Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br-].[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O.[CH3:34][C:35](=O)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>O>[CH3:34][CH:35]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=[CH:5][OH:4]
Reactant: CCCCCCCCC(C)=O
Reactant: OCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCC(C)CCCCC=CO
Temperature: 70 °C
Reaction time: 18 h
Yield: 49.5 %

Procedure:
Into a dried 5L, 3 neck round bottom flask fitted with mechanical stirring, nitrogen inlet, dropping funnel, thermometer and nitrogen outlet is added 80 g of 60% sodium hydride (2.0 mol) in mineral oil. The mineral oil is removed by washing with hexanes. Anhydrous dimethyl sulfoxide (500 ml) is added to the flask and heated to 70° C. until evolution of hydrogen stops. The reaction mixture is cooled to room temperature followed by addition of 1L of anhydrous tetrahydrofuran. (6-hydroxyhexyl) triphenylphosphonium bromide (443.4 g, 1 mol) is slurried with warm anhydrous dimethyl sulfoxide (50° C., 500 ml) and slowly added to the reaction mixture thru the dropping funnel while keeping the reaction at 25-30° C. The reaction is stirred for 30 minutes at room temperature at which time 2-decanone (171.9 g, 1.1 mol) is slowly added thru a dropping funnel. Reaction is slightly exothermic and cooling is needed to maintain 25-30° C. Mixture is stirred for 18 hrs. and then poured into a separatory funnel containing 600 ml of purified water and 300 ml of hexanes. After shaking the oil phase (top) is allowed to separate out and the water phase is removed. The extractions of the oil phase are continued using water until both phases are clear. The organic phase is collected, vacuum distilled and purified by liquid chromatography (90:10 hexanes:ethyl acetate, silica gel stationary phase) to obtain a clear, oily product (119.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([OH:11])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.[C:15](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N+:12]([O-:14])=[O:13])[C:6]([O:11][CH3:15])=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(O)c([N+](=O)[O-])cc1OC
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(OC)c([N+](=O)[O-])cc1OC
Temperature: 77.5 °C
Yield: 56.3 %

Procedure:
A mixture of 4,5-dimethoxy-2-nitro-phenol (2.00 g, 10 mmol), potassium carbonate (2.76 g, 20 mmol) and iodomethane (0.75 mL, 12 mmol) in DMF was placed in a sealed tube and heated at 75-80° C. for 20 h. The reaction was cooled and was filtered through Celite, washing with ethyl acetate. The filtrate was washed with water (the first wash was back-extracted with ethyl acetate), sodium bicarbonate and brine, was dried (sodium sulfate) and was evaporated. Purification by flash chromatography (SiO2) eluted with 1:1 ethyl acetate:hexanes provided 1,2,4-trimethoxy-5-nitro-benzene (1.20 g, 57% yield) as a yellow solid. 1H-NMR (CDCl3, 500 MHz) 7.53 (s, 1H), 6.50 (s, 1H), 3.92 (s, 3H), 3.91 (s, 3H), 3.84 (s, 3H) ppm; MS (FIA) 214.1 (M+H); HPLC (Method A) 3.253 min.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=O)[C:4]=2[CH:3]=1.CCCCCC.C(Cl)Cl.C1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C=CC=1.C1C2C(=CC3C(C=2)=CC=CC=3)C=CC=1>[OH-].[NH4+].O.[Zn].C(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)c2cc(Cl)ccc21
Agent: O=C1c2ccccc2C(=O)c2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: c1ccc2cc3ccccc3cc2c1
Product: Clc1ccc2cc3ccccc3cc2c1
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 14.4 %

Procedure:
A stirred suspension of 2-chloroanthraquinone (1260 g, 5.19 mol) in concentrated ammonium hydroxide (7.5 L) and water (2.5 L) was warmed to 40° C. Zinc dust (845 g, 12.93 mol) was added in one portion, changing the color to deep red. The mixture was stirred for 45 min at 50° C., then cautiously treated with a second portion of zinc dust (845 g). After the addition, the stirred mixture was heated gradually over 3 h to 90° C., then maintained at 90°-95° C. for 2 h (red color dissipated). TLC analysis (silica gel; hexane:methylene chloride (3:1)) showed complete conversion of the anthraquinone (Rf 0.35) to the desired anthracene (Rf 0.80). The reaction mixture was stirred overnight as it cooled to room temperature. The cooled mixture was treated with methylene chloride (4 L), stirred for 2 h, then filtered through Celite to remove the excess zinc. The filter cake was washed with methylene chloride (6×1 L). The methylene chloride layer was separated from the aqueous, then treated with 6N hydrochloric acid (3 L) and stirred for 2 h. A first crop of 2-chloroanthracene was collected by filtration and washed with water (4×1 L). Vacuum drying afforded a light yellow crystalline product weighing 804.6 g (mp 220°-221° C.). The methylene chloride portion of the filtrate was concentrated in vacuo to 10% of it's original volume. This produced an additional 158.5 g of the desired compound for a total yield of 963.1 g (87.2%). 1H NMR (CDCl3) 8.39 (s, 1H), 8.30 (s, 1H), 7.96 (s, 4H), 7.49 (s, 2H), 7.36 (d, J=8.7 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][C:22]1[C:23](=[O:28])[NH:24][CH:25]=[CH:26][CH:27]=1.N1NC(=O)C=CC=1>>[CH3:21][C:22]1[C:23](=[O:28])[N:24]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:10][C@H:11]([N:13]5[CH2:18][CH2:14][CH2:15][CH2:16][CH2:17]5)[CH2:12]4)[S:8][C:4]=3[CH:3]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Cc1ccc[nH]c1=O
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: O=c1cccn[nH]1
Product: Cc1cccn(-c2ccc3nc([C@H]4C[C@H](N5CCCCC5)C4)sc3c2)c1=O

Procedure:
The title compound was prepared according to the procedure described in Example 22, substituting the product of Example 44A for the product of Example 1E and substituting 3-methyl-2-pyridone for 3(2H)-pyridazinone. 1H NMR (400 MHz, CDCl3) δ ppm 8.02 (d, J=8.59 Hz, 1H) 7.89 (d, J=2.15 Hz, 1H) 7.42 (dd, J=8.75, 1.99 Hz, 1H) 7.22-7.34 (m, 2H) 6.19 (t, J=6.75 Hz, 1H) 3.53-3.68 (m, 1H) 2.80-2.94 (m, 1H) 2.51-2.91 (m, 3H) 2.32-2.50 (m, 4H) 2.20 (s, 3H) 1.99-2.12 (m, 1H) 1.58-1.73 (m, 4H) 1.43-1.54 (m, 2H). MS: (M+H)+=380.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCCCCCCCCCC>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: OB(O)c1ccccc1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Br
Agent: Cl[Pd]Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCCCCCCCC
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1-c1ccccc1
Reaction time: 3 h

Procedure:
Commercially available 1-bromo-2-nitro-4-trifluoromethyl-benzene (0.130 g, 0.48 mmol) was reacted with phenylboronic acid (0.072 g, 0.59 mmol) as described in Example 213a substituting dioxane for toluene, bis(triphenylphosphine)-palladium (II) chloride for palladium acetate and omitting the 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3.]undecane. The reaction was complete after three hours and the title biphenyl recovered in quantitative yield, sufficiently pure for use as isolated.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)=[CH:6][CH:5]=1.[OH-].[K+].Cl>CO.O>[Cl:26][C:21]1[CH:20]=[C:19]([C:13]2([C:15]([F:17])([F:16])[F:18])[O:12][N:11]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:27])=[O:2])=[CH:9][CH:8]=3)[CH2:14]2)[CH:24]=[C:23]([Cl:25])[CH:22]=1
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 100.4 %

Procedure:
In a solution of 3.99 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] benzoic acid methyl ester in 50 ml of methanol, a solution of 2.00 g of potassium hydroxide in 25 ml of water was added, stirred at room temperature for 3 days and then at 40° C. for 5 hours. After the completion of the reaction, the reaction mixture was cooled with ice, and poured in 200 ml of water, and adjusted to pH 1-2 with concentrated hydrochloric acid, and then extracted with ethyl acetate (50 ml×2), the organic phase was washed with water, dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 3.87 g of the aimed product as pale yellow crystal.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:16][C:17]2[CH:18]=[N:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13](=[S:15])[NH2:14])=[CH:9]2)[CH3:2].[C:27]([O:32][CH2:33][CH3:34])(=[O:31])[C:28]#[C:29][CH3:30].O1CCCC1.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:16][C:17]2[CH:18]=[N:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:15][CH:29]([CH2:28][C:27]([O:32][CH2:33][CH3:34])=[O:31])[CH2:30][N:14]=1)=[CH:9]2)[CH3:2]
Reactant: CC#CC(=O)OCC
Reactant: CCOc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=S)[nH]c12
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OCC)c3[nH]2)S1
Temperature: 40 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
To a stirred solution of 7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carbothioamide (0.41 g), ethyl 2-butynoate (0.25 mL), tetrahydrofuran (10 mL) and toluene (15 mL) was added tributylphosphine (0.31 mL) at room temperature under argon atmosphere. After stirring at 40° C. for 3 h, the reaction mixture was concentrated to give a light brown oil, which was purified by silica gel chromatography (ethyl acetate:hexane=30:70 to 50:50, volume ratio) to give the title compound (350 mg, 66%) as a light yellow oil. MS 504 (MH+).
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[C:12]([O:17][CH:18]([O:22][C:23](ON1C(=O)CCC1=O)=[O:24])[CH2:19][CH2:20][CH3:21])(=[O:16])[CH2:13][CH2:14][CH3:15]>CC(OC)(C)C.CC(C)=O.O>[C:12]([O:17][CH:18]([O:22][C:23]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:24])[CH2:19][CH2:20][CH3:21])(=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCCC(=O)OC(CCC)OC(=O)ON1C(=O)CCC1=O
Solvent: CC(C)=O
Solvent: COC(C)(C)C
Solvent: O
Product: CCCC(=O)OC(CCC)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (800 mg, 5 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]butyl butanoate (700 mg, 2.3 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 35 (210 mg, 27% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.87-0.95 (m, 8H), 1.22-1.41 (br. m, 5H), 1.56 (m, 2H), 1.68-1.73 (m, 4H), 1.89-1.92 (m, 2H), 2.13 (tt, J=12, 3.2 Hz, 1H), 2.30 (t, J=7.2 Hz, 2H), 6.65 (t, J=5.6 Hz, 1H), 7.45 (t, J=6.0 Hz, 1H), 12.04 (s, 1H). MS (ESI) m/z 366.21 (M+Na)+; 342.16 (M−H)−.
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[Br:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33]>C1(C)C=CC=CC=1>[Br:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([NH:1][C:2]1[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=1)=[O:33]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1cccc(Br)c1
Temperature: 103 °C
Reaction time: 3 h

Procedure:
In toluene (80 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (5.0 g) and triethylamine (1.5 ml), and a solution of 3-bromobenzoyl chloride (2.9 g) dissolved in toluene (10 ml) was gradually added thereto under cooling and the mixture was stirred at 103° C. for 3 hours.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].FC1C=CC(C(C2C=CC(F)=CC=2)=O)=CC=1.[C:23]([O:31]C)(=[O:30])[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].O>C1(C)C=CC=CC=1>[CH3:29][O:28][C:26]([C:25](=[CH2:1])[CH2:24][C:23]([OH:31])=[O:30])=[O:27]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)CCC(=O)OC
Agent: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(CC(=O)O)C(=O)OC
Temperature: 70 °C

Procedure:
Potassium t-butoxide (68.8 g) was weighed into a reaction flask equipped with a mechanical stirrer, placed under a nitrogen atmosphere and 700 mL of toluene was added followed by 4,4′-difluorobenzophenone (100 g). The reaction mixture was stirred mechanically and heated to 70° C. A solution of dimethyl succinate (80 g) in 100 mL of toluene was added to the reaction mixture over a 60 minute period. The reaction mixture was heated at 70° C. for 4 hours. After cooling to room temperature, the reaction mixture was poured into 500 mL of water and the toluene layer discarded. The aqueous layer was extracted with diethyl ether (1×400 mL) to remove the neutral products, and then acidified the aqueous layer with concentrated HCl. A brownish-yellow oily solid was obtained from the aqueous layer, and was extracted with 3×300 mL of ethyl acetate. The organic layers were combined, washed with saturated NaCl solution (1×500 mL) and dried over anhydrous sodium sulfate. Removal of the solvent by rotary evaporation yielded 122 g of 4,4-di(4-fluorophenyl))-3-methoxycarbonyl-3-butenoic acid as a brownish oily solid. This material was not purified further but was used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[CH:9][CH:8]=1.[NH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][CH2:23]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCCC1.CO.C1(C)C=CC=CC=1>[N:22]1([C:2]2[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=2)[CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][CH2:23]1
Reactant: COC(=O)CCc1ccc(OCc2cccc(Br)c2)cc1
Reactant: c1ccc2c(c1)CCCN2
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCc1ccc(OCc2cccc(N3CCCc4ccccc43)c2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 18 %

Procedure:
A mixture of methyl 3-{4-[(3-bromobenzyl)oxy]phenyl}propanoate (0.3 g, 0.86 mmol), 1,2,3,4-tetrahydroquinoline (0.17 mL, 1.29 mmol), tris(dibenzylideneacetone)dipalladium(0) (31 mg, 34 μmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (32 mg, 52 μmol), cesium carbonate (0.39 g, 1.2 mmol) and toluene (6.0 mL) was stirred under a nitrogen atmosphere at 90° C. for 16 hr. After cooling, the reaction mixture washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give an oil. Then, a mixture of the obtained oil, 1N aqueous sodium hydroxide solution (1.7 mL), methanol (2.0 mL) and tetrahydrofuran (4.0 mL) was stirred at room temperature for 2 hr. The reaction mixture was concentrated, and the residue as partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative HPLC (gradient cycle A), and the object fractions were collected and concentrated. Water was added to the residue, and the mixture was adjusted to pH 7 with saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (60 mg, yield 18%) as a beige powder. MS (APCI−): 386 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])/[C:6](=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)/[CH2:5]2>CO.[Pt]>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH:6]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]([F:24])([F:23])[F:25])=[CH:17][CH:16]=1)[CH2:5]2
Reactant: COc1cc2c(cc1Br)C/C(=C\c1ccc(SC(F)(F)F)cc1)C2=O
Agent: [Pt]
Solvent: CO
Product: COc1cc2c(cc1Br)CC(Cc1ccc(SC(F)(F)F)cc1)C2=O
Reaction time: 6 h

Procedure:
The 104 (125 mg, 0.467 mol) was dissolved in methanol 25 mL, Pt/C 10 mg added, the reaction stirred under hydrogen balloon for 6 h, filtered through celite bed and washed with excess methanol. The organic layer was concentrated to get the crude compound 143 and was purified by flash chromatography using 100-200 mesh silica gel. The compound 5-bromo-6-methoxy-2-(4-((trifluoromethyl)thio)benzyl)-2,3-dihydro-1H-inden-1-one 143 was eluted at 12% ethyl acetate in hexane as half white coloured solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[N:29]2[C:24]([CH:25]=[N:26][C:27]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([N:37]4[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]4)=[CH:33][CH:32]=3)=[N:28]2)=[CH:23][CH:22]=1.CC1(C)C(C)(C)OB([C:52]2[CH:61]=[CH:60][CH:59]=[CH:58][C:53]=2[O:54][CH2:55][C:56]#[N:57])O1.C(=O)([O-])[O-].[Na+].[Na+].O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[CH3:43][N:40]1[CH2:41][CH2:42][N:37]([C:34]2[CH:33]=[CH:32][C:31]([NH:30][C:27]3[N:26]=[CH:25][C:24]4=[CH:23][CH:22]=[C:21]([C:52]5[CH:61]=[CH:60][CH:59]=[CH:58][C:53]=5[O:54][CH2:55][C:56]#[N:57])[N:29]4[N:28]=3)=[CH:36][CH:35]=2)[CH2:38][CH2:39]1
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Reactant: CC1(C)OB(c2ccccc2OCC#N)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5ccccc5OCC#N)n4n3)cc2)CC1
Temperature: 55 °C

Procedure:
Into a 30 mL vial, Palladium Acetate (10 mg, 0.04 mmol), Triphenylphosphine (33 mg, 0.12 mmol) were added. The mixture was purged with nitrogen for 10 minutes. (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (110.0 mg, 0.2840 mmol), [2-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-acetonitrile (0.1472 g, 0.5681 mmol), N,N-Dimethylformamide (2.00 mL) and 1.50 M of Sodium carbonate in Water (2.0 mL, 3.0 mmol) were added. The reaction mixture was heated at 55° C. for 45 minutes. The reaction was partitioned with water and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The desired product was isolated via ISCO column chromatography with DCM and methanol as eluant (0 to 15% methanol). The collected fractions afforded (2-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-phenoxy)-acetonitrile as a yellow solid (65 mg, 52%). LCMS (E/I+) 440.2 (M+H). MP 95-101° C. NMR 1H (DMSO-d6)-9.16 (s, 1H), 8.92 (s, 1H), 7.88-7.98 (m, 1H), 7.48-7.58 (m, 3H), 7.34 (d, 1H, J=9.43), 7.26 (t, 1H, J=8.64 Hz), 6.94 (d, 1H, J=5.50), 6.90 (d, 1H, J=4.70 Hz), 6.81 (d, 2H, J=9.43 Hz), 5.19 (s, 2H), 3.03 (bs 3H), 2.45 (bs, 3H), 2.22 (s, 3H).
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][CH2:7][CH2:8][C@H:9]([OH:12])[CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16].C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([Si:5]([CH3:13])([CH3:14])[O:6][CH2:7][CH2:8][C@H:9]([OH:12])[CH2:10][O:11][S:15]([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H](O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)CCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.4 %

Procedure:
To a solution of (2S)-4-(tert-butyl-dimethyl-silanyloxy)-butane-1,2-diol (23.9 g, 108 mmol; second eluting compound in Preparation C, step C.i) and DMAP (2.65 g, 0.2 eq) in DCM (80 mL) cooled to 0° C. were added TEA (43.8 mL, 2.9 eq.) and a solution of TsCl (20.7 g, 1.1 eq.) in DCM (15 mL). The mixture was stirred at rt for 5 h, poured on sat. aq. NaHCO3 and extracted with DCM. The org. layer was dried over MgSO4 and concentrated. The residue was purified by CC (Hept/EA 2:1) to afford the title intermediate as a colourless oil (31.3 g, 77% yield).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:26])[C:6]([NH:9][C:10](=[O:25])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)([CH3:8])[CH3:7].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO.O>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:6]([CH3:8])([CH3:7])[C:5]([OH:26])=[O:4])=[O:25])=[CH:12][CH:13]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc(OCc2ccccc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(NC(=O)c1ccc(OCc2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.4 %

Procedure:
LiOH (38.5 mg, 0.9 mmol) was added to a stirred solution of 2-(4-benzyloxy-benzoylamino)-2-methyl-propionic acid methyl ester (200 mg, 0.6 mmol) in THF:MeOH:H2O (3:1:1, 3.5 mL), and the resulting mixture was stirred at room temperature for 4 hrs. The reaction mixture was concentrated under reduced pressure to get the residue. Cold water was then added, acidified it with aqueous citric acid solution and extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 170 mg (90% yield) of 2-(4-benzyloxy-benzoylamino)-2-methyl-propionic acid.
Reaction SMILES: [NH2:1][C:2]1([CH2:8]O)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>ClCCl.CN(C1C=CN=CC=1)C>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:1]2[C:2]3([CH2:7][CH2:6][O:5][CH2:4][CH2:3]3)[CH2:8]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: NC1(CO)CCOCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CC23CCOCC3)cc1
Reaction time: 18 h
Yield: 38.3 %

Procedure:
A solution of 4-aminotetrahydro-2H-pyran-4-methanol (16 g, 122 mmol) in dichloromethane (700 mL) was treated with triethylamine (85 mL, 610 mmol), p-toluenesulfonyl chloride (69.8 g, 366 mmol) and DMAP (1490 mg, 12.2 mmol) under nitrogen. After approximately 18 hours at room temperature, the reaction was filtered through a pad of silica gel. The filtrate was concentrated in vacuo then purified by chromatography on silica gel (5-20% EtOAc/hexane) to afford intermediate the title compound (12.5 g) as a white solid.