Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:25])[N:5]([CH2:22][C:23]#[CH:24])[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]3OCC[O:18]3)[CH:12]=2)=[N:7][C:8]=1[CH2:9][CH3:10])[CH3:2].Cl.CCOCC.O>C(OCC)(=O)C.CCCCCC>[CH2:1]([C:3]1[C:4](=[O:25])[N:5]([CH2:22][C:23]#[CH:24])[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[O:18])[CH:12]=2)=[N:7][C:8]=1[CH2:9][CH3:10])[CH3:2]
Reactant: C#CCn1c(-c2cccc(C3OCCO3)c2)nc(CC)c(CC)c1=O
Agent: Cl
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: C#CCn1c(-c2cccc(C=O)c2)nc(CC)c(CC)c1=O
Reaction time: 4 h
Yield: 86.4 %

Procedure:
To a solution of 2.3 g (6.8 mmol) of 5,6-diethyl-2-[3-(2-dioxolanyl)phenyl]-3-propargyl-4(3H)-pyrimidinone in 1 mL of ethyl acetate was added 50 mL of 6M hydrochloric acid and the mixture was stirred for 4 hours. The reaction was followed by gas chromatography and TLC(20% ethyl acetate in hexane). Upon completion of reaction, 75 mL of ether and 150 mL of water were added to the reaction mixture. The layers were separated and the aqueous layer was extracted twice with 50 mL of ether. The organic layers were combined, dried over MgSO4 and concentrated to yield 1.73 g of 5,6-diethyl-2-(3-formylphenyl)-3-propargyl-4(3H)-pyrimidinone (Compound 69) as a yellow oil (86%), which solidified on standing. Mp.=82°-86° C. 1H-NMR (CDCl3)δ1.25(6H,m), 2.4(1H, t), 2.65(4H,q), 4.6(2H,d), 7.7(1H, t), 8.05(2H,m), 8.25(1H,s), 10.15(1H,s).
Reaction SMILES: [C:1]1([C:7](=[O:24])[CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9]/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCOC(C)=O.[Pd]>[C:1]1([C:7](=[O:24])[CH:8]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1)C(C/C=C/c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)C(CCCc1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
To the compound of Example 9 Step 1 (0.20 g, 0.64 mmole) dissolved in EtOAc was added Pd/C. The reaction was then stirred for 2 h under 1 atmosphere of H2, and was then filtered through celite and evaporated.
Reaction SMILES: [CH:1]1([C:4]2[C:15]3[O:14][C:11]4([CH2:13][CH2:12]4)[CH2:10][C:9]([CH3:17])([CH3:16])[C:8]=3[CH:7]=[C:6]([C:18]#[CH:19])[CH:5]=2)[CH2:3][CH2:2]1.[CH3:20][O:21][C:22](=[O:32])[CH:23]([C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1)[CH3:24]>C(N(CC)CC)C.C(OCC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][O:21][C:22](=[O:32])[CH:23]([C:25]1[CH:26]=[CH:27][C:28]([C:19]#[C:18][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[C:15]3[O:14][C:11]4([CH2:13][CH2:12]4)[CH2:10][C:9]([CH3:16])([CH3:17])[C:8]=3[CH:7]=2)=[CH:29][CH:30]=1)[CH3:24]
Reactant: COC(=O)C(C)c1ccc(I)cc1
Reactant: C#Cc1cc(C2CC2)c2c(c1)C(C)(C)CC1(CC1)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)C(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
A solution of 8-cyclopropyl-6-ethynyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane] (described in U.S. Pat. No. 6,252,090; 0.068 g, 0.27 mmol), and methyl-2-(4-iodo phenyl)propionate (Reagent 1, 0.086 g, 0.3 mmol) in triethyl amine (3 mL), was treated with copper(I)iodide (0.028 g, 0.15 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (0.057 g, 0.08 mmol) was added and the reaction mixture was stirred overnight at room temperature. It was diluted with diethyl ether and filtered over a bed of celite. The filtrate was evaporated in vacuo to brown oil that was subjected to flash column chromatography over silica gel (230-400 mesh) to afford the title compound as an oil (0.072 g, 56%).
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]([CH2:25][CH3:26])([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)[C:5]1=[O:27])[CH:2]=C.[BH4-].[Na+].C[OH:31]>>[CH2:25]([C:6]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:12]=2)[CH2:7][CH2:8][CH2:9][CH2:10][N:4]([CH2:1][CH2:2][OH:31])[C:5]1=[O:27])[CH3:26]
Reactant: CO
Reactant: C=CCN1CCCCC(CC)(c2cccc(OCc3ccccc3)c2)C1=O
Agent: [BH4-]
Agent: [Na+]
Product: CCC1(c2cccc(OCc3ccccc3)c2)CCCCN(CCO)C1=O
Temperature: -40 °C
Reaction time: 0.42 h

Procedure:
A solution of 1-allyl-3-ethyl-3-(3-benzyloxy-phenyl)-azepan-2-one, as described in Step B above, (0.87 g, 2.4 mmol) in MeOH (20 mL) at −78° C. was saturated with 03 for 25 min. The solution was warmed to −40° C. for 10 min then NaBH4 (0.363 g, 9.6 mmol) was added and the reaction mixture was stirred at 25° C. for 1 hr. The MeOH was removed in vacuo , and the residue was partitioned between EtOAc and saturated NaHCO3 solution. The organic layer was washed with brine and dried (MgSO4). Filtration and concentration to dryness gave the title compound after chromatography on silica gel eluting with hexane/EtOAc, 1/1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>N1C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:29])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1
Reactant: O=C1CN=C(c2ccccn2)c2cc(Cl)ccc2N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccncc1
Product: S=C1CN=C(c2ccccn2)c2cc(Cl)ccc2N1
Temperature: 100 °C
Reaction time: 2 h
Yield: 185.1 %

Procedure:
A solution of 18.5 g of 7-chloro-5-(2-pyridyl)-3H-1,4-benzodiazepin-2(1H)-one (N. Ch. Hindley, T. M. McClymont & G. O. Chase; F. Hoffmann La Roche and Co., A. G., German Offenlegungsschrift 2,233,483, 1973) in 150 ml of pyridine was treated with 14.2 g of Lawesson reagent and the mixture was stirred at 100° C. for 2 h. After the addition of 1.0 g of Lawesson reagent the mixture was stirred at 100° C. for a further 0.5 h. and then evaporated in a vacuum. The residue was poured into 500 ml of saturated aqueous sodium hydrogen carbonate solution and the precipitate was filtered off (22 g). The red crystals were suspended in 100 ml of boiling methanol. After cooling 100 ml of diethyl ether were added and the crystals were filtered off. There were obtained 18.7 g of 7-chloro-5-(2-pyridyl)-3H-1,4-benzodiazepine-2(1H)-thione of m.p. 217-218° C.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:12]1[CH:18]2[CH:13]1[C:14]([CH3:21])([CH3:20])[CH2:15][C:16](=[O:19])[O:17]2.C(Cl)Cl.[CH3:25][OH:26]>>[CH3:25][O:26][CH:18]1[O:17][C:16](=[O:19])[CH2:15][C:14]([CH3:21])([CH3:20])[CH:13]1[OH:12]
Reactant: CO
Reactant: CC1(C)CC(=O)OC2OC21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: COC1OC(=O)CC(C)(C)C1O
Temperature: -10 °C
Reaction time: 16 h

Procedure:
A drop of p-toluene sulfonic acid was added at -15° C. to a solution of 1.42 g of 5.6-epoxy-4,4-dimethyl-tetrahydro-pyr-2-one melting at ≃22° C., 14 ml of methylene chloride and 320 mg of methanol and the mixture was stirred for 31/2 hours at -10° C. 0.4 ml of methanol were added and the mixture was stirred at -10° C. for 16 hours. 40.4 ml of methanol and a little p-toluene sulfonic acid were added and the mixture was stirred for 48 hours while letting the temperature rise to room temperature. The mixture was decanted and the liquid phase was washed with aqueous saturated sodium bicarbonate solution, then with water, was dried and evaporated to dryness under reduced pressure. The 1.45 g of residue was chromatographed over silica and was eluted with a 1-1 mixture of hexane-ethyl acetate to obtain 1.42 g of dl 6-methoxy-5-hydroxy-4,4-dimethyl-tetrahydro-pyr-2-one melting at 72° C. and having a Rf=0.20.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[C:6]([CH3:19])[CH:5]=1.FC(F)(F)S(O[C:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=1)(=O)=O>>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=2)=[C:6]([CH3:19])[CH:5]=1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: O=S(=O)(OC1=CCCCC1)C(F)(F)F
Product: COC(=O)c1ccc(C2=CCCCC2)c(C)c1
Yield: 95.2 %

Procedure:
3-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester of Step A (5.00 g, 18.1 mmol) and cyclohex-1-en-1-yl trifluoromethanesulfonate (4.58 g, 19.9 mmol) were reacted in the manner of Example 1, Step F. Purification by flash column chromatography on silica gel, eluting with 10% ethyl acetate in hexane, afforded the title compound (3.97 g) as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][C@@H:8]2[O:12][CH2:11][C@@H:10]([S:13]C(=O)C)[CH2:9]2)=[CH:4][CH:3]=1.[Na].CO>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]2[O:12][CH2:11][CH:10]([SH:13])[CH2:9]2)=[CH:17][CH:18]=1
Reactant: CC(=O)S[C@@H]1CO[C@@H](COc2ccc(F)cc2)C1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CO
Product: Fc1ccc(OCC2CC(S)CO2)cc1
Yield: 52.4 %

Procedure:
The title compound is prepared by the procedure of Example 16 using 0.943 g of product from Example 35, 0.86 ml of 25% .sodium methhoxide/methyl alcohol and 12 ml of tetrahydrofuran to give 0.417 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([OH:17])=O)[C:10]1=[O:18].[NH2:19][C:20]1[CH:41]=[CH:40][C:23]([O:24][C:25]2[CH:26]=[CH:27][C:28]3[N:29]([CH:31]=[C:32]([NH:34][C:35]([CH:37]4[CH2:39][CH2:38]4)=[O:36])[N:33]=3)[CH:30]=2)=[C:22]([F:42])[CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C.O1CCCC1>[CH:37]1([C:35]([NH:34][C:32]2[N:33]=[C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]4[CH:40]=[CH:41][C:20]([NH:19][C:15]([C:11]5[C:10](=[O:18])[N:9]([C:3]6[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=6[CH3:1])[CH:14]=[CH:13][CH:12]=5)=[O:17])=[CH:21][C:22]=4[F:42])=[CH:30][N:29]3[CH:31]=2)=[O:36])[CH2:38][CH2:39]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: Cc1cccc(C)c1-n1cccc(C(=O)O)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1-n1cccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.2 %

Procedure:
1-(2,6-Dimethylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (120 mg, 0.51 mmol), N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol) and HATU (340 mg, 0.91 mmol) were suspended in N,N-dimethylformamide (3.0 mL), and N,N-diisopropylethylamine (0.16 mL, 0.92 mmol) was added. After stirring at room temperature overnight, the mixture was diluted with ethyl acetate (5.0 mL) and tetrahydrofuran (5.0 mL). The mixture was washed twice with saturated aqueous sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=65/35→85/15). The fractions containing the object product were mixed. The solvent was evaporated under reduced pressure, and a small amount of hexane/ethyl acetate was added. The resulting precipitate was collected by filtration to give the title compound (130 mg, 49%) as a white solid.
Reaction SMILES: [CH2:1]([N:5]([CH2:43][CH2:44][CH2:45][CH3:46])[C:6]([C:8]1[N:9]=[C:10]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=2[C:31]([N:33]2[CH2:42][CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34]2)=[O:32])[N:11](COCC[Si](C)(C)C)[CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:43]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[N:9]=[C:10]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=2[C:31]([N:33]2[CH2:42][CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34]2)=[O:32])[NH:11][CH:12]=1)=[O:7])[CH2:44][CH2:45][CH3:46]
Reactant: CCCCN(CCCC)C(=O)c1cn(COCC[Si](C)(C)C)c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
To a solution methyl 4-(4-(dibutylcarbamoyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (180 mg, 0.28 mmol) in DCM (4 mL) was added trifluoroacetic acid (4 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirring was continued for 4 h. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in DCM and washed with sat. NaHCO3 solution. The organic layer was dried over Na2SO4 and concentrated to give crude product. The crude material was purified by flash chromatography (gradient from 0 to 5% methanol/CHCl3) to provide the title compound (130 mg, 91%). 1H NMR (CD3OD) δ 8.25-8.06 (m, 2H), 8.00-7.50 (m, 2H), 7.28-6.83 (m, 4H), 4.36 (br s, 1H), 4.01 (br s, 4H), 3.60-3.24 (m, 6H), 2.88-2.69 (m, 2H), 1.60-1.52 (m, 4H), 1.36-1.30 (m, 4H), 1.05-0.90 (m, 6H); MS(ESI−) m/z 515.2 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C:8]2([CH3:25])[CH2:12][O:11][S@@:10](=[O:13])[N:9]2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[O:23][CH3:24])[CH:7]=1.I([O-])(=O)(=O)=[O:28].[Na+]>C(OCC)(=O)C.C(#N)C.O.[Ru](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C@:8]2([CH3:25])[CH2:12][O:11][S:10](=[O:28])(=[O:13])[N:9]2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[O:23][CH3:24])[CH:7]=1
Reactant: COc1ccc(CN2[S@](=O)OCC2(C)c2cc(Br)ccc2F)c(OC)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(CN2[C@](C)(c3cc(Br)ccc3F)COS2(=O)=O)c(OC)c1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a mixture of (R)-4-(5-bromo-2-fluoro-phenyl)-3-(2,4-dimethoxy-benzyl)-4-methyl-[1,2,3]oxathiazolidine 2-oxide (15.7 g, 35.3 mmol, Eq: 1.00) and sodium periodate (8.31 g, 38.9 mmol, Eq: 1.1) in ethyl acetate (120 ml), acetonitrile (120 ml) and cold water (192 ml) at 23° C. was added ruthenium(III) chloride (73.3 mg, 353 μmol, Eq: 0.01) and this reaction mixture was stirred vigorously at 23° C. for 30 minutes. Extracted with sat NaHCO3, ethyl acetate, dried the organic layer over Na2SO4, filtered off and evaporated totally. The residue was purified by silica gel column chromatography with heptane/ethyl acetate to give the. The product fractions were collected and totally evaporated, dried in HV to give the (R)-4-(5-bromo-2-fluoro-phenyl)-3-(2,4-dimethoxy-benzyl)-4-methyl-[1,2,3]oxathiazolidine 2,2-dioxide (15.6 g, 33.9 mmol, 95.9% yield) as a white solid. MS (ISN): m/z=458.0 [M−H]− and 460.0 [M+2H]−.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=O)[CH:11]=[CH:12]C1C=CC=CC=1.[Al+3].[Cl-:21].[Cl-].[Cl-].BrC1C(F)=CC=C2C=1NC(=O)C=C2>ClC1C=CC=CC=1.O=P(Cl)(Cl)Cl>[Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]2[C:3]=1[N:9]=[C:10]([Cl:21])[CH:11]=[CH:12]2
Reactant: [Cl-]
Reactant: O=C(C=Cc1ccccc1)Nc1cccc(F)c1Br
Agent: O=c1ccc2ccc(F)c(Br)c2[nH]1
Agent: [Al+3]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Clc1ccccc1
Product: Fc1ccc2ccc(Cl)nc2c1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
To a solution of 2-bromo-3-fluoroaniline (6.5 g, 34.17 mmol) and pyridine (2.7 g, 34.17 mmol) in 20 ml of CH2Cl2, cinnamoyl chloride (5.95 g, 35.88 mol) in 10 ml CH2Cl2 are added dropwise and mixture was refluxed for 30 min. The reaction mixture is diluted with CH2Cl2, the organic layer washed with diluted HCl, saturated Na2CO3 solution, water, and dried (Na2SO4). The solvent is removed in vacuo to give 10.5 g of N-(2-bromo-3-fluorophenyl)-3-phenylacrylamide. To a solution of N-(2-bromo-3-fluorophenyl)-3-phenylacrylamide (10.5 g, 32.8 mmol) in 70 ml of chlor-benzene at 130° C. AlCl3 (21.9 g, 0.164 mol) is added portionwise, the mixture is stirred at this temperature 2 h and poured in ice-water. The precipitate is filtered off and dried. Yield 6.05 g (76%). 6 g (24.8 mmol) of 8-bromo-7-fluoro-1H-quinolin-2-one are refluxed in 30 mL of POCl3 during 2 h, then poured on ice, extracted with benzene. the benzene extract dried (Na2SO4) to yield 6.1 g 8-bromo-2-chloro-7-fluoroquinoline after solvent removal. To a mixture of 10 ml 10%-oleum and 1.4 g (22.2 mmol) of fuming HNO3 8-bromo-2-chloro-7-fluoroquinoline (4.8 g 18.5 mmol) is added portionwise. The mixture is heated at 100° C. for 2 h. Additional HNO3 (0.17 g) is added and stirred for additional 1 h. The reaction mixture is poured in ice-water, extracted with EtOAc, filtered through silica gel, and crystallized from heptane-toluene to yield 2.3 g (50%) 8-bromo-2-chloro-7-fluoro-5-nitroquinoline. 2.3 g (7.54 mmol) of 8-bromo-2-chloro-7-fluoro-5-nitroquinoline are heated at 100° C. for 5 h in a solution containing 16 ml of CH3COOH, 3.2 ml of H2O and 5 ml of conc. HCl. The mixture is poured in water, the formed precipitate is filtered off, stirred in EtOAc and filtered to yield 1.71 g. 8-bromo-7-fluoro-5-nitro-1H-quinolin-2-one. To a suspension 1.7 g (5.92 mmol) of 8-bromo-7-fluoro-5-nitro-1H-quinolin-2-one and 2.3 g (35.5 mmol) of HCOONH4 in 10 ml of ethanol 0.1 g 10% Pd—C are added, and stirred for 2 h at 60° C. A solid disappeared and then formed again. The precipitate is filtered off, dissolved in 3 ml of DMSO and filtered through silica gel. 15 ml of water are added to the eluate, the precipitate is filtered off and dried to yield 0.5 g (47%) 5-Amino-7-fluoro-1H-quinolin-2-one. 1H-NMR (DMSO-d6); δ=6.14 (dd, 1H), 6.20 (dd, 1H), 6.23 (d, 1H), 6.27 (br, 2H), 8.06 (d, 1H), 11.50 (br., 1H).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[N:10][C:9]([OH:12])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13]Cl>C(N(CC)CC)C>[C:1]1([N:7]2[C:11]([Cl:13])=[N:10][C:9]([OH:12])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCl
Reactant: Oc1ncn(-c2ccccc2)n1
Solvent: CCN(CC)CC
Product: Oc1nc(Cl)n(-c2ccccc2)n1

Procedure:
32.2 g of 1-phenyl-3-hydroxy-1,2,4-triazole and 40.5 g of triethylamine are dissolved in 300 ml of absolute alcohol. While cooling, 21.3 g of chlorine are passed in (20° to 30°C). Triethylamino hydrochloride is filtered off and the filtrate is concentrated in a rotary evaporator. The residue is treated with 300 ml of water and extracted 4 times with 200 ml of ether each time. The combined ethereal extracts are dried over sodium sulphate. The drying agent is filtered off and the filtrate concentrated. The solid residue is recrystallised from 70 ml of acetonitrile. Yield: 11.4 g (29.2 % of theory); m.p. 147°-149°C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:4][C:3]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=1[F:27].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1C)(C)(C)C.[OH-].[K+].[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>C(O)(C)(C)C.O.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].CCOC(C)=O>[F:27][C:19]1[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:18]=1[O:17][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[N:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1)[N:8]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:7]=[CH:6]2
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(Oc2cc3cnn(C4CCCCO4)c3cc2Br)c(F)c1
Agent: [Pd]
Agent: Cc1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2cc3cnn(C4CCCCO4)c3cc2N2CCOCC2)c(F)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
To a solution of 6-bromo-5-(2-fluoro-4-nitro-phenoxy)-1-(tetrahydropyran-2-yl)-1 H-indazole (8.0 g, 18 mmol) in tert-butanol (150 mL) and H2O (3.2 mL) is added Pd2(dba)3 (320 mg, 0.35 mmol), 2-di-tert-butylphosphino-2′-methylbiphenyl (480 mg, 1.54 mmol), KOH (3.2 g, 57 mmol) and morpholine (3.2 g, 36.7 mmol) under N2. After the mixture is stirred at 70° C. for 2 hours under a N2 atmosphere, it is filtered and the filtrate is concentrated. The residue is partitioned with EtOAc (100 mL) and saturated aqueous NH4Cl (30 mL). The organic layer is separated, dried over MgSO4, and concentrated. The residue is purified by silica gel column chromatography eluting with PE:EtOAc (3:1) to give the product (4.5 g, 56.5% yield). MS (m/z): 443.1 (M+H).
Reaction SMILES: B(Br)(Br)Br.[C:5]([C:8]1[CH:31]=[CH:30][C:11]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:29])[C:25]([O:27][CH3:28])=[O:26])[CH:20]=[CH:21][CH:22]=2)=[C:10]([CH2:32][CH2:33][C:34]([F:37])([F:36])[F:35])[C:9]=1[O:38]C)(=[O:7])[CH3:6].O>C(Cl)Cl>[C:5]([C:8]1[CH:31]=[CH:30][C:11]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:29])[C:25]([O:27][CH3:28])=[O:26])[CH:20]=[CH:21][CH:22]=2)=[C:10]([CH2:32][CH2:33][C:34]([F:36])([F:35])[F:37])[C:9]=1[OH:38])(=[O:7])[CH3:6]
Reactant: COC(=O)C(=O)Nc1cccc(OCCCOc2ccc(C(C)=O)c(OC)c2CCC(F)(F)F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(=O)Nc1cccc(OCCCOc2ccc(C(C)=O)c(O)c2CCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3.0 g of boron tribromide are added dropwise to a solution, cooled to -78° C., of 2.2 g of methyl N-{{3-{3-[4-acetyl-3-methoxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-phenyl}}-oxamate in 20 ml of methylene chloride in the course of 5 minutes. The mixture is then stirred at room temperature for 6 hours. 5 ml of water are added, with cooling, and the organic phase is separated off and evaporated under reduced pressure. Recrystallisation from methylene chloride/ether gives methyl N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-phenyl}}-oxamate.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH2:25][C:26]2[CH:27]=[C:28]([CH:35]=[CH:36][C:37]=2[Cl:38])[O:29][C@@H:30]([CH3:34])[C:31](O)=[O:32])[C:20]([CH3:39])=[C:19]3[CH3:40])=[O:15])[CH3:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].C[N:44](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:44][C:31](=[O:32])[C@@H:30]([O:29][C:28]1[CH:35]=[CH:36][C:37]([Cl:38])=[C:26]([CH:27]=1)[CH2:25][N:21]1[C:22]2[C:18](=[CH:17][C:16]([C:14]([NH:13][C@H:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][CH:7]=3)[CH3:12])=[O:15])=[CH:24][CH:23]=2)[C:19]([CH3:40])=[C:20]1[CH3:39])[CH3:34]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1c(C)n(Cc2cc(O[C@@H](C)C(=O)O)ccc2Cl)c2ccc(C(=O)N[C@@H](C)c3ccc(C(C)(C)C)cc3)cc12
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(C)n(Cc2cc(O[C@@H](C)C(N)=O)ccc2Cl)c2ccc(C(=O)N[C@@H](C)c3ccc(C(C)(C)C)cc3)cc12
Yield: 89.3 %

Procedure:
A solution of (S)-2-(3-((5-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-4-chlorophenoxy)propanoic acid (20 mg, 0.036 mmol), NH4Cl (19 mg, 0.36 mmol), HATU (14 mg, 0.036 mmol) and DIEA (25 μl, 0.144 mmol) in DCM (0.5 ml) was stirred at rt for 1 h. After concentration, the obtained oil was purified by reverse phase prep-HPLC (MeOH/Acetonitrile/water) to afford a white powder (18 mg). ESI-MS (m/z): 560/561/562 [MH]+.