Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH2:6]O)=[C:4]([F:11])[CH:3]=1.C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH2:6][Br:13])=[C:4]([F:11])[CH:3]=1
Reactant: OCc1cc(F)c(Br)cc1F
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cc(CBr)c(F)cc1Br
Reaction time: 2 h
Yield: 87.4 %

Procedure:
To a solution of 2 g (8.44 mmol) of 4-bromo-2,5-difluorobenzoic acid (prepared according to the procedure of Ishikawa et al., Kogyo Kagaku Zasshi, pg 972-979, 1970) in 20 mL of tetrahydrofuran was added 40 mL of a 1M solution of borane-tetrahydrofuran complex. The solution was heated under reflux for 64 h, cooled to ambient temperature and 100 mL of methanol was added. The reaction was then heated for a further 2 h, cooled and concentrated in vacuo. Purification by flash chromatography (silica gel, 9:1 hexane:ethyl acetate) afforded 1.6 g of 4-bromo-2,5-difluorobenzyl alcohol. To a solution of 1.3 g (5 6 mmol) of 4-bromo-2,5-difluorobenzyl alcohol in 20 mL of dichloromethane at 0° C. was added 2.27 g (6.7 mmol) of carbon tetrabromide and 1.8 g (6.7 mmol) of triphenylphosphine. The reaction was stirred for 2 h at this temperature, the solvent was removed in vacuo and the residue stirred with 100 mL of diethyl ether. The solution was filtered, concentrated in vacuo, and purified by flash chromatography (silica gel, 9:1 hexane:ethyl acetate) to afford 1.5 g of the title compound.
Reaction SMILES: C(N)CCC.[Cl:6][C:7]1[CH:8]=[C:9]([O:34]C(=O)C2C=CC=CC=2)[CH:10]=[C:11]([Cl:33])[C:12]=1[O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:28]([S:29][CH:30]([CH3:32])[CH3:31])=[N:27][N:26]=[N:25]2)=[CH:20][CH:19]=1>>[Cl:33][C:11]1[CH:10]=[C:9]([OH:34])[CH:8]=[C:7]([Cl:6])[C:12]=1[O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[C:28]([S:29][CH:30]([CH3:32])[CH3:31])=[N:27][N:26]=[N:25]2)=[CH:22][CH:23]=1
Reactant: CC(C)Sc1nnnn1-c1ccc(OCCCOc2c(Cl)cc(OC(=O)c3ccccc3)cc2Cl)cc1
Solvent: CCCCN
Product: CC(C)Sc1nnnn1-c1ccc(OCCCOc2c(Cl)cc(O)cc2Cl)cc1
Reaction time: 0.5 h

Procedure:
3.5 ml of n-butylamine are added dropwise at 0-5° C. to a solution of 2 g of benzoic acid 3,5-dichloro-4-{3-[4-(5-isopropylsulfanyl-tetrazol-1-yl)-phenoxy]-propoxy}-phenyl ester. After 30 minutes at 0-5° C. and one hour at room temperature, the reaction mixture is concentrated. Purification over silica gel yields 3,5-dichloro-4-{3-[4-(5-isopropylsulfanyl-tetrazol-1-yl)-phenoxy]-propoxy}-phenol. 1H-NMR (CDCl3) 300 MHz: 1.50 (d, 2H), 2.32 (m, 2H), 4.08-4.20 (m, 3H), 4.35 (t, 2H), 5.62 (s, 1H), 6.82 (s, 2H), 7.09 (d, 2H), 7.45 (d, 2H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:12](Cl)(=O)[C:13](Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].Cl.[OH-].[Na+]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([C:7]([C:2]2[CH:3]=[CH:4][C:12]([CH3:13])=[CH:6][CH:10]=2)=[O:9])[CH:10]=1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2cc(Br)ccc2Cl)cc1
Temperature: -10 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of compound 5-bromo-2-chlorobenzoic acid (20 g, 85.5 mmol) in 200 mL of CH2Cl2 containing oxalyl chloride (11.2 mL) was added 0.5 mL of DMF. Once the vigorous evolution of gas ceased, the reaction was stirred overnight and then the volatiles were removed under reduced pressure. After dissolving the crude 5-bromo-2-chlorobenzoyl chloride in 150 mL of toluene, the solution was cooled to −10° C. Then AlCl3 (22.4 g, 170 mmol) was added while insuring the temperature did not exceed 0° C. HCl gas emission was trapped by passing the gas over a stirred concentrated NaOH solution. HPLC-MS revealed the reaction to be 98% complete after the addition was finished. The reaction was quenched by pouring over ice. The suspension was diluted with H2O and extracted 3× with CH2Cl2. The combined organic extracts were washed 2× with 1N HCl, 1× with H2O, 2× with 1M NaOH, and 2× with brine prior to drying over Na2SO4. After removal of the volatiles, crystallization of the crude product from ethanol (80 mL) yielded intermediate AG (16 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@@H:3]([OH:9])[C@H:4]([CH:6]1[CH2:8][CH2:7]1)[OH:5].[NH:17](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:18]([C:42](O)=[O:43])[CH2:19][C:20]1[N:24]=[CH:23][N:22](C(OCC2C3C(=CC=CC=3)C3C2=CC=CC=3)=O)[CH:21]=1.C(N1CCOCC1)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C=O.C(Cl)Cl.N1CCCCC1>[NH2:17][C@@H:18]([CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1)[C:42]([NH:1][C@@H:2]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@@H:3]([OH:9])[C@H:4]([CH:6]1[CH2:8][CH2:7]1)[OH:5])=[O:43]
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reactant: O=C(N[C@@H](Cc1cn(C(=O)OCC2c3ccccc3-c3ccccc32)cn1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reaction time: 8 h
Yield: 70.9 %

Procedure:
A mixture of 343 mg (1.51 mmol) of (1S,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-l,2-butanediol, 995mg (1.66mmol) of Fmoc-His(Fmoc)-OH, 0.21 ml (1.61 mmol) of 4-ethylmorpholine, 449 mg (3.22 mmol) of HOBT and 347 mg (1.81 mmol) of EDC in 20 ml of dimethylformamide was left to stand at room temperature overnight. Thereafter, the reaction mixture was evaporated in a high vacuum, the residue was poured into a mixture of ice and 90 ml of sodium bicarbonate solution and extracted three times with 150 ml of ethyl acetate each time. The three ethyl acetate extracts were washed in succession with 70 ml of saturated ammonium chloride solution, 70 ml of 2N sodium bicarbonate solution and 70 ml of saturated sodium chloride solution, combined, dried over magnesium sulphate, filtered and evaporated. The crude product obtained was stirred at room temperature for 3 hours in 60 ml of methylene chloride and 2 ml of piperidine. Then, the reaction mixture was evaporated and the residue was triturated with 50 ml of hexane and filtered off. The filtrate was chromatographed on 70 g of silica gel with a 65:10:1 mixture of methylene chloride, methanol and ammonia as the eluent, whereby there were obtained 390 mg of (S)-α-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]imidazole-4-propionamide as a colourless foam; MS: 365 (M+H)+.
Reaction SMILES: [OH-:1].[Al+3:2].[OH-].[OH-].[P:5]([O-:9])([O-:8])([O-:7])=[O:6].[Na+].[Na+].[Na+]>O>[P:5](=[O:6])([OH:9])([OH:8])[OH:7].[OH-:1].[Al+3:2].[OH-:6].[OH-:6]
Reactant: O=P([O-])([O-])[O-]
Agent: [Al+3]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=P(O)(O)O

Procedure:
Aluminum hydroxide as a starting raw material was first ground in a ball mill, etc. and adjusted to a particle size of 1.0 μm. This product was mixed with water to produce a 50% by weight slurry containing the raw material particles in an amount of 50% by weight based on the weight of the slurry. Sodium phosphate was added to this slurry to give as phosphoric acid ions in an amount of 5.0×10−3 mol per mol of aluminum hydroxide, and was thoroughly mixed and dissolved.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([C:22](=[O:28])[C:23]([C:26]#[N:27])([CH3:25])[CH3:24])[CH:14]2[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]2)[CH2:10][C@H:9]1[C:29]([N:31]([CH3:33])[CH3:32])=[O:30])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H][H]>CO.[Pd]>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([C:22](=[O:28])[C:23]([CH3:24])([CH3:25])[CH2:26][NH2:27])[CH:14]2[CH2:19][CH2:18][C:17]([CH3:20])([CH3:21])[CH2:16][CH2:15]2)[CH2:10][C@H:9]1[C:29]([N:31]([CH3:32])[CH3:33])=[O:30])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: [H][H]
Reactant: CN(C)C(=O)[C@@H]1C[C@H](N(C(=O)C(C)(C)C#N)C2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)[C@@H]1C[C@H](N(C(=O)C(C)(C)CN)C2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C
Yield: 77.9 %

Procedure:
To a solution of 1-BOC-(2S,4S)-4-[(2-cyano-2-methylpropanoyl)(4,4-dimethylcyclohexyl)amino]-2-[(dimethylamino)carbonyl]pyrrolidine (1.07 g, 2.31 mmol) prepared in Step A in methanol was added Pd/C (9 mg), and carried out hydrogen reaction at rt for 10 h. After the reaction finished, the reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo, and purified by HPLC to give the title compound (0.84 g, 78%).
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[O:34][C:35]1[CH:40]=[C:39](Cl)[N:38]=[CH:37][N:36]=1)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1.[CH:51]([N:54](C(C)C)[CH2:55]C)(C)C.CNC.O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[O:34][C:35]1[CH:40]=[C:39]([N:54]([CH3:55])[CH3:51])[N:38]=[CH:37][N:36]=1)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2Oc2cc(Cl)ncn2)nc1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2Oc2cc(N(C)C)ncn2)nc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(6-chloro-pyrimidin-4-yloxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (170 mg) is dissolved in toluene (5 ml), and thereto are added diisopropylethylamine (136 μl), 2.0M-dimethylamine/tetrahydrofuran solution (0.4 ml) and the mixture is stirred at 50° C. for 1 day. The reaction solution is cooled to room temperature, and thereto are added aqueous citric acid solution and ethyl acetate, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=4:1→2:1) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(6-dimethylamino-pyrimidin-4-yloxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (115 mg). MS (m/z): 747 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](O)[CH:8]=[C:7]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1.O=P(Cl)(Cl)[Cl:24]>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:24])[CH:8]=[C:7]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1
Reactant: Oc1cc(Nc2ccc(Cl)c(Cl)c2)c2cccc(Br)c2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cc(Nc2ccc(Cl)c(Cl)c2)c2cccc(Br)c2n1
Yield: 38.8 %

Procedure:
8-Bromo-2-hydroxy-4-(3,4-dichlorophenyl)aminoquinoline (3.52 g, 9.16 mmol) and 26 mL of POCl3 were heated to 120° C. for 4 h. The bulk of the POCl3 was distilled (˜18 mL), and the reaction cooled. The solution was poured slowly onto warm water to get a gummy solid. The water was decanted and the solids washed with several portions of water. A final wash with toluene and drying under vacuum afforded 1.43 g of material (3.55 mmol, 38.8%). 1H NMR (300 MHz, DMSO): 9.58(s, 1H), 8.39(d, 1H, J=8.48 Hz), 8.15(d, 1H, J=7.67 Hz), 7.70(d, 1H, J=8.88 Hz), 7.66(d, 1H, J=2.42 Hz), 7.51(dd, 1H, J=8.48, 7.67 Hz), 7.44(d, 1H, J=8.88, 2.42 Hz), 6.90(s, 1H).
Reaction SMILES: O=[C:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][O:4][C:5](=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].C([NH2:26])(=O)C.B(F)(F)F.CCOCC>C([O-])(O)=O.[Na+]>[CH3:15][O:14][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1[O:4][CH:3]=[C:2]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:26]=1
Reactant: COC(=O)CCCCCCC(=O)OCC(=O)c1ccccc1
Reactant: CC(N)=O
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: COC(=O)CCCCCCc1nc(-c2ccccc2)co1
Yield: 87.8 %

Procedure:
Heat a mixture of octanedioic acid methyl ester 2-oxo-2-phenylethyl ester (6.93 g, 22.6 mmol), acetamide (6.75 g, 114 mmol) and boron trifluoride diethyl etherate (3.0 mL, 23.7 mmol) at 135-140° C. under nitrogen for 4 hours. Cool the mixture, dilute with saturated NaHCO3 solution (100 mL), and extract with ethyl acetate (250 mL). Wash the organic extract with 100 mL of saturated aqueous sodium chloride (brine) and dry over sodium sulfate. Remove the solvent under reduced pressure and purify the residue by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (85:15), to provide 7-(4-phenyloxazol-2-yl)heptanoic acid methyl ester (5.7 g, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(Oc2ccccc2)cc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(Oc2ccccc2)ccc1C(=O)O
Temperature: 20 °C
Reaction time: 4 h
Yield: 81.9 %

Procedure:
A mixture of methyl 2-methoxy-4-phenoxybenzoate (1.3 g, 5 mmol), lithium hydroxide monohydrate (571 mg, 13.6 mmol), tetrahydrofuran (150 mL), methanol (50 mL) and water (50 mL) was stirred at 20° C. for 4 hours. The mixture was adjusted to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (15 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to give 2-methoxy-4-phenoxybenzoic acid (1 g, 82%).
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH2:13][CH2:14][S:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=2)[CH2:8][C:7]1=[O:26])(=O)[CH2:2][CH2:3][CH3:4].Cl.[CH2:28]([O:30][NH2:31])[CH3:29].[OH-].[Na+]>C(O)C.O>[CH2:28]([O:30][NH:31][C:1](=[C:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH2:13][CH2:14][S:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][N:17]=2)[CH2:8][C:7]1=[O:26])[CH2:2][CH2:3][CH3:4])[CH3:29]
Reactant: CCON
Reactant: CCCC(=O)C1C(=O)CC(CCSc2ccc(C(F)(F)F)cn2)CC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCC(NOCC)=C1C(=O)CC(CCSc2ccc(C(F)(F)F)cn2)CC1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
0.6 Gram of 2-butyryl-5-[2-(5-trifluoromethyl-2-pyridylthio)ethyl]cyclohexane-1,3-dione was dissolved in a mixed solvent of 10 ml of ethanol and 1 ml of water, and 0.2 g of ethoxyamine hydrochloride and 0.07 g of sodium hydroxide were added to the resulting solution which was then stirred at room temperature for 2.5 hours. The reaction solution was poured into water, weakly acidified and extracted with ethyl acetate. After removing ethyl acetate, the residue was purified by thin layer chromatography (eluent, hexane:ethyl acetate=5:1) to obtain 0.45 g of 2-(1-ethoxyaminobutylidene)-5-[2-(5-trifluoromethyl-2-pyridylthio)ethyl]cyclohexane-1,3-dione.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21]4[CH:22]=[C:23]([CH:30]=[CH:31][CH:32]=4)[C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])=[CH:14][CH:15]=3)[O:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21]4[CH:22]=[C:23]([CH:30]=[CH:31][CH:32]=4)[C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])=[CH:14][CH:15]=3)[O:10][CH:9]=2)=[CH:6][CH:7]=1)(=[O:42])=[O:41]
Reactant: C=CCOC(=O)c1cccc(COc2ccc3c(=O)c(-c4ccc(N)cc4)coc3c2)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)c1cccc(COc2ccc3c(=O)c(-c4ccc(NS(C)(=O)=O)cc4)coc3c2)c1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a mixture of prop-2-enyl 3-{[3-(4-aminophenyl)-4-oxochromen-7-yloxy]methyl}benzoate, prepared as described in Example 7A, (169.5 mg, 0.397 mmol) and anhydrous pyridine (34.5 mg, 0.44 mmol) in dry methylene chloride (3 ml) at 0° C. was added methanesulfonyl chloride (68.1 mg, 0.60 mmol). The mixture was then stirred at room temperature for 21 hours, then mixed with silics gel and the solvent removed under reduced pressure. Flash chromatography of the silica gel mixture, eluting with methylene chloride/methanol (99.5/0.5) gave prop-2-enyl 3-[(3-{4-[(methylsulfonyl)amino]phenyl}-4-oxochromen-7-yloxy)methyl]benzoate as a white solid (160.9 mg). (ESI) m/z 506 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]>CC(C)CO>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:2][CH:1]([CH3:4])[CH3:3])=[CH:15][CH:16]=1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O)cc1)c1ccc(Cl)c(Cl)c1
Solvent: CC(C)CO
Product: CC(C)COc1ccc(C(=O)C(NC(=O)OC(C)(C)C)c2ccc(Cl)c(Cl)c2)cc1

Procedure:
The title compound was prepared from rac-[1-(3,4-dichloro-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and 2-methyl-1-propanol in analogy to Example 9c): MS (ISP): 452.1 and 454.1 (M+H)+, 352.1 and 354.2 ((M-Boc)+H)+ (100%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:9](F)[N:8]([C@@H:25]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:37][O:38][Na]>CO>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:9]([O:38][CH3:37])[N:8]([C@@H:25]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2c(F)c(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Reactant: CO[Na]
Solvent: CO
Product: COc1c(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc2n1[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Yield: 90 %

Procedure:
To a solution of (R)-tert-butyl 3-(4-amino-6-fluoro-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (3) (250 mg, 0.51 mmol) in MeOH was added MeONa. The resulting mixture was heated to reflux under N2 overnight. After cooling down to r. t., the reaction mixture was concentrated and the residue was partitioned between DCM and water. The layers were separated. The organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give (R)-tert-butyl 3-(4-amino-6-methoxy-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (87) (230 mg, 90% yield) as a yellow solid. LC-MS (ESI): m/z (M+1) 502.1.
Reaction SMILES: [CH3:1][P:2]([C:6]1[CH:11]=[C:10]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:8][C:7]=1[N+:19]([O-])=O)(=[O:5])[O:3][CH3:4].[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH3:1][P:2]([C:6]1[CH:11]=[C:10]([S:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:9]=[CH:8][C:7]=1[NH2:19])(=[O:5])[O:3][CH3:4]
Reactant: COP(C)(=O)c1cc(Sc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COP(C)(=O)c1cc(Sc2ccccc2)ccc1N

Procedure:
To a mixture of methyl P-methyl-2-nitro-5-phenylthiophenylphosphinate (3.0 g) and ammonium chloride (5.3 g) in 40 ml of ethanol and 20 ml of water is heated to 70°, and iron (3.0 g) is added portionwise over a period of about 10 minutes. After the reaction is completed, the reaction mixture is filtered and the filtrate is concentrated to a small volume, followed by extraction with methylene chloride, drying and evaporation to give methyl P-methyl-2-amino-5-phenylthiophenylphosphinate.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([NH:12][C@H:13]([C:21]([NH:23][C@H:24]([C:31]([NH:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[O:32])[CH2:25][O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[BrH:49].[ClH:50].O1CCOCC1>CO.[Pd]>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:21]([NH:23][C@H:24]([C:31]([NH:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[O:32])[CH2:25][O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:22])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9].[ClH:50].[BrH:49]
Reactant: COC(=O)CNC(=O)[C@H](COC(C)(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCNC(=N)N)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Br
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)CNC(=O)[C@H](COC(C)(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CCCNC(=N)N

Procedure:
6.3 g of Z-Arg-Phe-Ser(tBu)-Gly-OCH3 hydrobromide (8.5 mmols) are dissolved in 350 ml of methanol and 2.9 ml of hydrogen chloride in dioxane (3.09 N, 8.9 mmols) are added. The mixture is hydrogenated in the presence of 1.2 g of 10 % strength palladium-charcoal at room temperature and atmospheric pressure. After completion of the hydrogen uptake the solution is filtered and evaporated and the resulting residue is dissolved in 30 ml of methanol and the solution stirred into 700 ml of ether. Thereby a yellowish paste is produced which is again dissolved and precipitated in the same manner.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:17]([O-:20])([O-:19])=[O:18].[Na+:21].[Na+].COC(C)(C)C>O>[Na+:21].[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][S:17]([O-:20])(=[O:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S([O-])[O-]
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: O=S(=O)([O-])Cc1ccc(OCc2ccccc2)cc1
Temperature: 75 °C
Reaction time: 21 h
Yield: 18.8 %

Procedure:
A mixture of 25.51 g of 4-benzyloxybenzyl chloride and 28.78 g of sodium sulfite in 96 ml of water was stirred at 75° C. for 21 hours. After cooling to room temperature, the reaction solution was stirred with 100 ml of tert-butyl methyl ether, and the solids were filtered off with suction, washed twice with 20 ml of tert-butyl methyl ether, once with 20 ml of ice-water, twice with 20 ml of acetone and twice with 20 ml of dichloromethane. The precipitate was dried in a vacuum drying cabinet at 40° C. overnight. This gave the product (6.20 g) with a molecular weight of 300.3 g/mol (C14H13O4S.Na); MS (ESI): m/e=301 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=O)=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CC(C1C=CC(F)=CC=1O)=O.[C:35](=O)([O-:37])[O-:36].[K+].[K+]>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[O:37]1[C:6]2[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=2[CH:8]=[CH:9][C:35]1=[O:36]
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: CC(=O)c1ccc(F)cc1O
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccc2ccccc2o1
Temperature: 80 °C
Yield: 37 %

Procedure:
A solution of 4-chlorophenylacetic acid (11.05 g, 64.8 mmol) in DMF (100 mL) was treated with CDI (13.13 g, 81 mmol) in several portions over about 15 minutes and the mixture was stirred until gas evolution had ceased. 4-Fluoro-2-hydroxyacetophenone (5.0 g, 32.4 mmol) was added followed by potassium carbonate (15.7 g, 113.6 mmol) and 4-DMAP (about 1 g). The reaction mixture was warmed at about 80° C. for about 10 h then cooled to room temperature. Water (200 mL) was added and the aqueous layer was extracted with ethyl acetate. The combined organic layer was concentrated and the crude product was purified by flash chromatography (ethyl acetate/hexanes) to give a yield of about 3.5 g (38%) of a benzopyranone intermediate.