484.2 [M+H]+. Anal. Calcd for C27H25N5O4.3 C2HF3O2 : C, 48.01; H, 3.42 N, 8.48. Found: C, 48.40; H, 3.72; N, 8.77.
Reaction SMILES: C([O:8][C:9](=[O:25])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C1C=CC=CC=1.[OH-].[Na+].Cl>CCO>[CH2:18]([O:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[C:9]([OH:25])=[O:8])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(OCc1ccccc1)c1ccc(Cl)cc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(Cl)cc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a solution of 2-benzyloxy-4-chlorobenzoic acid benzyl ester in EtOH (500 mL) is added 1N NaOH (100 mL) and the mixture is stirred at 60° C. for 24 h. The mixture is allowed to cool to RT and is acidified with 1N HCl. The volume of the solution is reduced to 250 mL and the resulting precipitate is filtered, washed with water and dried to give the title compound as an off-white solid.
Reaction SMILES: C[O:2][C:3](OC)([C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)COCCOCCO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:12]1([C:10]([C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:2])=[O:11])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(OC)(C(=O)c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCCOCCOCCO
Solvent: O
Product: O=C(C(=O)c1ccccc1)c1ccccc1

Procedure:
A mixture of 153.8 g (0.6 mole) of benzil dimethyl ketal, 90.1 g (0.6 mole) of triethylene glycol and 3.9 g of toluene-4-sulfonic acid monohydrate are heated to 75°-85° C. under an aspirator vacuum (20-30 mbar). At about 63° C., everything is dissolved. The course of the reaction is monitored by thin-layer chromatography. The reaction is stopped as soon as less than 1% of benzil dimethyl ketal is present in the mixture or the amount of benzil formed is larger than the amount of benzil dimethyl ketal still present. This is the case after 2-3 hours. The yellow solution is then cooled and neutralized with 3.8 g of a 30% solution of sodium methylate in methanol. The mixture is then heated to 60° C. under an aspirator vacuum and the methanol is distilled off. The liquid residue is diluted with 500 ml of toluene, stirred with 10 g of activated carbon and filtered through a Hyflo bed. The filtrate is evaporated in vacuo. This gives 208.8 g of a yellow, viscous oil (photoinitiator no. 1).
Reaction SMILES: N1C=CC=CC=1.[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18](=[O:20])[CH3:19])[C@@H:13]([CH3:21])[CH2:12][NH:11]2.[Cl:22][C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[C:18]([N:14]1[C:15]2[C:10](=[CH:9][C:8]([Br:7])=[CH:17][CH:16]=2)[N:11]([C:23]([Cl:22])=[O:25])[CH2:12][C@@H:13]1[CH3:21])(=[O:20])[CH3:19]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(=O)N1c2ccc(Br)cc2NC[C@@H]1C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1c2ccc(Br)cc2N(C(=O)Cl)C[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Pyridine (0.150 mL, 1.86 mmol) was added to a solution of (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxalin-1(2H)-yl)ethanone (0.500 g, 1.86 mmol) in dichloromethane (6.6 mL). Triphosgene (0.197 g, 0.663 mmol) was then added in portions over ten minutes, and the reaction mixture stirred for 2 h at room temperature. The reaction was diluted with dichloromethane and washed with 1 N aqueous HCl solution. The organic phase was separated and washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated in a Genevac to afford (S)-4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carbonyl chloride, which was dissolved in 1,2-dichloroethane (9.0 mL) to afford a 0.2 M solution.