Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=1.[I:19]I>C(Cl)(Cl)Cl>[I-:19].[F:18][C:2]([F:1])([F:17])[C:3]1[CH:16]=[CH:15][C:14]2[C:5](=[N:6][C:7]3[C:12]([S+:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=1
Reactant: FC(F)(F)c1ccc2c(c1)Nc1ccccc1S2
Reactant: II
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1ccc2[s+]c3ccccc3nc2c1
Product: [I-]
Temperature: 25 °C

Procedure:
Commercially available 2-Trifluoromethylphenothiazine (1.14 g, 4.28 mmol) was dissolved in CHCl3 (20 mL) and a solution of I2 (3.25 g, 12.84 mmol) in CHCl3 (120 mL) was added. The mixture was warmed at 55° C. to 60° C. until the SM was consumed (by TLC). The reaction mixture was allowed to cool to RT and the solvent was evaporated. The residue was stirred in Et2O, filtered off and washed with Et2O until the filtrate was colorless. The intermediate was used without further purification.
Reaction SMILES: [CH2:1]=[CH:2][C:3]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])([CH3:5])[OH:4].[CH2:12]=[C:13]1[O:17][C:15](=[O:16])[CH2:14]1>CN(C)C1C=CN=CC=1>[O:17]=[C:13]([CH3:12])[CH2:14][C:15]([O:4][C:3]([CH3:5])([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH:2]=[CH2:1])=[O:16]
Reactant: C=C1CC(=O)O1
Reactant: C=CC(C)(O)CCC=C(C)C
Agent: CN(C)c1ccncc1
Product: C=CC(C)(CCC=C(C)C)OC(=O)CC(C)=O
Temperature: 55 °C
Yield: 92 %

Procedure:
A mixture of linalool (100 g, 0.648 mol) and 4-dimethylaminopyridine (0.40 g, 3.20 mmol) in a 500 mL three-necked round-bottomed flask fitted with a condenser, argon inlet, addition funnel, magnetic stirrer and internal thermometer is heated to 55° C. Diketene (54.50 g, 0.648 mol) is added dropwise in the course of 30 min. The mixture has a slight exotherm and turns from yellow to red during this time. After stirring an additional hour at 50° C., the mixture is cooled to room temperature. At this point, NMR analysis indicates the reaction is complete. The material from this lot is carried onto the next step. Purification of an earlier sample from this route by flash chromatography (elution with dichloromethane) yields the desired product in 92% yield and nearly colorless.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[C:11]([NH2:12])=[CH:10][C:9]([F:13])=[CH:8][N:7]=1.[Cl-].[Li+]>CS(C)=O.O>[NH2:12][C:11]1[C:6]([CH:2]=[O:1])=[N:7][CH:8]=[C:9]([F:13])[CH:10]=1
Reactant: Nc1cc(F)cnc1C1OCCO1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1cc(F)cnc1C=O
Temperature: 90 °C

Procedure:
To a solution of 2-(1,3-dioxolan-2-yl)-5-fluoropyridin-3-amine (5 g, 27.14 mmol) in DMSO: H2O (1:1) (162 mL) was added lithium chloride (6.9 g, 162.89 mmol). The reaction mixture was heated to 90° C. for 16 h and water was removed using dean-stark apparatus. Water was added to the reaction mass and extracted with EtOAc. Organic layer was washed with brine and dried over Na2SO4. The organic layer was concentrated in vacuo and purified by column chromatography on silica gel using 0-40% EtOAc in hexane to give 3-amino-5-fluoropicolinaldehyde: 1H NMR (400 MHz, DMSO-d6): δ 7.003-7.037 (m, 1H), 7.387 (br s, 2H), 7.944 (d, 1H, J=2.4 Hz), 9.853 (s, 1H); LC-MS (ESI) m/z 141.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]2([C:30]([O:32]CC)=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]2([C:30]([OH:32])=[O:31])[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[CH:5]=[C:6]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)[C:7]=1[O:8][CH2:9][C:10]([F:11])([F:12])[F:13]
Reactant: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C(F)(F)F)cc3)c2)CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C(F)(F)F)cc3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.6 %

Procedure:
A mixture of ethyl 4-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)tetrahydro-2H-pyran-4-carboxylate (400 mg, 0.78 mmol) and lithium hydroxide monohydrate (0.188 g, 7.8 mmol) in a MeOH/THF/Water solvent mixture (5 ml/5 ml5/ml) was stirred for 3 h at room temperature. After completion of reaction volatiles were removed under reduced pressure. Residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). Combined organic layer was washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 4-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)tetrahydro-2H-pyran-4-carboxylic acid (100 mg). 1H-NMR (CDCl3, 400 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.56 (s, 1H); 7.34 (s, 1H); 3.98 (q, 2H); 3.61 (t, 2H); 2.53 (dd, 2H); 1.99 (m, 2H).
Reaction SMILES: Br[C:2]1[C:3]([F:8])=[N:4][CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)(C)C.[O:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1>C1COCC1>[F:8][C:3]1[C:2]([C:17]2([OH:20])[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Fc1ncccc1Br
Reactant: O=C1CCOCC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC1(c2cccnc2F)CCOCC1
Reaction time: 8 h

Procedure:
To a solution of 3-bromo-2-fluoropyridine (0.93 g, 5.28 mmol) in THF (5 mL) was added dropwise isopropylmagnesium chloride (2.64 mL, 5.28 mmol, 2M solution) at room temperature. After overnight stirring, dihydro-2H-pyran-4(3H)-one (0.486 mL, 5.28 mmol) was added dropwise. Reaction was quenched with saturated NH4Cl solution and extracted with DCM. Purification by Biotage (0-10% MeOH/DCM) produced the desired product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH2:13][N:14]([CH:18]([CH3:20])C)[C:15](Cl)=[O:16])[CH:10]=[CH:11][CH:12]=2)=[CH:3][CH:2]=1.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:37]=[CH:36][C:31]([C:32]([NH:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.[CH2:38](N(CC)CC)C>ClCCl>[CH2:18]([N:14]([CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[CH:8]=1)[C:15](=[O:16])[O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:37]=[CH:36][C:31]([C:32](=[O:33])[NH:34][CH3:35])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1)[CH2:20][CH3:38]
Reactant: CCN(CC)CC
Reactant: CC(C)N(Cc1cccc(-c2ccncc2)c1)C(=O)Cl
Reactant: CNC(=O)c1ccc(-c2ccc(O)cc2)cc1
Solvent: ClCCl
Product: CCCN(Cc1cccc(-c2ccncc2)c1)C(=O)Oc1ccc(-c2ccc(C(=O)NC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask was placed a solution of N-[3-(4-pyridinyl)phenylmethyl]N-isopropylcarbamoyl chloride (310 mg, 1.07 mmol, 1 equiv) in dichloromethane (15 mL), 4-(4-hydroxyphenyl)-N-methylbenzamide from Example 1 Step 3 (291 mg, 1.28 mmol, 1.2 equiv) and triethylamine (216 mg, 2.13 mmol, 2 equiv). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 20 mL of dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-002(Agilent)): Column, Xbridge Prep C18, 5 um, 19*150 mm; mobile phase, water and CH3CN (45.0% CH3CN up to 75.0% in 10 min, hold 100.0% in 1 min, hold 45.0% in 2 min); Detector, uv 220 & 254 nm. The title compound was obtained as a white solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([S:29]([Cl:32])(=[O:31])=[O:30])[CH:24]=1>>[ClH:32].[N:11]1([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[S:29]([C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)(=[O:31])=[O:30])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]ccc23)CC1
Product: Cl
Product: O=S(=O)(c1cccnc1)n1ccc2c(N3CCNCC3)cccc21

Procedure:
The title compound was prepared from 4-(4-boc-piperazinyl)-indole and 3-pyridinylsulfonyl chloride according to Method 3: 1H NMR (270 MHz, DMSO-d6) δ 9.37 (br, 1 H), 9.18 (d, J=3 Hz, 1 H), 8.86 (d, J=5 Hz, 1 H), 8.39 (d, J=8 Hz, 1 H), 7.85 (d, J=3 Hz, 1 H), 7.70–7.60 (m, 2 H), 7.27 (t, J=8 Hz, 1 H), 7.00 (d, J=3 Hz, 1 H), 6.82 (d, J=8 Hz, 1 H), 3.24 (m, 8 H); MS (ESI+) for m/z 343 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:10]([CH3:20])=[CH:11][CH:12]=[C:13]2[C:18]=1[O:17][CH2:16][CH2:15][C:14]2=[O:19].Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl.C(Cl)(Cl)(Cl)Cl>CCOCC>[CH3:20][C:10]1[C:9]([N:8]=[C:22]=[O:24])=[C:18]2[C:13]([C:14](=[O:19])[CH2:15][CH2:16][O:17]2)=[CH:12][CH:11]=1
Reactant: Cc1ccc2c(c1N)OCCC2=O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc2c(c1N=C=O)OCCC2=O
Temperature: 25 °C
Yield: 276.5 %

Procedure:
0.15 ml of triethylamine was added to a mixture of 180 mg of 8-amino-7-methyl-4-chromanone, 103 mg of triphosgene and 8 ml of carbon tetrachloride at room temperature with stirring, and the reaction was allowed to proceed under reflux for 6.5 hr. The reaction mixture was cooled to room temperature, ether was added thereto, and insolubles were removed by filtration. The filtrate was concentrated to give 195 mg of the intended title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH2:9])=[C:4]([Cl:10])[N:3]=1.O.[CH:12](O)=[O:13]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH:12]=[O:13])=[C:4]([Cl:10])[N:3]=1
Reactant: O=CO
Reactant: Nc1nc(Cl)c(N)c(Cl)n1
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1nc(Cl)c(NC=O)c(Cl)n1
Temperature: 52.5 °C
Reaction time: 3 h

Procedure:
2,5-Diamino-4,6-dichloropyrimidine (0.01 mol; 2.0 g) and water (0.25 mol; 4.55 ml) were stirred at room temperature. 98% strength formic acid (0.4 mol; 18.27 g; 14.97 ml) was then added to the reaction. The reaction was subsequently heated to 50-55° C. and kept at this temperature for 3 h. Toluene (0.38 mol; 34.6 g; 40 ml) was then added for the azeotropic distillation under high vacuum at 50° C. (toluene was added twice to guarantee a good distillation, i.e. a total of 80 ml).
Reaction SMILES: [C:1]([O:7][CH2:8]Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:10]([C:12]1[N:22]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[C:37](=[O:42])[C:38](=[O:41])[C:39]=3[OH:40])=[CH:26][CH:25]=2)[C:15]2=[N:16][C:17]([CH3:21])=[CH:18][C:19]([CH3:20])=[C:14]2[N:13]=1)[CH3:11].[I-].[K+].C(OCC)C>CN(C)C(=O)C>[C:1]([O:7][CH2:8][O:42][C:37]1[C:38](=[O:41])[C:39](=[O:40])[C:36]=1[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:22]2[C:15]3=[N:16][C:17]([CH3:21])=[CH:18][C:19]([CH3:20])=[C:14]3[N:13]=[C:12]2[CH2:10][CH3:11])=[CH:25][CH:26]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2-c2c(O)c(=O)c2=O)cc1
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2-c2c(OCOC(=O)C(C)(C)C)c(=O)c2=O)cc1
Reaction time: 48 h

Procedure:
Chloromethyl pivalate (3.22 g) was added, dropwise, at ambient temperature, to a stirring suspension of 3-[4'-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl -2-yl]-4-hydroxycyclobut-3-ene-1,2-dione (4.21 g; preparable as in Example 4) in dry N,N-dimethylacetamide (40 ml). Potassium iodide (2.5 g) was added to the resulting mixture and stirring was continued am ambient temperature for 2 days. More chloromethyl pivalate (3.7 g) was added and stirring was continued for an additional 2 days. The mixture obtained was poured into diethyl ether (500 ml) to give a gum which was separated and then dissolved in a mixture of acetone (100 ml) and ethyl acetate (300 ml). The resulting solution was washed with saturated aqueous sodium bicarbonate solution (2×400 ml) then water (2×400 ml) and dried over magnesium sulphate. The solvents were evaporated under reduced pressure and the residue obtained was purified by flash chromatography on silica gel (eluting with ethyl acetate) to give 2-[4'-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl-2-yl]-3,4-dioxocyclobut-1-en-1-yloxymethyl pivalate, an active compound of the present invention, as a fellow foam (0.54 g) which melted slowly at 60°-80° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:16]=[C:17]([S:24][C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:38])OC(C)(C)C)[CH:28]=[CH:29][CH:30]=4)[C:18]4[S:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[CH3:40][N:41]([CH3:48])[CH2:42]/[CH:43]=[CH:44]/C(O)=O.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.C(Cl)(Cl)Cl.CC(O)C>[CH3:40][N:41]([CH3:48])[CH2:42]/[CH:43]=[CH:44]/[C:32]([NH:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([S:24][C:17]2[C:18]3[S:23][CH:22]=[CH:21][C:19]=3[N:20]=[C:15]([NH:14][C:11]3[CH:10]=[CH:9][C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[CH:13][CH:12]=3)[N:16]=2)[CH:26]=1)=[O:38]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: CN1CCN(c2ccc(Nc3nc(Sc4cccc(NC(=O)OC(C)(C)C)c4)c4sccc4n3)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: CC(C)O
Product: CN(C)C/C=C/C(=O)Nc1cccc(Sc2nc(Nc3ccc(N4CCN(C)CC4)cc3)nc3ccsc23)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 4 %

Procedure:
40 mg (0.09 mmol) of the compound obtained in Step 2 of Example 223 was dissolved in 1.5 mL of pyridine, and 22 mg (0.14 mmol) of (E)-4-(dimethylamino)-2-butenoic acid hydrochloride and 35 mg (0.18 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride were added thereto, and stirred for 30 minutes at 80° C. Upon the completion of the reaction, the resulting mixture was diluted with mixed solvent of chloroform:2-propanol (3:1(v/v)) and washed with saturated saline. The organic layer was separated, dried over anhydrous Na2SO4, and filtered and distilled under a reduced pressure. The resulting residue was separated by column chromatography (dichloromethane:methanol=6:1 (v/v)) to obtain 2 mg of the title compound (yield: 4%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10](O)=[S:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+]([O-])(O)=O.[N+:25]([O:28][CH2:29][CH2:30][NH2:31])([O-:27])=[O:26]>>[N+:25]([O:28][CH2:29][CH2:30][NH:31][C:10](=[S:11])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([O-:27])=[O:26]
Reactant: NCCO[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)C[C@@H](NC(=O)OC(C)(C)C)C(O)=S
Solvent: O=[N+]([O-])O
Product: CC(C)(C)OC(=O)C[C@@H](NC(=O)OC(C)(C)C)C(=S)NCCO[N+](=O)[O-]
Yield: 88 %

Procedure:
The procedures of Example 1 were analogously repeated using 322 mg of (2R)-2-tert-butoxycarbonylamino-3-tert-butoxycarbonylthiopropionic acid and 186 mg of 2-nitrooxyethylamine nitrate to give 365 mg of the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:13].[CH3:14][S:15]([NH:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)(=[O:17])=[O:16].C(=O)([O-])[O-].[Na+].[Na+].O>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>[NH2:6][C:5]1[CH:7]=[C:8]([C:9]([F:12])([F:11])[F:10])[C:2]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:18][S:15]([CH3:14])(=[O:16])=[O:17])[CH:24]=2)=[C:3]([Cl:13])[CH:4]=1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: Nc1cc(Cl)c(Br)c(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)Nc1cccc(-c2c(Cl)cc(N)cc2C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 75.3 %

Procedure:
A mixture of 4-bromo-3-chloro-5-(trifluoromethyl)aniline (573 mg, 2.09 mmol, Eq: 1.00), 3-(methylsulfonamido)phenylboronic acid (529 mg, 2.46 mmol, Eq: 1.18) and tetrakis(triphenylphosphine)palladium (0) (211 mg, 183 μmol, Eq: 0.0875) was degassed (vacuum/nitrogen cycles) then degassed dioxane (6.87 ml) (nitrogen bubbling with sonication) and a degassed (nitrogen bubbling with sonication) 2M solution of sodium carbonate in water (1.83 ml, 3.66 mmol, Eq: 1.75) were added. The mixture was stirred at 100° C. for 18 h. The reaction mixture was adsorbed unto silica (2 g), concentrated and purified on silica gel (silica 40 g, dichloromethane/ethyl acetate 100:0 to 80:20) to give 574 mg (75%) of the desired product as a yellow solid.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:41].C(=O)(O)[O-].[Na+]>ClCCl>[Br:41][CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:5]=1
Reactant: CCOC(=O)COc1ccc(CCO)cc1C(F)(F)F
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(CCBr)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
To a solution of ethyl 2-[4-(2-hydroxyethyl)-2-(trifluoromethyl)phenoxy]acetate (224 mg) in dichloromethane (2 ml) were added triphenylphosphine (260 mg) and carbon tetrabromide (396 mg), and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The extract was washed with water and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent:dichloro-methane/hexane=1/1) gave ethyl 2-[4-(2-bromoethyl)-2-(trifluoromethyl)phenoxy]acetate (178 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:6]([N:10]1[C:18]2[C:13](=[C:14](I)[CH:15]=[C:16]([C:19]([O:21]C)=[O:20])[CH:17]=2)[CH:12]=[CH:11]1)[CH2:7][CH2:8][CH3:9]>C1COCC1.[Cl-].[Zn+2].[Cl-]>[CH2:6]([N:10]1[C:18]2[C:13](=[C:14]([C:2]3[O:1][CH:5]=[CH:4][N:3]=3)[CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=2)[CH:12]=[CH:11]1)[CH2:7][CH2:8][CH3:9]
Reactant: c1cocn1
Reactant: CCCCn1ccc2c(I)cc(C(=O)OC)cc21
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCCCn1ccc2c(-c3ncco3)cc(C(=O)O)cc21
Temperature: 85 °C
Yield: 70.4 %

Procedure:
To a −72° C. solution of oxazole (0.069 g) in dry THF (20 mL) was added dropwise 1.6 M N-butyl lithium (0.68 mL). The mixture was stirred at −72° C. for 30 minutes at which time 1.0 M zinc chloride (3.3 mL) was added. The mixture was allowed to warm to 0° C. at which time methyl 1-butyl-4-iodo-1H-indole-6-carboxylate (0.37 g) and tetrakis triphenylphosphine palladium (0) (0.07 g) were added and the mixture heated to 85° C. The mixture was heated at 85° C. for 20 h then cooled to room temperature and partitioned between water and ethyl acetate. The layers were separated and the organic layer washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Column chromatography was performed on silica gel (100 mL) using 20% ethyl acetate in hexanes as eluent. The residue was dissolved in methanol (10 mL) and 1N NaOH (3 mL) and heated at 60° C. for 2 h. The mixture was acidified to pH 4 with 1N HCl and extracted with ethyl acetate. The ethyl acetate extracts were dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give 0.2 g of the title compound: MS (ESI+) for C16H16N2O3 m/z 283.16 (M+H)+.
Reaction SMILES: CO.C1COCC1.C[O:9][C:10](=[O:39])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29](=[N:36][O:37][CH3:38])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:23][CH:22]=2)=[CH:15][CH:14]=1.[OH-].[Na+]>O>[CH3:38][O:37]/[N:36]=[C:29](/[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)\[CH2:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:19][C:16]2[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][C:10]([OH:39])=[O:9])=[CH:14][CH:15]=2)=[CH:22][CH:23]=1
Reactant: CON=C(COc1ccc(COc2ccc(CCC(=O)OC)cc2)cc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CO/N=C(\COc1ccc(COc2ccc(CCC(=O)O)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.7 %

Procedure:
To a 25 mL RB flask fitted with magnetic stirrer was charged 2 mL of methanol and 1 mL of THF. To the stirred solvent, was added 3-{4-[4-(2-methoxyimino-2-phenyl-ethoxy)-benzyloxy]-phenyl}-propanoic acid methyl ester (0.085 g, 0.19 mmol). To the stirred solution, NaOH (0.015 g, 0.375 mmol) in water (1 mL) was added. The resulting solution was stirred at RT for 3 h. After completion of the reaction (reaction monitored by TLC), the solvent was evaporated under reduced pressure. The RM was diluted with 1 mL of water, cooled to 0° C., then acidified with 1N HCl (5 mL), and extracted with ethyl acetate (10 mL×2), organic layer was given water (5 mL) and saturated brine solution wash (5 mL), dried over anhydrous Na2SO4 and evaporated to dryness to yield colorless solid (0.050 g, yield: 63.3%); purity: 97.65%.
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4]C)C.CNC.Cl[C:12]1[N:20]2[CH:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH2:22][O:23][C:18]3=[C:19]2[C:14](=[C:15]([F:37])[CH:16]=[C:17]3[C:30]2[C:31]([CH3:36])=[N:32][O:33][C:34]=2[CH3:35])[N:13]=1>CN1CCCC1=O.CO>[CH3:36][C:31]1[C:30]([C:17]2[C:18]3[O:23][CH2:22][CH:21]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[N:20]4[C:12]([N:3]([CH3:4])[CH3:1])=[N:13][C:14]([C:19]=34)=[C:15]([F:37])[CH:16]=2)=[C:34]([CH3:35])[O:33][N:32]=1
Reactant: CCN(CC)CC
Reactant: Cc1noc(C)c1-c1cc(F)c2nc(Cl)n3c2c1OCC3c1cccnc1
Agent: CNC
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cc1noc(C)c1-c1cc(F)c2nc(N(C)C)n3c2c1OCC3c1cccnc1
Temperature: 150 °C
Yield: 19.1 %

Procedure:
Triethylamine (16 μL, 0.12 mmol) and dimethylamine (0.2 mL, 4 mmol) were added to 2-chloro-7-(3,5-dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (15 mg, 0.040 mmol) in N-methylpyrrolidinone (0.41 mL) and the mixture was heated in a microwave at 150° C. for 20 min. The mixture was diluted with methanol and purified by preparative LCMS using pH 10 buffer to afford the title compound (3.0 mg, 19%). LCMS calc. for C21H21FN5O2 (M+H)+: m/z=394.2. found: 394.1.
Reaction SMILES: C(OC([NH:11][CH2:12][C@@H:13]([CH2:17][C@H:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:14]([OH:16])=[O:15])=O)C1C=CC=CC=1.[H][H]>>[NH2:11][CH2:12][CH:13]([CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:14]([OH:16])=[O:15]
Reactant: [H][H]
Reactant: CC(C)CCC[C@@H](C)C[C@H](CNC(=O)OCc1ccccc1)C(=O)O
Product: CC(C)CCCC(C)CC(CN)C(=O)O
Yield: 67.3 %

Procedure:
2(R)-(Benzyloxycarbonylamino-methyl)-4(R),8-dimethyl-nonanoic acid (0.148 g, 0.566 mmol) was treated with hydrogen in the presence of 20% pd/C to give 0.082 g of 2-aminomethyl-4,8-dimethyl nonanoic acid after filtration and purification via silica gel chromatography (85/15 CH2Cl2/MeOH). m/z 216.3 (M+).