Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][C:19](O)=[O:20])[C:13]1=[O:22].B>C1COCC1.ClCCl.[OH-].[Na+]>[CH3:11][C:4]1[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([CH3:1])[C:3]=1[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][OH:20])[C:13]1=[O:22]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1-n1cccc(CC(=O)O)c1=O
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc([N+](=O)[O-])cc(C)c1-n1cccc(CCO)c1=O
Temperature: 27 °C
Reaction time: 1 h

Procedure:
26.5 g (87.7 mmol) of [1-(2,6-dimethyl-4-nitrophenyl)-2-oxo-1,2-dihydropyridin-3-yl]acetic acid were introduced as initial charge in 265 ml of THF at RT. 132 ml of 1M borane solution in THF (132 mmol) were added dropwise. During this addition, the temperature increased to 27° C. The reaction mixture was stirred for 1 h at RT and then the same amount of borane solution was added. The reaction mixture was stirred overnight at RT. It was diluted with 500 ml of dichloromethane, and 500 ml of 1N sodium hydroxide solution were added with cooling. The reaction mixture was stirred for 30 min, the phases were separated and the organic phase was washed with water, dried over sodium sulphate, filtered and evaporated to dryness on a rotary evaporator. This gave 12.6 g (48%) of the desired product as crystalline solid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([F:45])[C:27]([F:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:50][B-](F)(F)F.ClC1C=CC=C(Cl)[N+]=1F.O.O[Li].O>CC#N>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[C:36]([F:50])[N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([F:45])[C:27]([F:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)c(F)cc1-c1cccc-3c1
Reactant: F[B-](F)(F)F
Agent: F[n+]1c(Cl)cccc1Cl
Agent: [Li]O
Solvent: O
Solvent: CC#N
Product: Cc1cc2nc3c(F)n2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)c(F)cc1-c1cccc-3c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 5.2 %

Procedure:
To a solution of methyl(2S)-2-(tert-butoxy)-2-[(22S)-17,18-difluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (22 mg, 0.033 mmol, 1 equiv) in MeCN (0.33 mL) was added 2,6-dichloro-1-fluoropyridin-1-ium, tetrafluoroborate salt (8 mg, 0.031 mmol, 1 equiv). The reaction turned dark orange. After 3 h, the reaction was concentrated in vacuo. The crude fluoride product was taken up in 9:1 MeOH:water (1.8 mL) and LiOH.H2O (27 mg, 0.651 mmol, 20 equiv) was added. The reaction was heated to 60° C. for 4 h. Upon cooling to ambient temperature, the reaction was filtered and purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 40-90% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to provide the product (1.1 mg, 5%) 1H NMR (400 MHz, CD3OD) δ 8.33 (d, J=1.5 Hz, 1H), 7.97 (d, J=8.1 Hz, 1H), 7.57 (t, J=7.7 Hz, 1H), 7.37-7.33 (m, 1H), 7.32-7.27 (m, 1H), 7.19 (s, 1H), 7.11 (dd, J=12.8, 7.0 Hz, 1H), 6.04 (br. s., 1H), 4.56 (d, J=5.9 Hz, 1H), 3.76-3.48 (m, 4H), 3.28 (d, J=11.0 Hz, 1H), 2.71 (d, J=6.8 Hz, 1H), 2.53 (s, 3H), 2.09-1.64 (m, 10H), 1.28 (s, 9H), 1.27 (s, 3H), 1.19 (d, J=6.1 Hz, 3H); LCMS (ESI, M): 679.3.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Ca+2].[OH-].[Cl:12][CH2:13][CH2:14]CC(Cl)=O.CO.Cl>C1(C)C=CC=CC=1>[CH3:8][O:7][C:1](=[O:6])[CH2:2][C:3](=[O:4])[CH2:5][CH2:14][CH2:13][Cl:12]
Reactant: O=C(Cl)CCCCl
Reactant: COC(=O)CC(C)=O
Agent: Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)CC(=O)CCCCl
Temperature: 60 °C
Reaction time: 1 h

Procedure:
In an atmosphere of nitrogen, methyl acetoacetate (480 g, 4.14 mol), calcium hydroxide (80.0 g, 1.08 mol) and toluene (4822 ml) were added to a 10 liter capacity flask, and dehydration/draining was carried out under toluene reflux. After 1 hour, by cooling to 60° C., 4-chlorobutanoic acid chloride (254 g, 1.8 mol) was added dropwise thereto, followed by stirring at 60° C. Further 1 hour thereafter, methanol (1325 g, 41.4 mol) was added thereto, followed by stirring for 6 hours under methanol reflux. After completion of the reaction, the reaction was stopped with 432 ml (2.16 mol) of 5 N hydrochloric acid, and then the organic layer was separated and the organic layer was washed with 5% sodium carbonate aqueous solution and water. After evaporation of the solvent under a reduced pressure using an evaporator, the residue was distilled under a reduced pressure (75 to 85° C./0.1 ton) to obtain crude 6-chloro-3-oxo-hexanoic acid methyl ester (1); 214.9 g (GC purity; δ 0.3%).
Reaction SMILES: [NH4+:1].[NH4+].C([NH:11][C:12]1[N:20]=[CH:19][N:18]=[C:17]2[C:13]=1[N:14]=[CH:15][N:16]2[CH:21]1[O:25][CH:24]([CH:26]=[CH:27][P:28](=[O:31])([O-:30])[O-:29])[CH:23]([OH:32])[CH:22]1[F:33])(=O)C1C=CC=CC=1>[NH4+].[OH-]>[NH4+:11].[NH4+:1].[NH2:11][C:12]1[N:20]=[CH:19][N:18]=[C:17]2[C:13]=1[N:14]=[CH:15][N:16]2[CH:21]1[O:25][CH:24]([CH:26]=[CH:27][P:28](=[O:29])([O-:30])[O-:31])[CH:23]([OH:32])[CH:22]1[F:33]
Reactant: O=C(Nc1ncnc2c1ncn2C1OC(C=CP(=O)([O-])[O-])C(O)C1F)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Product: Nc1ncnc2c1ncn2C1OC(C=CP(=O)([O-])[O-])C(O)C1F
Reaction time: 24 h
Yield: 195.9 %

Procedure:
Compound 56.3 (65 mg, 0.14 mmol) was dissolved in concentrated NH4OH (1.5 mL) and stirred for 24 h and then concentrated in vacuo. The residue was subjected to reverse phase HPLC eluting with 5-50% CH3CN-water gradient to give 56.4 (52 mg, 93% yield): white solid (bis-ammonium salt); 1H NMR (D2O, 300 MHz) 8.11 (s, 1H), 7.89 (s, 1H), 6.20 (m, 2H), 5.86 (app t, J=16.0 Hz, 1H), 4.84 (d, J=52.8 Hz, 1H), 4.16 (m, 2H); 31P NMR (D2O 121.4 MHz) 9.6; 19F NMR (D2O, 282 MHz) −195 (m, 1F); MS (ESI) m/z 346 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[N:6]=1.[CH3:28][N:29]=[C:30]=[O:31].[OH-].[Na+]>O1CCCC1>[CH3:28][NH:29][C:30](=[O:31])[NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:9]2)[N:6]=1
Reactant: Nc1nc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cs1
Reactant: CN=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CNC(=O)Nc1nc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cs1
Reaction time: 3 h

Procedure:
To a stirred solution of 2-amino-4-[4-(diphenylmethoxy)piperidinomethyl]thiazole (1.0 g) in dry tetrahydrofuran (10 ml) was added dropwise methyl isocyanate (0.34 ml) at ambient temperature. After the addition had been completed, the reaction mixture was stirred for 3 hours. 1N Sodium hydroxide solution (3 ml) was added thereto and stirring was continued for 30 minutes. The reaction mixture was concentrated under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After removal of solvent, the residue was subjected to column chromatography on silica gel and eluted with a mixture of chloroform and methanol (20:1 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was triturated with 70% ethanol to give white powder. Recrystallization from 70% ethanol gave 2-(3-methylureido)-4-[4-(diphenylmethoxy)piperidinomethyl]thiazole (0.3 g).
Reaction SMILES: [C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=3)[C:10]3[CH:22]=[CH:23][CH:24]=[CH:25][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.C(N(C(C)C)CC)(C)C.[CH3:41][N:42]([CH3:48])[CH:43]1[CH2:47][CH2:46][NH:45][CH2:44]1>C(Cl)Cl.CN(C=O)C>[CH3:41][N:42]([CH:43]1[CH2:47][CH2:46][N:45]([C:17](=[O:18])[C:16]2[CH:15]=[CH:14][C:13]([CH2:12][N:11]3[C:10]4[CH:22]=[CH:23][CH:24]=[CH:25][C:9]=4[N:8]=[C:7]3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:21][CH:20]=2)[CH2:44]1)[CH3:48]
Reactant: O=C(O)c1ccc(Cn2c(-c3ccccc3)nc3ccccc32)cc1
Reactant: CN(C)C1CCNC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C1CCN(C(=O)c2ccc(Cn3c(-c4ccccc4)nc4ccccc43)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The 4-(2-phenyl-benzoimidazol-1-ylmethyl)-benzoic acid (0.2 mmol) obtained in step 2 is dissolved in DCM (5 mL) and oxalylchloride (0.2 mL, 0.4 mmol, 2 M solution in DCM) and DMF (2 drops) are added. The solution is stirred for 2 hours at room temperature then concentrated in vacuo. The residue is dissolved in THF, treated with diisopropylethylamine (DIEA) (0.09 mL, 0.5 mmol) and 3-(dimethylamino)pyrrolidine (0.22 mmol, 22 uL), stirred at room temperature overnight then concentrated. This residue is dissolved in a mixture of DMSO, MeOH and water (1.5 mL) and purified by reverse-phase semi-preparative HPLC1 to the title product as a white powder (13 mg), identified by HPLC2 and MS [425.2 m/e (M+H)].
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([S:14][CH3:15])=[C:10]([CH:13]=1)[CH2:11][OH:12].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([S:14][CH3:15])=[C:10]([CH:13]=1)[CH:11]=[O:12]
Reactant: COCCCc1ccc(SC)c(CO)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCCCc1ccc(SC)c(C=O)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a dichloromethane solution of 5-[3-(methyloxy)propyl]-2-(methylthio)benzyl alcohol (1 eq.) from the previous step was added sodium bicarbonate (5 eq.) and DMP (1.1 eq.). The resulting reaction suspension was stirred for 1.5 h at RT. The reaction was quenched with sat. aq. NaHSO3 and then extracted with dichloromethane. The combined organic extracts were washed further with 1 N aq. NaOH, water and brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded the crude title compound as a colorless oil.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].N[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:16])=[O:15].N1C=CC=CC=1.Cl>C(#N)C>[CH2:5]([O:4][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:16])=[O:15])=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccccc1S(N)(=O)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CCOC(=O)c1ccccc1S(N)(=O)=O
Temperature: 25 °C
Yield: 90.1 %

Procedure:
A solution of 3.5 g of ethyl chloroformate in 10 ml of anhydrous acetonitrile is dropwise added to a solution of 5.5 g of 2-aminobenzenesulfonamide and 2.5 g of pyridine in 80 ml of anhydrous acetonitrile at room temperature during 2 hours. After stirring at room temperature, the mixture is poured into ice water and acidified with 100 ml of 2N-hydrochloric acid solution. The mixture is extracted with ethyl acetate twice, washed with an aqueous saturated sodium hydrogen carbonate and then with a saturated brine, and dried over anhydrous sodium sulfate. Then the mixture is concentrated under reduced pressure. The residue is crystallized from chloroform to give 6.6 g of the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][C:15](=[O:19])[CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:20](Br)[C:21]#[CH:22]>C1COCC1.CN(C=O)C>[CH2:3]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:22][C:21]#[CH:20])[C:15](=[O:19])[CH2:14]1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C#CCN1CCN(C(=O)OCc2ccccc2)CC1=O
Reaction time: 0.08 h
Yield: 100 %

Procedure:
Sodium hydride (0.82 g, 23.0 mmol, 60% mineral oil dispersion) is added to a solution of 4-benzyloxycarbonylpiperazin-2-one (5.13 g, 21.9 mmol) in THF/DMF (75 mL, 3/1 v/v) at 0° C. The mixture is stirred for 5 minutes, then propargyl bromide (3.7 mL, 41.5 mmol) is added dropwise. The resulting solution is stirred for 1 hour then brought to room temperature and stirred for 2 hours. The reaction is quenched with saturated ammonium chloride solution then diluted with ethyl acetate and washed with water (4×) and brine. The organic layer is dried over MgSO4, filtered and concentrated to dryness. The residue is purified by column chromatography eluting with 5% MeOH/CH2Cl2 to give the product (5.96 g, 21.9 mmol) as a white solid. 1H NMR (CDCl3, 300 MHz) δ7.3 (m, 5H), 5.12 (s, 2H), 4.25 (s,2H), 4.16 (s, 2H), 3.75 (m, 2H), 3.47 (m, 2H), 2.22 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[NH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13](=[O:20])[CH2:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13](=[O:20])[CH2:12][CH2:11][CH2:10]1)=[O:7]
Reactant: O=C(Cl)CCCCCl
Reactant: O=C1CCCNc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCCN(C(=O)CCCCCl)c2ccccc21
Temperature: 10 °C
Reaction time: 1 h

Procedure:
5-Chlorovaleryl chloride (18.61 mmol, 2.89 g) in dimethylformamide (20 ml) was added dropwise at 10° to a suspension of 1,2,3,4-tetrahydro-5H-1-benzazepin-5-one (12.41 mmol, 2.00 g, preparation according to J. Org. Chem 1972, 37, 2849) and potassium carbonate (14.89 mmol, 2.06 g) in dimethylformamide (40 ml). The reaction mixture was stirred first at 10° C. for 1 h and then under reflux for 3 h. The precipitated salts were filtered off and the filtrate was concentrated to dryness. CH2Cl2 was added to the oil obtained in this way and the mixture was washed three times with 50 ml each time of a 5% aqueous sodium hydrogencarbonate solution, neutralized with 0.1N HCl (20 ml) and then washed three times with a saturated sodium chloride solution. The organic phase was dried over Na2SO4 and concentrated under reduced pressure; yield 3.90 g (80% pure).
Reaction SMILES: [CH:1]1([N:4]([CH3:19])[CH:5]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]3[CH:10]=[C:9]([C:17]#[CH:18])[CH:8]=[CH:7][C:6]2=3)[CH2:3][CH2:2]1.[CH3:20][O:21][C:22](=[O:50])[CH:23]([C:25]1[CH:30]=[CH:29][C:28](C#CC2C=C(C3CC3)C3OC4(CC4)CC(C)(C)C=3C=2)=[CH:27][CH:26]=1)[CH3:24].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.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>[CH3:20][O:21][C:22](=[O:50])[CH:23]([C:25]1[CH:26]=[CH:27][C:28]([C:18]#[C:17][C:9]2[CH:8]=[CH:7][C:6]3[CH:5]([N:4]([CH:1]4[CH2:3][CH2:2]4)[CH3:19])[CH2:14][CH2:13][C:12]([CH3:15])([CH3:16])[C:11]=3[CH:10]=2)=[CH:29][CH:30]=1)[CH3:24]
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2N(C)C1CC1
Reactant: COC(=O)C(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C(C)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1

Procedure:
Following General Procedure B and using 5-(cyclopropyl-methyl-amino)-2-ethynyl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene (Intermediate 168, 0.116 g, 0.46 mmol), methyl-2-(4-iodophenyl)propionate (Reagent 1, 0.17 g, 0.59 mmol), triethyl amine (0.75 mL), copper(I)iodide (0.07 g, 0.37 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.022 g, 0.019 mmol) followed by flash column chromatography over silica gel (230-400 mesh) and preparative normal phase HPLC using 5% ethyl acetate in hexane as the eluent, the title compound was obtained (0.08 g, 42%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][C:17]([CH3:19])=[O:18]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:7]=1)[O:8][CH2:16][C@H:17]1[CH2:19][O:18]1
Reactant: CC(C)=O
Reactant: Oc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccc(Br)cc1OC[C@H]1CO1
Yield: 82 %

Procedure:
A solution of the crude 5-bromo-2-fluorophenol (4.0 g) prepared using literature procedure [EP0238272] and (2R)-glycidyl 3-nitrobenzenesulfonate (5.37 g) in dry acetone (175 mL) was treated with potassium carbonate (8.58 g) and refluxed under nitrogen for 12 h. The reaction was cooled, filtered and filtrate was concentrated in vacuo and the residue was flash chromatographed (20% ethyl acetate/hexanes) to yield the desired product (4.25 g) in 82% yield. 1H NMR (400 MHz, CDCl3): 7.15-6.96 (m, 3H), 4.33 and 4.30 (dd, 1H), 4.02 and 4.00 (dd, 1H), 3.41-3.37 (m, 1H), 2.97 (m, 1H), 2.78 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:19][NH:20][C:21]([C:23]1[C:31]2[C:26](=[CH:27][C:28]([OH:32])=[CH:29][CH:30]=2)[NH:25][C:24]=1[CH3:33])=[O:22].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:19][NH:20][C:21]([C:23]1[C:31]2[C:26](=[CH:27][C:28]([O:32][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:29][CH:30]=2)[NH:25][C:24]=1[CH3:33])=[O:22]
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](O)C1
Reactant: CNC(=O)c1c(C)[nH]c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)[nH]c2cc(Oc3ccnc4cc(C(=O)N5CCC(O)C5)sc34)ccc12

Procedure:
This material was prepared by the reaction of 7-chloro-2-[(R)-3-hydroxypyrrolidine-1-carbynyl]thieno[3,2-b]pyridine 4a with 6-hydroxy-2-methyl-1H-indol-3-carboxylic acid methylamide and Cs2CO3 in a manner as previously described for Example 1. 1H NMR (300 MHz, CD3OD) δ 8.48 (1H, d, J=5.5 Hz), 7.91 (1H, d, J=17.3 Hz), 7.86 (1H, d, J=8.6 Hz), 7.21 (1H, s), 7.00 (1H, d, J=8.6 Hz), 6.69 (1H, d, J=5.5 Hz), 4.50 (1H, m), 4.05–3.70 (4H, m), 2.97 (3H, s), 2.63 (3H, s), 2.40–1.90 (2H, m). LCMS (ESI+) [M+H]/z Calc'd 451. found 451.
Reaction SMILES: N1CCC[C@H]1C(O)=O.[OH-].[Na+].Br[C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH2:19][C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[CH:23]=2)=[O:21])=[CH:14][CH:13]=1.[CH3:36][S:37]([O-:39])=[O:38].[Na+]>CS(C)=O.[Cu]I.C(OCC)(=O)C.O>[CH3:36][S:37]([C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH2:19][C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[CH:23]=2)=[O:21])=[CH:14][CH:13]=1)(=[O:39])=[O:38]
Reactant: CS(=O)[O-]
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(Br)cc2)c2ccccc2C)ccn1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cc(C(=O)C[C@H](c2ccc(S(C)(=O)=O)cc2)c2ccccc2C)ccn1
Temperature: 110 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
To a solution of L-proline (35 mg) in dimethyl sulfoxide (4 mL) was added at room temperature sodium hydroxide (12 mg). The reaction mixture was stirred at room temperature for 30 min. (R)-3-(4-Bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one (example 142, step 2, 150 mg), sodium methanesulfinate (311 mg) and copper(I) iodide (58 mg) were added. The reaction mixture was heated at 110° C. and stirred for 4 hours. Water and ethyl acetate were added, the phases were separated and the inorganic one was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (50% to 100% ethyl acetate in n-heptane) to yield the title compound as an yellow oil (57%), MS (ESI+): m/z=394.0 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([PH:9](=O)[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.Cl[SiH](Cl)Cl.[PH3]=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([PH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc([PH](=O)c2ccc(OC)cc2)cc1
Agent: Cl[SiH](Cl)Cl
Agent: O=[PH3]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(Pc2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
A solution-suspension of 1.4 g (5.34 mmol) of bis(4-methoxyphenyl)phosphine-oxide in 18 mL of toluene was treated under argon with 3.35 g (2.5 mL, 25 mmol) of trichlorosilane in one portion. This resulted in moderate heat and gas evolution and led to complete solution of the phosphine oxide. The mixture was heated at 90° for 5 h, whereupon the clear colorless solution was cooled to 0°. With vigorous stirring, 8.0 mL of 2 N aqueous sodium hydroxide solution (16 mmol) was added slowly while cooling the mixture in an ice-bath to moderate the vigorous reaction. When all the sodium hydroxide had been added, the mixture was allowed to warm to room temperature and stirred vigorously until all solid dissolved (30-90 min), leaving two clear, colorless liquid phases. The layers were allowed to separate and the toluene layer was drawn off under argon via a cannula. The aqueous layer was extracted with 2×20 mL of toluene. The combined toluene extracts were dried (deoxygenated brine and sodium sulfate), filtered, and stripped of solvent on the rotary evaporator at 80°/5 mm Hg to give 1.11 g (84.5%) of crude product. The thick oil was distilled by bulb to bulb distillation at 115°-135°/0.02 mm Hg for 1 h to give 0.747 g (57%) of bis-(4-methoxyphenyl)phosphine as a colorless thick oil which shortly crystallized to colorless, slightly greasy crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:13]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br)[CH:11]=[CH:10][C:9]=2[N:8]=1)[CH3:2].[OH:32][C:33]1[CH:43]=[CH:42][C:36]2[C:37](=[O:41])[CH2:38][CH2:39][O:40][C:35]=2[C:34]=1[CH2:44][CH2:45][CH3:46].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:13]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:32][C:33]3[CH:43]=[CH:42][C:36]4[C:37](=[O:41])[CH2:38][CH2:39][O:40][C:35]=4[C:34]=3[CH2:44][CH2:45][CH3:46])[CH:11]=[CH:10][C:9]=2[N:8]=1)[CH3:2]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: CCOC(=O)CCc1ccc2c(CCC(=O)OCC)c(OCCCCCBr)ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCCCOc2ccc3nc(CCC(=O)OCC)ccc3c2CCC(=O)OCC)ccc2c1OCCC2=O
Temperature: 90 °C
Reaction time: 18 h
Yield: 54.8 %

Procedure:
A mixture of 0.96 g of the partially purified 6-[(5-bromopentyl)oxy]-2,5-quinolinedipropanoic acid diethyl ester from the preceding example, 0.402 g (1.95 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, 1.08 g (7.8 mmol) of anhydrous granular potassium carbonate and 25 mL of 2-butanone was stirred at 90° C. for 18 hr. A second portion of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one (0.117 g, 0.57 mmol) was added and the reaction was continued for another 22.5 hr. The mixture was cooled and filtered through anhydrous magnesium sulfate and the solids were washed with ethyl acetate. The filtrate and washes were combined and concentrated under reduced pressure. The crude product was purified by flash chromatography on 110 g of silica gel, eluting with hexane-ethyl acetate (5:2) to give 0.66 g (54.8%) of the title compound as a white solid, mp 59°-61° C.