Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14]2[N:18]3[CH:19]=[CH:20][C:21](Cl)=[CH:22][C:17]3=[N:16][CH:15]=2)[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27].[O-]P([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>O1CCOCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([C:32]4[CH:33]=[CH:34][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:30][CH:31]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1nc(-c2cnc3cc(Cl)ccn23)cs1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1nc(-c2cnc3cc(-c4ccc(S(C)(=O)=O)cc4)ccn23)cs1
Temperature: 100 °C
Reaction time: 4 h
Yield: 67.4 %

Procedure:
To a suspension of [4-(7-chloro-imidazo[1,2-a]pyridin-3-yl)-thiazol-2-ylmethyl]-carbamic acid tert-butyl ester (0.180 g, 0.49 mmol, 1.0 eq.) in dioxane/water (2:1, 6 mL), add 4-(methylsulphonyl)-benzeneboronic acid (0.108 g, 1.1 eq.), K3PO4 (0.208 g, 2.0 eq.), S-phos (0.025 g, 12.5% eq.) and Pd(OAc)2 (0.006 g, 0.05 eq.). Deoxygenate the reaction mixture and fill with nitrogen and stir at 100° C. for 4 hours. Cool the mixture to room temperature and dilute with 5:95 MeOH/DCM (100 mL). Wash the mixture with saturated aqueous saturated sodium chloride (2×20 mL), water (2×20 mL), dry, filter, and concentrate. Purify the residue on silica gel with a 0-80% EtOAc/Hexane gradient, then with 5:95 MeOH/DCM to give 0.160 g of the title compound as a slightly yellow solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:12])([F:11])[C:5]([NH:7][CH:8]([CH3:10])[CH3:9])=[O:6].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.O>CN(C=O)C>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][N:7]([CH:8]([CH3:10])[CH3:9])[C:5](=[O:6])[C:4]([F:12])([F:11])[F:3]
Reactant: BrCCCCBr
Reactant: CC(C)NC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N(CCCCBr)C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 24 %

Procedure:
21 g (520 mmol) of 60% sodium hydride are suspended in 700 ml of anhydrous DMF under an inert atmosphere, and the mixture is cooled to 0° C. 40.5 g (260 mmol) of 2,2,2-trifluoro-N-isopropylacetamide are slowly added portionwise. After 15 minutes, 62 ml (520 mmol) of 1,4-dibromobutane are added. The reaction medium is then heated at 60° C. for 3 hours, and then cooled to room temperature, poured into 1 L of water and extracted with ethyl acetate. The organic phase is washed with water and dried, and the residue obtained is purified by distillation. A colorless oil is obtained (m=0.18 g, yield=24%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:15])=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:15][C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C=C(C)c1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C=C(CBr)c1ccc(F)cc1

Procedure:
Ethyl 3-(4-fluorophenyl)-2-butenoate (548 g, 2.7 mol), N-bromosuccinimide (500 g, 2.8 mol) and benzoyl peroxide (6 g) are combined in carbon tetrachloride (4 L). The mixture is heated at reflux and irradiated with a UV lamp for 4 days. The mixture is then filtered and the filtrate evaporated, and the residue is dissolved in ether and washed five times with saturated aqueous sodium carbonate and once with brine. The ether layer is dried with magnesium sulfate and evaporated, to provide the title compound.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26]([C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](Cl)=[O:36])=[CH:30][CH:29]=1)#[N:27]>C1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:35](=[O:36])[CH2:34][C:31]3[CH:32]=[CH:33][C:28]([C:26]#[N:27])=[CH:29][CH:30]=3)[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Reactant: N#Cc1ccc(CC(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN1CCC(OC(=O)Cc2ccc(C#N)cc2)N(c2nnc(C(C)(C)C)s2)C1=O

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl- 6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. α-(4-Cyanophenyl)acetyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol- 2-yl)-3-methyl-6-[α-(4-cyanophenyl)acetyloxy]-2(1H)-pyrimidinone as the residue.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1.B(F)(F)F.CCOCC>CCOC(C)=O>[CH:13]1([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: C1=CCCCC1
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Yield: 78 %

Procedure:
Ethyl 4-hydroxybenzoate (1.0 g, 6.02 mmol) and cyclohexene (6.0 mL) were mixed together and boron trifluoride diethyl etherate (0.38 mL, 3.01 mmol) was then added. The mixture was heated under reflux for 2 h and then cooled to rt. EtOAc (20 mL) was added and the solution washed with 5% NaOH solution (3×40 mL) and with H2O (50 mL). The organic layer was dried over Na2SO4 and the solvent was evaporated. The crude product was absorbed over silica gel and purified by column chromatography using a Teledyne ISCO apparatus, eluting with Cy:EtOAc (from 100:0 to 90:10) to afford the title compound (1.17 g, 78%), as white solid. MS (ESI) m/z: 249 [M−H]+; 1H NMR (DMSO-d6): δ 1.29 (t, J=7.1 Hz, 3H), 1.33-1.49 (m, 5H), 1.50-1.59 (m, 1H), 1.63-1.79 (m, 2H), 1.89-1.98 (m, 2H), 4.26 (q, J=7.1 Hz, 2H), 4.41-4.49 (m, 1H), 7.02 (d, J=8.8 Hz, 2H), 7.87 (d, J=8.8 Hz, 2H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26]([OH:28])=O)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:34][C:35]1[CH:36]=[C:37]([CH2:43][NH2:44])[CH:38]=[CH:39][C:40]=1[O:41][CH3:42].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:34][C:35]1[CH:36]=[C:37]([CH2:43][NH:44][C:26]([C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:32][CH3:33])=[O:22])[CH:24]=2)=[O:28])[CH:38]=[CH:39][C:40]=1[O:41][CH3:42]
Reactant: COc1ccc(CN)cc1Br
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(OC)c(Br)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[({[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (0.564 g, 1.25 mmol), {[3-bromo-4-(methyloxy)phenyl]methyl}amine (0.27 g, 1.25 mmol, HBTU (0.474 g, 1.25 mmol), and TEA (0.348 mL, 2.5 mmol) were combined in CH2Cl2 (30 mL). The mixture was stirred overnight at room temperature. The solvents were concentrated, and the residue taken up in EtOAc, washed with 1N NaOH, brine, dried and concentrated to give the crude product which was purified using CombiFlash on a 40 g column eluted with 0-10% MeOH/CH2Cl2 to afford the title compound as a white solid. LC-MS m/z 649.5 (M+H)+, 1.76 min (ret time); mp 130-132° C.; analytical HPLC shows 100% purity, (ret time 12.776 min).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([O:10][CH3:11])[C:3]=1[NH2:4].C([Sn](CCCC)(CCCC)[C:17]([O:19]CC)=[CH2:18])CCC.Cl>O1CCOCC1>[NH2:4][C:3]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[C:17](=[O:19])[CH3:18]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COc1cc(F)cc(Br)c1N
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(F)cc(C(C)=O)c1N
Temperature: 100 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
To a solution of 2-bromo-4-fluoro-6-methoxy aniline (4.80 g, 21.8 mmol), which had been obtained in Reference example 3(3a), in 1,4-dioxane (200 mL), tributyl (1-ethoxy vinyl) tin (11.1 mL, 32.7 mmol) and tetrakistriphenyl phosphine palladium (2.52 g, 2.18 mmol) were added, and the mixture was stirred for 16 hours at 100° C. After cooling the reaction solution to room temperature, 1 N aqueous hydrogen chloride solution (100 mL) was added and stirred further for 2 hours. The reaction solution was concentrated under reduced pressure, neutralized by adding 1 N aqueous sodium hydroxide solution, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=4/1) to give the title compound as a yellow solid substance (2.80 g, yield 70%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][NH:6][N:7]=2)[CH:3]=1.[Li]CCCC.CN([CH:19]=[O:20])C.O>C1COCC1.CCCCCC>[N:7]1[NH:6][CH:5]=[C:4]2[C:8]=1[CH:9]=[CH:10][C:2]([CH:19]=[O:20])=[CH:3]2
Reactant: Brc1ccc2n[nH]cc2c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1ccc2n[nH]cc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-Bromo-2H-indazole (2 g, 9.85 mmol) was dissolved in THF (50 mL) and cooled down to −40° C. n-BuLi in n-hexane (1.6 M, 15.4 mL) was added dropwise. After 15 min stirring, DMF (1.53 mL, 19.7 mmol) was added and the RM was stirred 30 min at −40° C. before warming up to rt. After 1 h, water was added (60 mL) and the mixture was extracted 3 times with EtOAc. Combined organic layers were washed with brine and dried on Na2SO4. After evaporation of the solvent the crude was purified by flash chromatography (CombiFlash® Companion System®, with 12 g RediSep® silica gel column, n-hexane/EtOAc=100:0->50:50) to afford the title compound (tR 3.63 min (conditions 3), MH−=145).
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:24]=[C:23]([CH3:25])[C:18]([O:19][CH2:20][CH2:21][OH:22])=[C:17]([CH2:26][CH3:27])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:28])[N:5]=1)[CH3:2].CCN(C(C)C)C(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl.CC(=O)OCC>[CH2:29]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:24]=[C:23]([CH3:25])[C:18]([O:19][CH2:20][CH2:21][O:22][S:41]([CH3:40])(=[O:43])=[O:42])=[C:17]([CH2:26][CH3:27])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:28])[N:5]=1)[CH3:30]
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
To a solution of 2-{4-[5-(2-diethylamino-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-ethanol (850 mg, 2.07 mmol) and DIPEA (401 mg, 3.11 mmol) in DCM (20 mL), methane sulfonylchloride (285 mg, 2.49 mmol) is slowly added. The mixture is stirred at rt for 30 min before it is diluted with EA and washed with sat. aq. NaHCO3-solution. The washing is extracted back three times with EA. The combined org. extracts are dried over MgSO4, filtered, concentrated and dried to give crude methanesulfonic acid 2-{4-[5-(2-diethylamino-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-ethyl ester (925 mg) as a yellow solid; LC-MS: tR=0.94 min; [M+1]+=489.18.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17]Cl)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1)([O-:3])=[O:2].[CH2:27]([N:30]([CH2:32][CH2:33][CH3:34])O)[CH2:28][CH3:29].[H-].[Na+]>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][N:30]([CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH3:29])=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1)([O-:3])=[O:2]
Reactant: CCCN(O)CCC
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 15, 8-nitro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is treated with a cold mixture of N,N-dipropylhydroxylamine and sodium hydride in dimethyl-formamide to give 8-nitro-1-[(dipropylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, N1 -oxide.
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]1[CH:14]=[C:15]([NH:24][C:25](=[O:50])[N:26]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]([NH:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([C:47](=[O:49])[NH2:48])[CH:42]=3)[C:37]([OH:39])=[O:38])=[CH:32][CH:31]=2)[CH3:27])[CH:16]=[CH:17][C:18]=1[S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])=O)C1C=CC=CC=1>C1COCC1.CO.CCOC(C)=O.Cl.[Pd]>[NH2:11][CH2:12][C:13]1[CH:14]=[C:15]([NH:24][C:25](=[O:50])[N:26]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]([NH:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([C:47](=[O:49])[NH2:48])[CH:42]=3)[C:37]([OH:39])=[O:38])=[CH:32][CH:31]=2)[CH3:27])[CH:16]=[CH:17][C:18]=1[S:19]([CH2:22][CH3:23])(=[O:21])=[O:20]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)N(C)CCc2ccc(C(Nc3cccc(C(N)=O)c3)C(=O)O)cc2)cc1CNC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CCS(=O)(=O)c1ccc(NC(=O)N(C)CCc2ccc(C(Nc3cccc(C(N)=O)c3)C(=O)O)cc2)cc1CN

Procedure:
A solution of 28G (225 mg, 0.32 mmol) in THF/MeOH/EtOAc (1:1:1) and HCl (1.0 M, 1.5 mL) with Pd/C (50 mg, 10%) was stirred under H2 (60 psi) for 20 h. The mixture was filtered through Celite and concentrated in vacuo to yield 28H (160 mg, 83%). MS (ESI) m/z 568.3 (M+H)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][N:11]1[C:15](=[O:16])[CH2:14][S:13][C:12]1=[S:17].[CH:18](=O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(O)(=O)C.N1CCCCC1.C(COC)OC>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][N:11]1[C:15](=[O:16])[C:14](=[CH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[S:13][C:12]1=[S:17]
Reactant: O=C1CSC(=S)N1N=c1sc2ccccc2s1
Reactant: CCCCCCCC=O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: COCCOC
Product: CCCCCCCC=C1SC(=S)N(N=c2sc3ccccc3s2)C1=O

Procedure:
A slurry of 2.0 g of 3-[(1,3-benzodithiol-2-ylidene)amino]-2-thioxo-4-thiazolidinone (see example 37), octanal (15 ml, excess) and acetic acid/piperidine (10 drops) in anhydrous glyme (400 ml) is heated at reflux for 18 hours. The reaction mixture is chilled in an ice bath and the resultant precipitate collected by filtration. The precipitate is recrystallized twice from dimethylformamide to yield 1.02 g of the title compound, melting point 185° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].C([O-])=[O:13].[Na+]>C(O)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][OH:13])=[CH:6][CH:7]=1
Reactant: O=C[O-]
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(CO)c1ccc(F)cc1

Procedure:
2 g of 2-bromo-1-(4-fluorophenyl)ethanone, and 6 eq of sodium formate in 15 mL of Ethanol/Water are irradiated under microwave for 5 min at 150° C., 11 bars. After filtration and evaporation of ethanol, water is added. The expected product is isolated by filtration
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][NH:20][C:21]3=[O:24])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].CCOC(C)=O>C1COCC1.CCCCCC.CCOC(C)=O>[CH2:40]([O:39][C:37](=[O:38])[CH2:36][N:20]1[CH2:19][CH2:18][C:17]2[C:22](=[CH:23][C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]3)=[CH:15][CH:16]=2)[C:21]1=[O:24])[CH3:41]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)C(=O)NCC3)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)CN1CCc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 7-(4-t-butoxycarbonylpiperazin-1-yl)-3,4-dihydro-1(1H)-isoquinolinone (1-3) (2.37 g, 7.16 mmol) in THF (30 mL) at -78° C. under argon was treated with NaHMDS (1M solution in THF; 7.88 mL, 7.88 mmol) and the temperature was allowed to rise to -50° C. over 30 minutes. The solution was cooled back to -78° C. and ethyl bromoacetate (1.19 mL, 10.7 mmol) was added in one lot. After stirring at ambient temperature for 3 hours, the mixture was poured into EtOAc, extracted with 1N HCl, washed with brine (twice), dried (MgSO4) and evaporated to give an oil. Column chromatography (hexane/EtOAc 1:1 then 1:2) gave 1-4 as a solid. Rf (silica; hexane/EtOAc 1:1)=0.38.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][NH:5][C:6]=1[CH3:7].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>CC(N(C)C)=O.CCOC(C)=O>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][N:5]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:6]=1[CH3:7]
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1n[nH]c(C)c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1nn(COCC[Si](C)(C)C)c(C)c1Br
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a stirring suspension of 4-bromo-3,5-dimethyl-1H-pyrazole (3.5 g, 20 mmol) and Cs2CO3 (13 g, 40 mmol) in 40 mL DMA was added (2-chloromethoxy-ethyl)-trimethyl-silane (5.3 mL, 30 mmol) at room temperature. The resulting mixture was stirred for 1 hour and was diluted with 100 mL EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was then purified by SiO2 chromatography (eluting with EtOAc/Heptane system) to give 4-bromo-3,5-dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazole 6.1 g (100%). MS(ESI) m/z 307.3 (M+H)+. Step 2 was performed using General procedure L (Suzuki) to give the product. MS(ESI) m/z 386.4 (M+H)+.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([OH:20])[CH3:19])=[CH:14][C:13]=1[O:21][CH3:22].C(N(CC)CC)C>ClCCl.O>[CH3:19][C:18]([C:15]1[CH:16]=[CH:17][C:12]([F:11])=[C:13]([O:21][CH3:22])[CH:14]=1)=[O:20]
Reactant: COc1cc(C(C)O)ccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1cc(C(C)=O)ccc1F
Temperature: -78 °C
Reaction time: 0.05 h
Yield: 98.9 %

Procedure:
A solution of dimethyl sulfoxide (1.33 mL) in dichloromethane (5 mL) was added dropwise to a solution of oxalyl chloride (1.63 mL) in dichloromethane (80 mL) in a nitrogen atmosphere at −78° C. After stirring the reaction solution at −78° C. for 3 minutes, a solution of 1-(4-fluoro-3-methoxyphenyl)ethanol (2.6 g) in dichloromethane (15 mL) was added dropwises to the reaction solution. Further, the reaction solution was stirred at −78° C. for 20 minutes, and triethylamine (10.8 mL) was added dropwise to the reaction solution. Then, the reaction solution was stirred at −78° C. for 10 minutes, and further stirred at room temperature for 30 minutes. Water and dichloromethane were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 2.54 g of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15](=[O:22])[C:16](=[CH:20][CH:21]=2)[C:17]([OH:19])=[O:18])=[CH:9][CH:8]=1)=[O:5])#[N:2].C(N(CC)CC)C.[N-:30]=[N+:31]=[N-:32].[Na+].[Cl-].[NH4+].Cl>CO.CN(C)C=O>[NH:30]1[C:1]([CH2:3][C:4]([NH:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[NH:14][C:15](=[O:22])[C:16](=[CH:20][CH:21]=3)[C:17]([OH:19])=[O:18])=[CH:11][CH:12]=2)=[O:5])=[N:2][N:32]=[N:31]1
Reactant: N#CCC(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(Cc1nnn[nH]1)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Yield: 80.3 %

Procedure:
A mixture of 13.4 g (45 mmol) of 6-(4-cyanoacetylaminophenyl)-1,2-dihydro-2-oxonicotinic acid from Example 5, 130 ml of dimethylformamide, 6.3 ml (45 mmol) of triethylamine, 9.75 g (150 mol) of sodium azide, and 8.03 g (150 mmol) of ammonium chloride is heated on the steam bath for 48 hrs. The reaction mixture is diluted with 600 ml of methanol and the resulting solution slowly acidified with 90 ml of 2 N hydrochloric acid. The precipitated solid is filtered, washed with methanol, and dried under vacuum at 60° for 24 hours to give 12.3 g of 6-[4-[(1H-tetrazol-5-ylacetyl)amino]phenyl]-1,2-dihydro-2-oxonicotinic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:10][C:9]=2[O:19]C)=[CH:4][CH:3]=1.C(O)(=O)C>Br>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:10][C:9]=2[OH:19])=[CH:6][CH:7]=1
Reactant: COc1cc(C(C)C(=O)O)ccc1-c1ccc(F)cc1
Agent: Br
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc(-c2ccc(F)cc2)c(O)c1

Procedure:
A solution of 2-(4'-fluoro-2-methoxy-4-biphenylyl)-propionic acid (10 g.) in a mixture of hydrobromic acid (270 ml. of 48%w/v aqueous acid) and glacial acetic acid (90 ml.) was refluxed for 3.5 hours. The resulting solution was poured onto crushed ice, causing the precipitation of a solid product. This product was collected by filtration, washed with water, dried and recrystallised from chloroform/light petroleum (b.p. 62°-68° C.) to give 2-(4'-fluoro-2-hydroxy-4-biphenylyl)-propionic acid, m.p. 138°-142° C.
Reaction SMILES: C([O:5][C:6](=[O:24])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=2)(=[O:16])=[O:15])[CH:10]=1)(C)(C)C>ClCCl>[Br:23][C:19]1[CH:18]=[C:17]([S:14]([N:11]2[CH:12]=[CH:13][C:9](/[CH:8]=[CH:7]/[C:6]([OH:24])=[O:5])=[CH:10]2)(=[O:15])=[O:16])[CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2cccc(Br)c2)c1
Solvent: ClCCl
Product: O=C(O)/C=C/c1ccn(S(=O)(=O)c2cccc(Br)c2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.6 %

Procedure:
A mixture of 2.0 g (E)-3-[1-(3-bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylic acid tert-butyl ester with 60 ml dichloromethane and 6.0 ml TEA is stirred at ambient temperature for 24 h. The dichloromethane and TFA is evaporated and the residue is coevaporated with toluene for a few times. By this method 0.77 g brown solid is obtained.