Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:14]2[C:13]([CH3:16])([CH3:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:17]1([C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:23]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:24]=[CH:25][C:26]([NH:27][C:3]2[CH:4]=[CH:5][C:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:13]([CH3:16])([CH3:15])[C:14]=3[CH:2]=2)=[CH:28][CH:29]=1
Reactant: CC1(C)c2ccccc2-c2cccc(Br)c21
Reactant: Nc1ccc(-c2ccccc2)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC1(C)c2ccccc2-c2ccc(Nc3ccc(-c4ccccc4)cc3)cc21

Procedure:
50 g of bromo-9,9-dimethyl-9H-fluorene (183 mmol), 38 g of p-phenylaniline (220 mmol), 1.5 g of DPPF (2.7 mmol), 0.5 g of palladium(II)acetate and 45 g of sodium tert-butoxide (486 mmol) are heated at the boil in 1.5 l of toluene under a protective-gas atmosphere for 18 h. The mixture is subsequently partitioned between toluene and water, and the organic phase is washed three times with water, dried over Na2SO4 and evaporated in a rotary evaporator. The residue which remains is recrystallised from heptane/ethyl acetate. The yield is 33 g (91.5 mmol, 50%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[Cl:20][C:21]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1COCC1>[Cl:20][C:21]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](/[N:12]=[C:6]1\[S:7][C:8]([CH3:11])=[C:9]([CH3:10])[N:5]\1[CH2:4][CH2:3][O:2][CH3:1])=[O:24]
Reactant: COCCn1c(C)c(C)sc1=N
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1cccc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.4 %

Procedure:
To the product of Example 126A (0.20 g, 1.1 mmol) in 35 mL THF was added Et3N (0.37 mL, 2.7 mmol). This mixture was cooled to 0° C. and 2,3-dichlorobenzoyl chloride (Lancaster, 0.27 g, 1.3 mmol) in 5 mL THF was added dropwise via syringe. This mixture stirred at ambient temperature for 1 hour then was warmed to reflux and was allowed to stir for 3 hours. The mixture was cooled to ambient temperature and was quenched with 5 mL saturated, aqueous NH4Cl and diluted with 10 mL EtOAc. The layers were separated and the aqueous layer was extracted 2×5 mL EtOAc and 2×5 mL CH2Cl2. The combined organics were washed 1×5 mL saturated, aqueous NaCl then were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified via flash column chromatography (SiO2, 10% CH3OH:EtOAc). The material was still impure so it was purified again via flash column chromatography (SiO2, 1:1 hexanes:EtOAc) to provide the title compound (0.105 g, 0.29 mmol, 27% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.26 (s, 3H), 2.28 (s, 3H), 3.30 (s, 3H), 3.76 (t, J=4.6 Hz, 2H), 4.40 (t, J=4.2 Hz, 2H), 7.23 (t, J=7.7 Hz, 1H), 7.49 (dd, J=8.0, 1.5 Hz, 1H), 7.72 (dd, J=7.6, 1.5 Hz, 1H); MS (DCI/NH3) m/z 359 (M+H)+; Anal. calculated for C15H16Cl2N2O2S: C, 50.15; H, 4.49; N, 7.80. Found: C, 50.17; H, 4.26; N, 7.69.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([NH:16][C:17](=[O:19])[CH3:18])[CH:10]=[C:11]([N+:13]([O-])=O)[CH:12]=2)[CH2:3][CH2:2]1>[Pd].CO>[NH2:13][C:11]1[CH:10]=[C:9]([NH:16][C:17](=[O:19])[CH3:18])[CH:8]=[C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:12]=1
Reactant: CC(=O)Nc1cc(N2CCOCC2)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1cc(N)cc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure V by stirring N-(3-morpholino-5-nitrophenyl)-acetamide (0.014 g, 0.051 mmol), 10% palladium on carbon (5.5 mg, 5.13 μmol), and methanol (1 mL) at 23° C. to afford N-(3-amino-5-morpholinophenyl)acetamide as a tan amorphous solid. Mass Spectrum (ESI) m/e=236.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:13]([CH3:14])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[C@@H:8]([NH2:10])[CH3:9].C(N(CC)CC)C.[C:22](Cl)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[N:13]([CH3:14])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[C@@H:8]([NH:10][C:22](=[O:23])[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:9]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OCc1ccccc1)c1nc2ccn(C)c2cc1Br
Temperature: 13 °C
Reaction time: 1.5 h
Yield: 94.4 %

Procedure:
To a stirred solution of (S)-1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethan-1-amine (1.0 g, 3.93 mmol) in DCM (20 mL) was added triethylamine (796 mg, 7.87 mmol) followed by CbzCl (808 mg, 4.72 mmol) at 0° C. The reaction mixture was stirred at about 0 to 26° C. for 1.5 hours. After the solvent was removed, the residue was purified by silica gel column chromatography (PE/EtOAc=10:1) to give the title compound as a yellow oil (1.44 g, 94.7%).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][CH:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5][C:4]([CH3:18])([CH3:17])[NH:3]1.[O:20]1[CH2:44][CH:21]1[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH:41]3[O:43][CH2:42]3)=[CH:35][CH:34]=2)([CH3:32])[CH3:31])=[CH:26][CH:25]=1>CO>[OH:43][CH:41]([CH2:42][N:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:6]1[CH2:7][C:2]([CH3:1])([CH3:19])[NH:3][C:4]([CH3:17])([CH3:18])[CH2:5]1)[CH2:40][O:39][C:36]1[CH:37]=[CH:38][C:33]([C:30]([C:27]2[CH:28]=[CH:29][C:24]([O:23][CH2:22][CH:21]([OH:20])[CH2:44][N:8]([CH:6]3[CH2:5][C:4]([CH3:18])([CH3:17])[NH:3][C:2]([CH3:19])([CH3:1])[CH2:7]3)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:25][CH:26]=2)([CH3:32])[CH3:31])=[CH:34][CH:35]=1
Reactant: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Reactant: CCCCCCCCNC1CC(C)(C)NC(C)(C)C1
Solvent: CO
Product: CCCCCCCCN(CC(O)COc1ccc(C(C)(C)c2ccc(OCC(O)CN(CCCCCCCC)C3CC(C)(C)NC(C)(C)C3)cc2)cc1)C1CC(C)(C)NC(C)(C)C1
Reaction time: 6 h

Procedure:
A mixture of 13 g of 2,2,6,6-tetramethyl-4-octylaminopiperidine and 8 g of 2,2-bis[p-(2,3-epoxypropoxy)phenyl]propane in 200 ml of methanol was refluxed, with stirring, for 6 hours. At the end of this time, the solvent was removed from the residue by evaporation under reduced pressure, leaving a residue, which was purified by column chromatography through silica gel eluted with a 20:4:2:1 by volume mixture of ethyl acetate, benzene, ethanol and triethylamine. The desired compound was obtained in the form of a colourless, transparent, very viscous liquid having an Rf value of 0.27 on thin layer chromatography on silica gel developed with a 20:4:2:1 by volume mixture of ethyl acetate, benzene, ethanol and triethylamine.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]2[N:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH:11]=2)[CH2:4]1.C(N(CC)CC)C.[Cl:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1.O>CN(C=O)C>[Cl:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([N:3]2[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]3[N:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH:11]=3)[CH2:4]2)=[O:36])=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCCNC2)nc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCCN(C(=O)c3ccc(Cl)cc3)C2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
To a solution of ethyl (2E)-3-{6-[(3R)-3-piperidinylamino]-3-pyridinyl}acrylate dihydrochloride (300 mg, 0.86 mmol) in DMF (4 mL) were added triethylamine (349 mg, 3.45 mmol) and 4-chlorobenzoyl chloride (181 mg, 1.03 mmol) at 0° C. under nitrogen and the mixture was stirred at same temperature for 1 hr and at ambient temperature for 2 hrs. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (hexane-EtOAc=1-1) to give ethyl (2E)-3-(6-{[(3R)-1-(4-chlorobenzoyl)-3-piperidinyl]amino}-3-pyridinyl)acrylate (270 mg, 76%) as an amorphous powder.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]3[C:13]([C:17]([NH:19][CH2:20][C:21]4([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[O:18])=[C:12]([Cl:29])[CH:11]=[CH:10][C:9]=3[N:8]=2)[CH2:3]1.[CH3:30][C:31]([Si:34]([CH3:40])([CH3:39])[O:35][CH2:36][CH:37]=O)([CH3:33])[CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCl>[Si:34]([O:35][CH2:36][CH2:37][NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]3[C:13]([C:17]([NH:19][CH2:20][C:21]4([OH:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)=[O:18])=[C:12]([Cl:29])[CH:11]=[CH:10][C:9]=3[N:8]=2)[CH2:3]1)([C:31]([CH3:33])([CH3:32])[CH3:30])([CH3:40])[CH3:39]
Reactant: N[C@H]1CCN(c2ccc3c(C(=O)NCC4(O)CCCCCC4)c(Cl)ccc3n2)C1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCN[C@H]1CCN(c2ccc3c(C(=O)NCC4(O)CCCCCC4)c(Cl)ccc3n2)C1
Reaction time: 0.08 h

Procedure:
2-[(3S)-3-Aminopyrrolidin-1-yl]-6-chloro-N-[(1-hydroxycycloheptyl)methyl]-quinoline-5-carboxamide (17.6 g) was suspended in dichloromethane (300 ml) and molecular sieves (17.6 g) were added under a nitrogen atmosphere. [[(1,1-dimethylethyl)-dimethylsilyl]-oxy]acetaldehyde (7.2 ml) was added dropwise with stirring over 5 minutes and the mixture was stirred at room temperature for 6 hours. Sodium triacetoxyborohydride (17.9 g) was added in one portion and the mixture was stirred at room temperature for a further 17 hours before water (10 ml) was added, the mixture was stirred at room temperature for 30 minutes, concentrated onto silica in vacuo and purified by flash column chromatography (SiO2, 1:2:97-1:8:91 7M NH3 in methanol:methanol:dichloromethane as gradient elution) to afford the subtitle product as a colourless solid (16.0 g). Impure fractions (4.1 g) were repurified by flash column chromatography (SiO2, 1:2:97-1:8:91 7M NH3 in methanol:methanol:dichloromethane as gradient elution) to afford a second crop of the subtitle product (2.8 g).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[Sn:19](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23]>>[CH2:28]([Sn:19]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: [Li]CCCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(-c2ccccc2)cc1

Procedure:
2.5 M of n-BuLi (2.1 mL/hexane, 5.32 mmol) was added to 4-bromobiphenyl (1.24 g, 5.32 mmol/THF (20 mL)) and reacted at −78° C. for 40 minutes under a dry and anaerobic operation condition to form a solution. SnBu3Cl (1.65 mL, 5.85 mmol) was then added to the solution and reacted at −78° C. for 1 hour. After returning to room temperature, the solution was continuously reacted for 8 hours. After the reaction was completed, the solution was extracted by ether (30 mL) and deionized water (50 mL). An organic phase was collected. After removal of ether by a rotary concentrator, the organic phase was purified by reduced-pressure distillation to form a transparent colorless oily product (21, 1.83 g, 78%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([F:10])=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=1[O:21][CH3:22].Cl>O1CCOCC1>[F:10][C:5]1[C:6]([NH:8][CH3:9])=[N:7][C:2]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[O:21][CH3:22])=[N:3][CH:4]=1
Reactant: CNc1nc(Cl)ncc1F
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: C1COCCO1
Product: CNc1nc(Nc2ccc(C(=O)O)cc2OC)ncc1F
Temperature: 120 °C
Yield: 88.4 %

Procedure:
A mixture of 50 mg 2-chloro-5-fluoro-N-methylpyrimidin-4-amine, 57 mg 4-Amino-3-methoxybenzoic acid, 0.1 mL 4N HCl in 1,4-dioxane and 1 mL N-butanol was placed in a 10 mL snap-top microwave vial (CEM Corp.) and heated to 120° C. microwave for 40 min. The reaction was monitored by LC/MS. The precipitated solid was filtered to yield 80 mg of 4-(5-fluoro-4-(methylamino)pyrimidin-2-ylamino)-3-methoxybenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:16]=[C:15]([CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1)[NH2:17]
Reactant: Cc1cccc(COc2ccc([N+](=O)[O-])cc2Cl)n1
Agent: [Fe]
Solvent: CC(=O)O
Product: Cc1cccc(COc2ccc(N)cc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
2-[(2-chloro-4-nitrophenoxy)methyl]-6-methylpyridine (4.87 g, 17.5 mmol) and iron powder (4.87 g, 87.4 mmol) were mixed in 150 mL acetic acid, and were stirred at rt overnight. The reaction mixture was filtered through a pad of Celite®, and washed with EtOAc. The filtrate was concentrated in vacuo and neutralized with saturated Na2CO3 solution. The contents were extracted with EtOAc (5×300 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude material was triturated with Hex/EtOAc (2:1) to afford 3-chloro-4-[(6-methylpyridin-2-yl)methoxy]aniline (3.84 g, 88%) as a white solid. 1H-NMR (DMSO) δ 7.70 (dd, 1H), 7.31 (d, 1H), 7.17 (d, 1H), 6.88 (d, 1H), 6.65 (d, 1H), 6.44 (dd, 1H), 5.01 (s, 2H), 4.93 (s, 2H), 2.46 (s, 3H); LCMS RT=0.25 min; [M+H]+=249.2.
Reaction SMILES: C(O[Cl:6])(C)(C)C.[CH2:7]([O:9][C:10]([CH:12]1[CH2:21][C:20]2[C:15](=[C:16]([O:24][CH3:25])[CH:17]=[CH:18][C:19]=2[O:22][CH3:23])[CH2:14][O:13]1)=[O:11])[CH3:8]>C(Cl)Cl>[CH2:7]([O:9][C:10]([CH:12]1[CH2:21][C:20]2[C:15](=[C:16]([O:24][CH3:25])[C:17]([Cl:6])=[CH:18][C:19]=2[O:22][CH3:23])[CH2:14][O:13]1)=[O:11])[CH3:8]
Reactant: CCOC(=O)C1Cc2c(OC)ccc(OC)c2CO1
Reactant: CC(C)(C)OCl
Solvent: ClCCl
Product: CCOC(=O)C1Cc2c(OC)cc(Cl)c(OC)c2CO1
Reaction time: 3 h
Yield: 46 %

Procedure:
Under argon and at room temperature, was added dropwise 0.820 g (7.6 mmol) of t-butylhypochlorite to a stirred solution containing 1.973 g (7.4 mmol) of the isochroman from step 5 in 75 ml of anhydrous CH2Cl2. The reaction mixture was stirred for 3 hours and then washed successively with 25 ml portions of saturated aqueous sodium thiosulfate, water and brine. After drying over Na2SO4, the organic layer was evaporated and the residue was flash chromatographed with 2.5% ethyl acetate in toluene as the eluting solvent mixture. The title compound was obtained in 46% yield (1.02 g). (MP: 95.0° C.) 1H NMR (200 MHz, CDCl3) δ: 1.35 (t, 3H, J=7.1 Hz, CH3), 2.93 (broad dd, J=16.8, 10.3 Hz, HCHaCHC=O), 3.16 (broad dd, J=16.9, 3.2 Hz, HCHeCHC=O), 3.78 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 4.27 (dd, J=10.2, 3.3 Hz, --CH), 4.31 (q, 2H, J=7.1Hz, OCH2), 4.63 (broad d, 1H, J=16.2 Hz, HCHa0), 5.01 (d, 1H, J=16.2 Hz, HCHe0), 6.73 (s, 1H, ArH).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C@H:15]2[CH2:18][C@@H:17]([O:19][CH3:20])[CH2:16]2)[C:13]2[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:25][C:22]1[CH:23]=[CH:24][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:14]([C@H:15]3[CH2:18][C@@H:17]([O:19][CH3:20])[CH2:16]3)[C:13]=2[CH:21]=1
Reactant: CO[C@H]1C[C@@H](n2c([C@H](C)NC(=O)OC(C)(C)C)nc3ccc(F)cc32)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CO[C@H]1C[C@@H](n2c([C@H](C)N)nc3ccc(F)cc32)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of {(S)-1-[6-fluoro-1-(cis-3-methoxycyclobutyl)1Hbenzoimidazol-2-yl]ethyl}carbamic acid tert-butyl ester (0.22 g, 0.61 mmol) in DCM (5 mL) was added TFA (3 mL) and the mixture was stirred at RT for 1.5 h. The volatiles were removed in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo. The crude material was used in the following step without further purification. Yellow oil (quantitative). LCMS (Method B): RT 1.72 min [M+H]+ 263.90.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([O-:14])=[O:13]>ClCCl>[CH:1]([NH:4][S:21]([C:18]1[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:20][CH:19]=1)(=[O:22])=[O:23])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.7 %

Procedure:
To a stirred solution of isopropylamine (6.8 mL, 79.6 mmol) and triethylamine (16.6 mL, 119.4 mmol) in dichloromethane (300 mL) was added the solution of 4-nitro-benzenesulfonyl chloride (8.8 g, 39.8 mmol) in dichloromethane (50 mL) at 0° C. The mixture solution stirred at room temperature for 4 h. The mixture solution was stirred at room temperature for 4 h and then washed with brine (50 mL×2) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford N-isopropyl-4-nitro-benzenesulfonamide (9.3 g, 96%) as a white powder: MS (ESI) M+1=245.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]C)=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:15]I>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1
Reactant: CI
Reactant: COC(=O)Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C(=O)O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl (4-fluorophenyl)acetate (0.5 g) was dissolved in DMF (81 mL). The mixture was cooled in an ice bath and NaH (131 mg, 60% w/w in mineral oil) was added. The mixture was stirred for 1 h at RT and again cooled in an ice bath before the addition of MeI (633 mg). The mixture was warmed to RT and, the reaction was quenched with ½ (sat.) aqueous ammonium chloride. Work up consisted of extraction of the aqueous layer with ether (2×). The combined organic fractions were washed with water and brine, then dried (MgSO4). The solvent was evaporated under reduced pressure and methyl 2-(4-fluorophenyl)propanoate was purified on silica gel (ethyl acetate/hexanes). Methyl 2-(4-fluorophenyl)propanoate (420 mg) was dissolved in 12 mL THF and 6 mL MeOH. 6 mL of KOH (2M) was added and the mixture was stirred for 2 h at RT. Water was added and the organic solvents were removed. The base was quenched with icy hydrochloric acid (1N), DCM was added and the phases separated with a phase separator. The solvent was removed under reduced pressure to provide the title compound.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:18]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][Br:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1-c1cccc2ccccc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccccc1-c1cccc2ccccc12
Yield: 91.2 %

Procedure:
114 g (0.52 mol) of 18 and 103 g (0.58 mol) of N-bromo-succinimide were dissolved in 2000 cm3 of tetrachloromethane at room temperature, 3 g of azobisisobutyronitrile were added, and the mixture was refluxed for 4 hours. The succinimide which precipitated was filtered off, the solvent was removed in vacuo, and the residue was purified by filtration through 1000 g of silica gel (hexane/methylene chloride 9:1), giving 141 g (82%) of 19 as a colorless lachrymatory oil.
Reaction SMILES: CC1C(O[C@@H]2O[C@H](C)[C@@H](O)[C@H](O[C@H]3O[C@H](C)[C@@H](O)[C@H](O)C3)C2)=C[C:5]2[C:10](C=1O)=[C:9](O)[C:8]1C([C@@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@H](O[C@H]4O[C@H](C)[C@H](O[C@H]5O[C@H](C)[C@@H](O)[C@](O)(C)C5)[C@H](O)C4)C3)[C@H:17]([C@H:19](OC)[C:20]([C@@H:22](O)[C@H:23](O)C)=O)[CH2:18][C:7]=1[CH:6]=2)=O.[OH-].[Na+].C[N:80](C)C=O>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].O>[CH:9]1[C:8]2[NH:80][C:17]3[C:18](=[CH:23][CH:22]=[CH:20][CH:19]=3)[C:7]=2[CH:6]=[CH:5][CH:10]=1
Reactant: CN(C)C=O
Reactant: CO[C@H](C(=O)[C@@H](O)[C@@H](C)O)[C@@H]1Cc2cc3cc(O[C@H]4C[C@@H](O[C@@H]5C[C@@H](O)[C@H](O)[C@@H](C)O5)[C@H](O)[C@@H](C)O4)c(C)c(O)c3c(O)c2C(=O)[C@H]1O[C@H]1C[C@@H](O[C@@H]2C[C@@H](O)[C@@H](O[C@@H]3C[C@](C)(O)[C@H](O)[C@@H](C)O3)[C@@H](C)O2)[C@H](O)[C@@H](C)O1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc2c(c1)[nH]c1ccccc12

Procedure:
Heparin adipic hydrazide (70 mg) was dissolved in 6 ml of 0.1M sodium phosphate buffer, pH 5.8. Mithramycin (10 mg) was dissolved in 1 ml dimethylformamide and this solution was mixed with the heparin adipic hydrazide solution and left for 21/2% days at room temperature. The reaction mixture was then applied to a column of Sephadex G25 equilibrated in H2O whose pH had been raised to approximately 10 by the addition of dilute NaOH. The conjugate, which elated in the void volume, was collected and freeze dried. Quantitation of the drug by u.v spectrophotometric analysis and of the heparin by carbazole assay gave the composition of the conjugate as 0.54 mol mithromycin:mol heparin. The conjugate (Table III) has the structure shown in FIG. 2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].BrC1C=C(O)C=CC=1.[C:18]1([CH:24]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27](=[O:34])[C:26]2=[O:35])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.FC(F)(F)C1OC(CN2C3C(=CC=CC=3)C(=O)C2=O)=CC=1>>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:27]2([OH:34])[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:25]([CH:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:26]2=[O:35])=[C:4]([OH:9])[CH:3]=1
Reactant: Oc1ccc(F)c(F)c1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Agent: Oc1cccc(Br)c1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc(F)c(F)cc1O

Procedure:
Following the procedure as described in PREPARATION 2A and making non-critical variations using 3,4-difluorophenol to replace 3-bromophenol, and 1-(diphenylmethyl)-1H-indole-2,3-dione to replace 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione, 3-(4,5-difluoro-2-hydroxyphenyl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one was obtained (61%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ9.23 (br s, 1H), 7.47-7.44 (m, 1H), 7.35-7.21 (m, 9H), 7.18-7.11 (m, 2H), 6.90 (s, 1H), 6.83 (dd, J=11.2, 6.9 Hz, 1H), 6.67 (dd, J=11.2, 8.7 Hz, 1H), 6.56-6.51 (m, 1H), 4.13 (br s, 1H); MS (ES+) m/z 426.2 (M−17).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([CH3:12])=[C:10](Cl)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[CH3:14][CH:15]1[CH2:20][CH:19]([CH3:21])[CH2:18][NH:17][CH2:16]1>C(O)C>[CH2:1]([O:5][C:6]1[C:11]([CH3:12])=[C:10]([N:17]2[CH2:18][CH:19]([CH3:21])[CH2:20][CH:15]([CH3:14])[CH2:16]2)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ncnc(Cl)c1C
Reactant: CC1CNCC(C)C1
Solvent: CCO
Product: CC#CCOc1ncnc(N2CC(C)CC(C)C2)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.1 %

Procedure:
Into 3 ml of ethanol was resolved 0.3 g of 4-(2-butynyloxy)-6-chloro-5-methylpyrimidine, 0.47 g of 3,5-dimethylpiperidine (cis/trans=about 3/1) was added therein, and the mixture was stirred for 16 hours under reflux condition. The reaction mixture was cooled to near room temperature, and concentrated. Into the residue was added a saturated ammonium chloride aqueous solution, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.33 g of 4-(2-butynyloxy)-5-methyl-6-(3,5-dimethylpiperidino)pyrimidine (hereinafter, referred to as Compound (9)). Compound (9) had the cis/trans diastereomer originated two methyls on the piperidine ring. The ratio of the cis/trans diastereomer was about 3.8/1.