Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3](OC)[CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Br:12]>ClC1C=CC=CC=1>[Br:12][C:7]1[C:6]2[S:5][CH:4]=[CH:3][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COC(CSc1ccccc1Br)OC
Solvent: Clc1ccccc1
Product: Brc1cccc2ccsc12
Yield: 88.8 %

Procedure:
To a 500 ml 3-neck flask was weighed out 15 g of polyphosphoric acid (PPA) followed by chlorobenzene (250 ml). After the mixture was heated to reflux (2-bromo-phenylsulfanyl)-acetaldehyde dimethylacetal (8.0 g in 60 ml chlorobenzene, 28.9 mmol) was added dropwise over 2.5 h via addition funnel and refluxed for an additional 24 h. After the reaction cooled it was filtered through a silica plug and concentrated to 6.04 g amber colored oil. Further purification by column chromatography (100% hexanes) afforded 5.47 g (89%) product as a clear oil: 1H NMR (300 MHz, DMSO-d6): δ 7.37 (1H, t, J=7.8 Hz), 7.63 (2H, m), 7.90 (1H, d, J=5.5 Hz), 7.94 (1H, d, J=7.9 Hz).
Reaction SMILES: C1(CO[CH2:9][CH:10]2[S:14][CH2:13][CH:12]([S:15][C:16](=[O:18])[CH3:17])[CH2:11]2)C=CC=CC=1.C[Si]([I:23])(C)C>C(Cl)(Cl)Cl>[I:23][CH2:9][CH:10]1[S:14][CH2:13][CH:12]([S:15][C:16](=[O:18])[CH3:17])[CH2:11]1
Reactant: CC(=O)SC1CSC(COCc2ccccc2)C1
Reactant: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: CC(=O)SC1CSC(CI)C1
Reaction time: 2 h

Procedure:
A 0° C. mixture, under argon, of 0.44 g of product from Example 139 in 5 ml of dry chloroform is treated with 0.55 ml of trimethylsilyl iodide. The reaction is stirred, in the dark, for 2 hours. The reaction is quenched with 100 ml of saturated sodium sulfite, extracted with methylene chloride and the layers separated. The organic layer is dried, filtered and concentrated in vacuo. The residue is purified by chromatography (silica gel: 0 -100% methylene chloride/hexane) to give 0.31 g of the product.
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][CH2:4][CH2:3]1.[CH:21]1([C:24]([NH2:32])([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH3:25])[CH2:23][CH2:22]1>>[CH:21]1([C:24]([NH:32][C:12](=[O:14])[C:9]2[CH:8]=[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:6]([C:2]3([F:1])[CH2:3][CH2:4][CH2:5]3)=[CH:11][N:10]=2)([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH3:25])[CH2:23][CH2:22]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2(F)CCC2)cn1
Reactant: Cc1nc(C(C)(N)C2CC2)no1
Product: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(C3(F)CCC3)cn2)C2CC2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(1-fluorocyclobutyl)-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (example 285a) and 1-Cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (CAN 1155536-64-3) as starting materials and the racemate was separated into its enantiomers by preparative chiral HPLC (Chiralpak AD, ethanol/heptane). The title compound was the second enantiomer collected; MS (ESI, m/z): 443.3 (M+H+).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[OH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:23]([CH3:34])[CH:22]=1.[Br:35][C:36]1[N:41]=[C:40]([CH:42](O)[CH2:43][O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH:39]=[CH:38][CH:37]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:35][C:36]1[N:41]=[C:40]([CH:42]([O:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:23]([CH3:34])[CH:22]=2)[CH2:43][O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH:39]=[CH:38][CH:37]=1
Reactant: CCOC(=O)COc1ccc(O)cc1C
Reactant: CC(C)(C)[Si](C)(C)OCC(O)c1cccc(Br)n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(OC(CO[Si](C)(C)C(C)(C)C)c2cccc(Br)n2)cc1C
Temperature: 25 °C
Yield: 27.2 %

Procedure:
To a solution of Ph3P (1.10 g, 4.19 mmol) in dry THF (30 mL), was treated with ethyl [(4-hydroxy-2-methylphenyl)oxy]acetate (696 mg, 3.31 mmol) and 1-(6-bromo-2-pyridinyl)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethanol (1.00 g, 3.01 mmol) and the resulting solution cooled to 0° C. (ice/water bath) under nitrogen. DIAD (0.829 ml, 4.21 mmol) in THF (30 ml) was then added drop-wise over 2 h using a syringe pump. The resulting mixture was then allowed to warm to ambient temperature over 22.5 h and was then reduced under vacuum to give an orange oily residue. Purification by SPE (silica, 10 g cartridge) eluting with cyclohexane:EtOAc (gradient, 1:1 to 0:1) afforded the title compound (429 mg).
Reaction SMILES: CC(O)(C)C.[K].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[C:10]([C:18](=O)[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH:9]=1>COCCOC>[Br:7][C:8]1[CH:9]=[C:10]2[C:11](=[CH:12][CH:13]=1)[NH:14][C:15](=[O:17])[CH:16]=[C:18]2[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1
Reactant: CC(=O)Nc1ccc(Br)cc1C(=O)c1cccc(Cl)c1
Agent: [K]
Solvent: COCCOC
Solvent: CC(C)(C)O
Product: O=c1cc(-c2cccc(Cl)c2)c2cc(Br)ccc2[nH]1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
2-Methyl-2-propanol, potassium salt (1.635 mol) was added portionwise at room temperature to a solution of intermediate 3 (0.328 mol) in 1,2-dimethoxyethane (1200 ml) and the mixture was stirred at room temperature for one night. The mixture was evaporated till dryness, the residue was poured into water and ice and decanted. The oily residue was taken up in DIPE, the precipitate was filtered off, washed with EtOAc, acetonitrile and diethyl ether and dried, yielding 88.6 g (80.76%) of 6-bromo-4-(3-chlorophenyl)-2(1H)-quinolinone (intermediate 4).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH2:5]O.P(Br)(Br)[Br:13].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH2:5][Br:13]
Reactant: COc1cc(Br)cc(CO)c1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(Br)cc(CBr)c1
Reaction time: 0.17 h
Yield: 214.3 %

Procedure:
11 Grams (51 mmole) of 3-bromo-5methoxy benzyl alcohol was dissolved in 100 ml methylene chloride and cooled in an ice-bath. 2.0 ml (20 mmole) of phosphorus tribromide was added dropwise to this solution at room temperature, and the mixture was allowed to stir for 10 minutes. Saturated sodium bicarbonate solution was then added, and the mixture was extracted with ether and washed with sodium bicarbonate solution. Evaporation of the ether yielded 12 grams of 3-Bromo-5-methoxy-benzyl bromide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[O:4][C:5]1[N:10]=[C:9]([C:11]2[N:16]=[C:15](O)[CH:14]=[C:13]([CH2:18][CH2:19][CH3:20])[N:12]=2)[CH:8]=[CH:7][CH:6]=1.P(Cl)(Cl)([Cl:27])=O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:27][C:15]1[CH:14]=[C:13]([CH2:18][CH2:19][CH3:20])[N:12]=[C:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([O:4][C:3]3[CH:21]=[CH:22][CH:23]=[CH:24][C:2]=3[Cl:1])[N:10]=2)[N:16]=1
Reactant: CCCc1cc(O)nc(-c2cccc(Oc3ccccc3Cl)n2)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCc1cc(Cl)nc(-c2cccc(Oc3ccccc3Cl)n2)n1
Yield: 87.3 %

Procedure:
To solution of 2-(6-o-chlorophenoxy-2-pyridinyl)-4-hydroxy-6-n-propylprimidine (5 g) in toluene (100 ml), was added phosphoryl chloride (5 g). The mixture was heated under refluxing for one hour and left to stand to room temperature. Aqueous sodium carbonate solution was added thereto until the reaction solution became about pH 8 to be separated into two layers. Toluene layer was washed with water and dried over anhydrous magnesium sulfate. The toluene layer was concentrated under reduced pressure to obtain 4-chlono-2-(6-o-chlorophenoxy-2-pyridinyl)-6-n-propylpyrimidine (4.6 g, yield 87%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH:4]=[CH2:5].[CH3:7][Si:8]([CH3:20])([CH3:19])[N:9]1[CH:14]=[CH:13][CH:12]([Si](C)(C)C)[CH:11]=[CH:10]1>O1CCCC1>[CH3:7][Si:8]([N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]1[CH:4]([C:3]([O:2][CH3:1])=[O:6])[CH3:5])([CH3:20])[CH3:19]
Reactant: C=CC(=O)OC
Reactant: C[Si](C)(C)C1C=CN([Si](C)(C)C)C=C1
Solvent: C1CCOC1
Product: COC(=O)C(C)C1C=CC=CN1[Si](C)(C)C
Temperature: 50 °C
Reaction time: 70 h

Procedure:
Following the procedure of Example 1, 8.6 g (0.1 mol) of acrylic acid methyl ester are brought to reaction with 22.6 g (0.1 mol) of 1,4-bis-(trimethylsilyl)-1,4-dihydropyridine. Upon addition of 20 ml of tetrahydrofuran the mixture is stirred at 50°C for 70 hours. The distillation in high vacuum yields 21.1 g (68%) of 1,4-bis-(trimethylsilyl-2-(1-carbomethoxyethyl)-1,2-dihydropyridine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N+:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32])([O-:24])=[O:23]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N+:22]([O-:24])=[O:23])(=[O:32])=[O:33])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-aminopiperidine-1-carboxylic acid tert-butyl ester (400 mg, 200 mmol) in anhydrous dichloromethane (14 mL) under argon was added triethylamine (340 μL, 2.4 mmol) and the solution cooled in an ice bath. 2-Nitrophenylsulfonyl chloride (443 mg, 2.0 mmol) was added and the reaction allowed to stir at rt for 16 h. The crude solution was washed with water (2×30 mL) before removing the solvent in vacuo. The crude material was purified by chromatography using ethyl acetate/petroleum ether (30-60%) as the eluent to give the title compound as an off-white powder. δH (d6 DMSO): 8.43 (2H, m), 8.17 (1H, s), 8.09 (2H, m), 3.80-3.69 (2H, m), 3.31-3.23 (1H, m), 2.86-2.69 (2H, m), 1.63-1.51 (2H, m), 1.39 (9H, s), 1.29-1.17 (2H, m).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]4=[N:20][S:21](=[O:25])(=[O:24])[CH2:22][CH2:23][N:18]4[CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1>C1COCC1.CO.[Pt](=O)=O>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([CH:14]3[C:19]4=[N:20][S:21](=[O:24])(=[O:25])[CH2:22][CH2:23][N:18]4[CH2:17][CH2:16][CH2:15]3)=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccc(C(F)(F)F)cc4)cc3)C2=N1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: O=S1(=O)CCN2CCCC(c3ccc(Oc4ccc(C(F)(F)F)cc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 58.3 %

Procedure:
To a suspension of NaH (60%, 418 mg) in THF (dry) (25 mL) was added 2-chloroethanesulfonyl chloride (0.659 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(4-(4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-amine (690 mg) in THF (dry) (40 mL) was added at 0° C. and the mixture was stirred at room temperature overnight. The mixture was quenched with water at 0° C. Water, EtOAc and THF were added and the extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was washed with IPE/EtOAc, dried in vacuo to give 9-{4-[4-(trifluoromethyl)phenoxy]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (579.1 mg) as a slightly yellow solid. Platinum(IV) oxide (30 mg) was added to a solution of 9-{4-[4-(trifluoromethyl)phenoxy]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (505 mg) in THF (dry) (15 mL) and MeOH (15 mL) and the mixture was stirred at room temperature under hydrogen for 6 hr. Platinum(IV) oxide (30 mg), MeOH (15 mL) and THF (dry) (15 mL) were added and the mixture was stirred at 50° C. under hydrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (297.2 mg) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([C:20]2[C:29]([OH:30])=[C:28]3[C:23]([CH:24]=[CH:25][CH:26]=[N:27]3)=[C:22]([Cl:31])[CH:21]=2)[NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:41](Cl)(=[O:43])[CH3:42]>C(Cl)Cl>[C:41]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]([C:20]2[C:29]([OH:30])=[C:28]3[C:23]([CH:24]=[CH:25][CH:26]=[N:27]3)=[C:22]([Cl:31])[CH:21]=2)[NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:43])[CH3:42]
Reactant: CC(=O)Cl
Reactant: Nc1cccc(C(NC(=O)COc2ccccc2)c2cc(Cl)c3cccnc3c2O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1cccc(C(NC(=O)COc2ccccc2)c2cc(Cl)c3cccnc3c2O)c1
Yield: 57.6 %

Procedure:
To the suspension of N-[(3-aminophenyl)(5-chloro-8-hydroxyquinolin-7-yl)methyl]-2-phenoxyacetamide (150 mg, 0.35 mmol) in methylenechloride (4 ml) cooled to 0 C was added DIEA (50 mg, 0.38 mmol) followed by acetylchloride (32.4 mg, 0.42 mmol). Purification by flush chromatography (eluent 30% acetone/DCM) afforded 96 mg (57%) of N-[[3-(acetylamino)phenyl](5-chloro-8-hydroxyquinolin-7-yl)methyl]-2-phenoxyacetamide as a white solid.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:14])[CH:10]=2)[CH:5]=1.[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.CN(C)C=O>[CH2:15]([O:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:14])[CH:10]=2)[CH:5]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: Oc1ccc2cc(O)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Oc1ccc2cc(OCc3ccccc3)ccc2c1
Temperature: 25 °C

Procedure:
To a suspension of sodium hydride (12 g, 0.3 mol 60% in mineral oil) in 600 ml toluene and 400 ml dimethyl formamide was added 2,6-dihydroxynaphthalene (80 g, 0.5 mol) and the mixture was heated to reflux over a thirty minute period. Benzyl chloride (65 ml, 71.5 g, 0.56 mol) was added dropwise and the mixture was refluxed for 10 hours. After cooling to room temperature, the mixture was washed 6 times with water to remove the dimethyl formamide. The resulting toluene solution was washed twice with 150 ml 0.5N sodium hydroxide to remove unreacted starting material and then with water and dried over anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration and the filtrate was concentrated to 150 ml. The solid which had crystallized was collected by vacuum filtration and washed with a small amount of toluene to yield 2-benzyloxy-6-hydroxynaphthalene.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([O:23][C@@H:24]([C@H:26]3[CH2:30][NH:29][C:28](=[O:31])[CH2:27]3)[CH3:25])=[N:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)=[CH:10][C:5]=2[N:4]=[CH:3]1.[CH3:32][C:33]([CH3:35])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C([O-])(O)=O.[Na+].CO>[CH:33]([N:20]1[CH2:19][CH2:18][N:17]([C:14]2[CH:13]=[CH:12][C:11]([C:9]3[N:8]=[C:7]([O:23][C@@H:24]([C@H:26]4[CH2:30][NH:29][C:28](=[O:31])[CH2:27]4)[CH3:25])[C:6]4[N:2]([CH3:1])[CH:3]=[N:4][C:5]=4[CH:10]=3)=[CH:16][CH:15]=2)[CH2:22][CH2:21]1)([CH3:35])[CH3:32]
Reactant: CC(C)=O
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)cc2)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)N1CCN(c2ccc(-c3cc4ncn(C)c4c(O[C@H](C)[C@H]4CNC(=O)C4)n3)cc2)CC1
Temperature: 25 °C
Yield: 59.5 %

Procedure:
A mixture of (R)-4-((R)-1-(3-methyl-6-(4-(piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3A.13 (29 mg, 0.069 mmol), acetone (18 μL, 0.24 mmol) and sodium triacetoxyborohydride (66 mg, 0.31 mmol) in THF (1.0 mL) was stirred at room temperature over the weekend. The reaction was diluted with saturated NaHCO3 (aq) and methanol. The mixture was concentrated to dryness and the residue was purified via prep HPLC (2-95% acetonitrile in water, 0.1% trifluoroacetic acid buffer) to isolate (R)-4-((R)-1-((6-(4-(4-isopropylpiperazin-1-yl)phenyl)-3-methyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one 3.35 (19 mg) as its trifluoroacetic acid salt.
Reaction SMILES: [Cl:1][C:2]([Cl:15])([Cl:14])[CH2:3][C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:7])[CH2:5][OH:6].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:6][CH2:5][C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:7])[CH2:3][C:2]([Cl:14])([Cl:15])[Cl:1])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: OCC(O)(CC(Cl)(Cl)Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC(O)(CC(Cl)(Cl)Cl)c1ccccc1

Procedure:
4,4,4-Trichloro-2-phenyl-2-hydroxybutanol (160 grams; 0.60 mole) was mixed with about 2000 milliliters (ml.) of methylene chloride and triethylamine (63.6 grams; 0.63 mole) was added thereto. The resulting mixture was cooled in an ice-methanol bath to a temperature of about -6 to about -8° C. Methanesulfonyl chloride (69 grams; 0.60 mole) in about 250 ml. of methylene chloride was added dropwise to the stirred reaction mixture over a period of about 45 minutes. The reaction mixture temperature was maintained below about 0° C. during the addition and, following the completion of the methanesulfonyl chloride solution; the reaction mixture temperature was allowed to come to room temperature. Thereafter, the reaction mixture was washed with water (four - 700 ml. portions), then with 700 ml. of a 10% sodium carbonate solution, and finally with another 700 ml. portion of water. An additional 600 ml. of methylene chloride was added to the organic product layer which was then dried over sodium sulfate. The volume of the organic product mixture was reduced to about 400 ml. by evaporation of the carrier medium in vacuo. The resulting white product precipitate was obtained by filtration. As a result of such operations, the desired 4,4,4-trichloro-2-phenyl-2-hydroxybutyl 1-methanesulfonate product was obtained as a white crystalline solid having a melting point of 128°-130° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.N1C=CC=CC=1.[N:17]([CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24])=[N+:18]=[N-:19]>C(Cl)Cl>[N:17]([CH2:20][CH2:21][CH2:22][C:23]([CH:5]1[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:9])=[O:24])=[N+:18]=[N-:19]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: [N-]=[N+]=NCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(C(=O)CCCN=[N+]=[N-])C(=O)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (3.82 g, 26.5 mmol) and pyridine (4.20 g, 53.0 mmol) in 150 ml of CH2Cl2 was added dropwise a solution of crude 4-azidobutyric chloride (3.90 g, 26.5 mmol) in 30 ml of CH2Cl2 at 0° C. The mixture was stirred at 0° C. for 1 hr then at room temperature for 1 hr. The solution was, washed with 0.5N aqueous HCl (60 ml), water (60 ml) followed by brine (60 ml) and dried. After evaporation of solvent, 5-(4-azidobutanoyl)-2,2-dimethyl-1,3-dioxane-4,6-dione was obtained as a light pink oil (6.20 g, 92%).
Reaction SMILES: N[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.N([O-])=O.[Na+].[BrH:18]>O>[Br:18][CH:2]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[C:11]([OH:13])=[O:12]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(Br)Cc1ccc(O)cc1

Procedure:
Tyrosine (20 g) is dissolved in HBr (100 ml, 48% diluted with 200 ml water). To the cooled solution NaNO2 in 30 ml water is added dropwise. The product is extracted with ethyl acetate and after common treatment 2-bromo-3-(4-hydroxyphenyl)-propionic acid is obtained, which is used without purification for the next step.
Reaction SMILES: [CH2:1]([C:4]1[C:17]([OH:18])=[C:16]([Cl:19])[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:20])[C:6]=2[CH:5]=1)[CH:2]=C.ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl.[C:36](=[O:39])([O-])[O-:37].[K+].[K+]>O>[Cl:19][C:16]1[C:15]2[O:14][C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:7](=[O:20])[C:6]=2[CH:5]=[C:4]2[CH2:1][CH:2]([C:36]([OH:37])=[O:39])[O:18][C:17]=12
Reactant: O=C([O-])[O-]
Reactant: C=CCc1cc2c(=O)c3ccccc3oc2c(Cl)c1O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(O)C1Cc2cc3c(=O)c4ccccc4oc3c(Cl)c2O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.7 %

Procedure:
A mixture of 2-allyl-4-chloro-3-hydroxy-9-oxo-9H-xanthene (2.0 g), m-chloroperbenzoic acid (3.6 g) and chloroform (100 ml) was stirred at room temperature for 5 hours and thereafter left to stand overnight. To the mixture, potassium carbonate (8 g) and water (200 ml) were added and the resulting mixture was extracted with chloroform. The chloroform layer was dried and the solvent was distilled off. The residue was dissolved in acetone (400 ml) and to the stirred solution, a mixture of chromium trioxide (1.7 g), water (10 ml) and concentrated sulfuric acid (3 g) was added dropwise at room temperature. After standing overnight, the mixture was filtered and the filtrate was evaporated to dryness under vacuum. After addition of water, the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 0.9 g of 11-chloro-2,3-dihydro-5-oxo-5H-furo[3,2-b]xanthene-2-carboxylic acid. m.p. 290°-293° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 316.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:26]([C:40]2[CH:45]=[C:44]([O:46][CH2:47][CH3:48])[CH:43]=[C:42]([O:49][CH:50]([CH3:52])[CH3:51])[C:41]=2[F:53])[NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:38]=[C:37]([CH3:39])[O:36][N:35]=3)=[CH:30][CH:29]=2)[N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.[CH:54]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1B(O)O)=[O:55].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[CH2:47]([O:46][C:44]1[CH:43]=[C:42]([O:49][CH:50]([CH3:51])[CH3:52])[C:41]([F:53])=[C:40]([CH:26]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[N:38]=[C:37]([CH3:39])[O:36][N:35]=3)=[CH:32][CH:33]=2)[C:4]2[N:5]([C:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[C:2]([C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=3[CH:54]=[O:55])[N:3]=2)[CH:45]=1)[CH3:48]
Reactant: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: O=Cc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3ccccc3C=O)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 150 °C
Yield: 96.4 %

Procedure:
A suspension of Intermediate 66.3 (100 mg, 0.13 mmol), 2-formyl phenylboronic acid (30 mg, 0.2 mmol), Na2CO3 (56 mg, 0.52 mmol) in 3:1 DME/H2O (4 mL) was degassed and then added in Pd(PPh3)4 (10 mg). The reaction mixture was heated to 150° C. for 8 min in microwave. The reaction mixture was then partionated between EtOAc and sat. NaCl, the organic layer was collected and dried over (Na2SO4), filtered and concentrated. The residue was subject to chromatographic purification (0-30% EtOAc/hexanes gradient), 100 mg (65%) of Intermediate 122.1 was obtained. LCMS (2 min gradient) RT 2.35 min, 798.3 (M+H).