Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.[CH:24]([C:26]1[O:27][CH:28]=[C:29]([C:31]([O:33]CC)=[O:32])[N:30]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[C:16]1([C@@H:14]2[CH2:15][C@H:13]2[NH:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:24][C:26]3[O:27][CH:28]=[C:29]([C:31]([OH:33])=[O:32])[N:30]=3)[CH2:11][CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Reactant: CCOC(=O)c1coc(C=O)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: O=C(O)c1coc(CN2CCC(CN[C@@H]3C[C@H]3c3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
To a solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (100 mg, 0.306 mmol) in 1,2-dichloroethane (DCE) (2 mL) were added ethyl 2-formyloxazole-4-carboxylate (67.4 mg, 0.398 mmol) and sodium triacetoxyborohydride (97 mg, 0.460 mmol), and the mixture was stirred at room temperature for 18 h. The mixture was quenched with water (2 mL) and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was dissolved in methanol (2.0 mL) and sodium hydroxide (1 mL, 1.0 mmol) was added. The mixture was stirred at room temperature for 3 h and concentrated. The residue was treated with methanol and filtered. The filtrate was purified using reverse-phase HPLC under the acidic conditions to a TFA salt of the product. The TFA salt was treated with ACN (1 mL) and 1NHCl (0.5 mL) and concentrated. The residue was dried under vacuum to give 75 mg of product (HCl salt) as off-white solid. MS: (M+H)+=356.2. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.42 (q, 1H), 1.54-1.85 (m, 3H), 2.10-2.30 (m, 3H), 2.60 (ddd, J=10.36, 6.69, 3.66 Hz, 1H), 3.04 (dt, J=7.58, 4.04 Hz, 1H), 3.72-3.86 (m, 2H), 4.69 (s, 2H), 7.11-7.44 (m, 5H), 8.60-8.78 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]2[C:18](=[N:19][OH:20])[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6]2=[N:7][C:8]=1[C:9]([NH2:11])=[O:10])#[N:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].O>CN(C=O)C>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][O:20][N:19]=[C:18]1[C:5]2[C:6](=[N:7][C:8]([C:9](=[O:10])[NH2:11])=[C:3]([C:1]#[N:2])[N:4]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]1=2)[CH3:33]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1nc2c(nc1C(N)=O)-c1ccccc1C2=NO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CON=C1c2ccccc2-c2nc(C(N)=O)c(C#N)nc21
Temperature: 70 °C
Reaction time: 24 h
Yield: 22 %

Procedure:
To a suspension of 33 (300 mg, 1.1 mmol) and Cs2CO3 (405 mg, 1.2 mmol) in DMF (15 ml), ethyl bromoacetate (0.14 ml, 1.26 mmol) was added dropwise and the mixture was stirred at 70° C. for 24 h. The suspension was cooled at room temperature, H2O (30 ml) was added and the mixture was extracted with CH2Cl2 (70 ml). The organic phase was dried over Na2SO4 and the volatile solvent was evaporated under reduced pressure. A 1:1 mixture of n-hexane/iPr2O was added and after 2 h the obtained solid was collected by filtration. The crude was purified by flash chromatography (CH2Cl2/MeOH 85:15) affording 37 (85 mg, 22%) as green-brown solid. 1H NMR (300 MHz, DMSO d6): δ 8.78 (bs, 1H), 8.73 (bs, 1H), 8.00 (dd, 1H), 7.82 (m, 2H), 7.67 (ddd, 1H), 4.87 (s, 2H), 4.19 (q, 2H), 1.25 (t, 3H). ESI+MS: calcd for C17H13N5O4: 351.32; found: 352.1 (MH+).
Reaction SMILES: C([N:4]1[C:12]2[CH:7]([N:8](C(=O)C)[CH2:9][N:10](C(=O)C)[C:11]=2Cl)[N:6]([C@@H:20]2[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]2[OH:22])[CH2:5]1)(=O)C.[CH2:29]([NH:33][CH2:34][C:35]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:36]=1[CH3:42])[CH:30]=[CH:31][CH3:32].C(N(CC)CC)C>C(O)(C)C>[CH2:29]([N:33]([CH2:34][C:35]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:36]=1[CH3:42])[C:11]1[C:12]2[N:4]=[CH:5][N:6]([C:7]=2[N:8]=[CH:9][N:10]=1)[C@@H:20]1[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]1[OH:22])[CH:30]=[CH:31][CH3:32]
Reactant: CC(=O)N1CN(C(C)=O)C2C(=C1Cl)N(C(C)=O)CN2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CC=CCNCc1cc(C)ccc1C
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC=CCN(Cc1cc(C)ccc1C)c1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 0.17 h

Procedure:
10 g. Triacetyl-6-chloro-9-(β-D-ribofuranosyl)-purine, 5.7 g. N-but-2-enyl-(2,5-dimethylbenzyl)-amine and 2.5 g. triethylamine were heated under reflux for 1 hour in 150 ml. isopropanol. Subsequently, the solvent was removed in a vacuum and the residue taken up in chloroform. The chloroform phase was washed several times with water, dried and evaporated. The syrupy residue was dissolved in 150 ml. methanol and the solution mixed with 5 ml. 1N sodium methylate solution and then boiled for 10 minutes. Thereafter, the methanol was replaced by ethyl acetate and the ethyl acetate solution washed two or three times with water. After drying and evaporating the solution, the residue was recrystallized twice from 100 ml. methanol/water (1:1), with the addition of active charcoal. There were finally obtained 5.9 g. (56% of theory) N(6)-but-2-enyl-N(6)-(2,5-dimethylbenzyl)-adenosine, which had a melting point of 125°-127°C.
Reaction SMILES: [CH:1]1([CH:6]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32]O)=[CH:28][CH:27]=2)[C:7]([NH:9][C:10]2[C:11]([CH3:25])=[C:12]([CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]=[CH:14][CH:15]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Br)(Br)(Br)[Br:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:35][CH2:32][C:29]1[CH:30]=[CH:31][C:26]([CH:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:7]([NH:9][C:10]2[C:11]([CH3:25])=[C:12]([CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:27][CH:28]=1
Reactant: Cc1c(CCC(=O)OC(C)(C)C)cccc1NC(=O)C(c1ccc(CO)cc1)C1CCCC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(CCC(=O)OC(C)(C)C)cccc1NC(=O)C(c1ccc(CBr)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
6.0 g (13.29 mmol) of tert-butyl(+/−)-3-[3-({cyclopentyl[4-(hydroxymethyl)phenyl]acetyl}amino)-2-methylphenyl]propanoate were dissolved in 375 ml of dry THF, and 9.25 g (27.9 mmol) of carbon tetrabromide were added. Over a period of 1.5 h, 9.06 g (34.54 mmol) of triphenylphosphine were then added in small portions. The reaction mixture was stirred at RT for 5 h, and the solid was then filtered off and the filtrate was concentrated. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 5:1→1:1). This gave 7.22 g (about 100% of theory, purity about 95%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9]/[N:10]=[C:11](/[C:15]1[N:16]=[C:17]([NH:20][C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:18][CH:19]=1)\[C:12](O)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.Cl.[NH2:59][CH:60]1[C:85](=[O:86])[N:62]2[C:63]([C:69]([O:71][CH:72]([C:79]3[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=3)[C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)=[O:70])=[C:64]([CH2:67][Cl:68])[CH2:65][S:66][C@H:61]12>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][C:6]([CH2:8][O:9]/[N:10]=[C:11](/[C:15]1[N:16]=[C:17]([NH:20][C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[S:18][CH:19]=1)\[C:12]([NH:59][CH:60]1[C:85](=[O:86])[N:62]2[C:63]([C:69]([O:71][CH:72]([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)[C:79]3[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=3)=[O:70])=[C:64]([CH2:67][Cl:68])[CH2:65][S:66][C@H:61]12)=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67 %

Procedure:
To an ice-cooled solution of (Z)-2-t-butoxycarbonylmethoxyimino-2-(tritylaminothiazol-4-yl)acetic acid (IVg') (2.71 g, 5 mmoles) in CH2Cl2 (20 ml) was added PCl5 (1.24 g, 6 mmoles), and the solution was stirred for 20 minutes at room temperature. The acid chloride solution was added under ice-cooling to a solution of the silylated 7-ACA ester, which was prepared by adding bis(trimethylsilyl)acetamide (BSA, 3.7 ml, 15 mmoles) to a stirred suspension of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride (V) (2.25 g, 5 mmoles) in CH2Cl2 (20 ml). The reaction mixture was stirred at room temperature for 30 minutes, diluted with ethyl acetate (200 ml) and washed with an aqueous NaHCO3 solution and water. After drying over Na2SO4, the solution was evaporated and the residue was purified by silica gel chromatography (Wako gel C-200, 60 g). The desired fractions, eluted by CHCl3, were combined and concentrated to give 3.16 g (67%) of the title compound VIg'.
Reaction SMILES: C([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(O)=O.[Br:29]Br>C(Cl)(Cl)(Cl)Cl>[Br:29][CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(=O)O)OC(C)=O
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCC(CCCC(Br)CCCCCCC(=O)OCC)OC(C)=O

Procedure:
A mixture of ethyl 8-carboxy-12-acetoxyheptadecanoate (31.5 g., 0.079 mole), red mercuric oxide (12.8 g., 0.059 mole), and carbon tetrachloride (200 ml.) is stirred at room temperature while bromine (12.6 g., 0.079 mole) is added dropwise during one hour. The resulting mixture is heated at reflux for one hour. The mixture is then cooled, filtered, washed with dilute hydrochloric acid, water and brine and dried over sodium sulfate. The solution is evaporated in vacuo to leave the product as a yellow residual weighing 24.5 g. The product is purified by chromatography on a column containing 250 g. of silica gel using chloroform as eluting solvent. There is obtained 14.4 g. of purified ethyl 8-bromo-12-acetoxyheptadecanoate, a yellow oil with Rf 0.49 on silica gel thin layer chromatography with chloroform elution. pmr (CDCl3) δ 0.90 (3H,t); 2.03 (3H, s CH3CO); 4.07 (1H, m HCBr); 4.13 (2H, q); 4.92 (1H, m HCO).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1[S:10][C:9]([CH:11]2OCC[O:12]2)=[CH:8][CH:7]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1[S:10][C:9]([CH:11]=[O:12])=[CH:8][CH:7]=1
Reactant: Clc1cccc(Cc2ccc(C3OCCO3)s2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=Cc1ccc(Cc2cccc(Cl)c2)s1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.2 %

Procedure:
To a solution of 2-(5-(3-chloro-benzyl)-thiophen-2-yl)-[1,3]dioxolane described in Preparation Example 43 (1.6 g, 5.7 mmol) in methanol (20 mL) was added citric acid aqueous solution (20 mL), and the solution was stirred at room temperature for 20 minutes. An aqueous solution of sodium bicarbonate and ethyl acetate were added to the reaction solution, which was then partitioned, the organic layer was washed with water twice and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the title compound (1.2 g, 5.08 mmol, 89.2%) was obtained as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[O:11]([NH2:13])[CH3:12]>>[CH3:12][O:11][N:13]=[CH:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[F:1]
Reactant: CON
Reactant: O=Cc1ccccc1F
Agent: Cl
Product: CON=Cc1ccccc1F
Yield: 98 %

Procedure:
Reaction of 2-fluorobenzaldehyde with methoxylamine hydrochloride as described in the preparation of compound 3-A gave the title oxime ether as a clear oil (98% yield). HPLC indicated a 91:9 mixture of E- and Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 3.99 (3H, s, OCH3), 7.07 (1H, m, aromatic), 7.14 (1H, m, aromatic), 7.34 (1H, m, aromatic), 7.82 (1H, m, aromatic), 8.31 (1H, s, CH).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH:5]([C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH2:18][C:19]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=2)=O)=[CH:13][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].Cl.[NH2:37][OH:38].C(=O)([O-])O.[Na+]>>[CH2:1]([O:3][C:4](=[O:35])[CH:5]([C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH2:18]/[C:19](=[N:37]\[OH:38])/[C:21]2[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=2)=[CH:13][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc([C@H](CC(=O)c2ccnc(C)c2)c2ccccc2C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)C(C(=O)OCC)c1ccc([C@H](C/C(=N\O)c2ccnc(C)c2)c2ccccc2C)cc1

Procedure:
In analogy to example 1, step 2, from 2-{4-[(S)-3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-phenyl}-malonic acid diethyl ester and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a mixture of E and Z isomers (2.7:1) as a white oil, MS (ESI+): m/z=489.3 ([M+H]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([Br:25])[CH:19]=3)[CH2:12][CH2:11]2)=[N:2]1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34]>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:33](=[O:35])[CH3:34])=[C:20]([Br:25])[CH:19]=3)[CH2:12][CH2:11]2)=[N:2]1
Reactant: Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1Br
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1Br
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A 2 dram vial was charged with 0.09 g (0.2 mmol) of 4-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-2-bromo-phenylamine and 0.87 mL CH2Cl2. This mixture was treated with 36 μL triethylamine (0.26 mmol) and 17 μL acetyl chloride and stirred at rt for 15 h. The reaction was quenched with aqueous 1M NaHCO3, the organic layer separated, dried, and concentrated in vacuo. This gave a quantitative yield of the desired product as a white solid. MS (APCI): 461 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=8 Hz, 1H), 7.77 (d, J=8 Hz, 1H), 7.43 (t, J=7.5 Hz, 1H), 7.32 (t, J=7.5 Hz, 1H), 7.26 (s, 1H), 6.95–6.93 (m, 1H), 6.7 (d, J=8 Hz, 1H), 3.98 (br s, 2H), 3.57–3.55 (m, 4H), 2.72–2.58 (m, 8H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[C@H:7]([NH2:15])[CH2:6][C@@H:5]1[CH3:16])(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.C1[C:31]([N+]([O-])=O)=[CH:30][CH:29]=[C:28]([O:35][C:36](Cl)=[O:37])C=1.C1(O)CCC1>ClCCl>[CH:28]1([O:35][C:36](=[O:37])[NH:15][C@H:7]2[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=3)[N:4]([C:1](=[O:3])[CH3:2])[C@@H:5]([CH3:16])[CH2:6]2)[CH2:29][CH2:30][CH2:31]1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](N)C[C@@H]1C
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: OC1CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC2CCC2)C[C@@H]1C

Procedure:
(cis)-1-Acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see Intermediate 4) (200 mg, 0.706 mmol) was dissolved in dichloromethane (DCM) (5 mL), mixed with DIPEA (0.370 mL, 2.119 mmol) followed by 4-nitrophenyl chloridocarbonate (157 mg, 0.777 mmol, available from Fluka) and stirred under nitrogen. Cyclobutanol (0.082 mL, 1.059 mmol) was added after 1.75 hours. The reaction was allowed to stir under nitrogen for 17 hours. The reaction was partitioned between distilled water (20 mL) and EtOAc (60 mL). The aqueous layer was extracted with EtOAc (60 mL) and the organic fractions were combined, washed (brine (50 mL)), dried (sodium sulfate) and evaporated to dryness to give a yellow solid (346 mg). The residue was purified by SP4 on a 25+M Biotage silica column, eluting with a gradient of 0 to 50% ethyl acetate in cyclohexane. Product-containing fractions were evaporated to dryness to give a clear, colourless solid (39 mg). LCMS (Method C): Rt=1.05, MH+=383
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH:13][NH2:14])=[O:12])[CH:9]=2)[N:4]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:3]=1.C1COCC1.[N:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[C:31]=S.Cl.C(N=C=NCCCN(C)C)C>O>[C:33]([NH:30][C:31]1[O:12][C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:16])=[O:17])[CH:3]=[C:2]3[I:1])=[N:13][N:14]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)N=C=S
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)NN)ccc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(NC(C)(C)C)o4)ccc32)cc1
Temperature: 60 °C
Yield: 51.4 %

Procedure:
3-Iodo-1-tosyl-1H-indole-5-carbohydrazide (625 mg, 1.373 mmol) in a 250 mL RBF was treated with THF (25 mL) and 2-isothiocyanato-2-methylpropane (0.871 mL, 6.86 mmol) (Aldrich). The flask was fitted with a reflux condenser and heated at 60° C. for 2.5 h. The reaction was cooled to RT, the THF was removed in vacuo and replaced with DMF (10.00 mL). The solution was treated with N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (395 mg, 2.059 mmol), fitted with a reflux condenser and heated to 80° C. for 2 h. The mixture was treated with H2O and extracted with EtOAc (2×50 mL), washed with brine and dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography (eluting with 0-100% EtOAc in Hex) to give N-tert-butyl-5-(3-iodo-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (378.7 mg, 0.706 mmol, 51.4) as a white amorphous solid. MS (ESI, pos. ion) m/z: 536.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.19 (s, 1H), 8.12 (d, J=8.8 Hz, 1H), 7.98 (s, 1H), 7.90 (dd, J=8.7, 1.5 Hz, 1H), 7.69 (s, 2H), 7.43 (d, J=8.2 Hz, 2H), 2.33 (s, 3H), 1.37 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:5]=1.[OH-].[Na+].O.Cl>O1CCOCC1>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][O:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:21])=[O:2]
Reactant: COC(=O)c1cccc(OCCc2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccc(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
1 g (3.07 mmol) of 3-[2-(2,4-Dichlorophenyl)-ethoxy]-benzoic acid methyl ester was dissolved in 20 ml of dioxan. 2N aqueous NaOH was added to the solution to give a pH of 13. The reaction solution was heated at 50° C. for 3 h, and stirred at RT for 16 h. 5 ml water was added, followed by concentrated hydrochloric acid to give a pH of 1 to 2, whereupon the product precipitated from solution. The suspension was stirred for 30 min, then the product was filtered off and dried under reduced pressure.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([Si:17]([C:20]1[C:25]([F:26])=[CH:24][N:23]=[C:22]([F:27])[C:21]=1[Cl:28])([CH3:19])[CH3:18])([CH3:16])([CH3:15])[CH3:14].[F:29][C:30]1[C:35]([C:36](N(OC)C)=[O:37])=[CH:34][CH:33]=[CH:32][N:31]=1>C1COCC1>[Si:17]([C:20]1[C:21]([Cl:28])=[C:22]([F:27])[N:23]=[C:24]([C:36]([C:35]2[C:30]([F:29])=[N:31][CH:32]=[CH:33][CH:34]=2)=[O:37])[C:25]=1[F:26])([C:13]([CH3:16])([CH3:14])[CH3:15])([CH3:19])[CH3:18]
Reactant: CON(C)C(=O)c1cccnc1F
Reactant: CC(C)(C)[Si](C)(C)c1c(F)cnc(F)c1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)[Si](C)(C)c1c(F)c(C(=O)c2cccnc2F)nc(F)c1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of diisopropylamine (52.41 g, 72.59 mL, 517.9 mmol) in THF (967.3 mL) was cooled to −20° C. n-BuLi (2.5M in hexane) (198.5 mL of 2.5 M, 496.3 mmol) was added dropwise over 15 minutes via cannula maintaining the internal temperature below −15° C. The solution was warmed to 0° C. then immediately re-cooled to −90° C. A solution of tert-butyl-(3-chloro-2,5-difluoro-4-pyridyl)-dimethyl-silane (113.84 g, 431.6 mmol) in THF (85.35 mL) was added dropwise over 20 min via cannula at such a rate that the internal temperature was kept below −85° C. During addition the solution first changed to bright yellow then slowly became an orange coloured suspension. The reaction mixture was stirred at −85° C. for 1 h. A solution of 2-fluoro-N-methoxy-N-methylpyridine-3-carboxamide (91.40 g, 496.3 mmol) in THF (85.35 mL) was added dropwise over 15 minutes via cannula at such a rate that the internal temperature was kept below −80.7° C. (ideally below −85° C.). The mixture turned dark orange brown after the addition. The mixture was stirred at −85° C. for 90 minutes after which time Lc/Ms indicated the reaction was complete. The cooling bath was removed and the mixture warmed to −50° C. Saturated ammonium chloride solution (400 mL) was added and the mixture allowed to warm up to RT. The mixture was diluted with ethyl acetate (1.5 L). The aqueous phase was separated and extracted with more ethyl acetate (300 ml). The combined organics were washed with brine (300 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to a brown oil. The crude was purified on silica gel (CombiFlash Companion XL, 1.5 kg column, 0.5-10% ethyl acetate in petroleum ether, 0-50% ethyl acetate in petroleum ether). This gave the title compound as a yellow oil which solidified on standing (159.6 g, 95%); 1H NMR (CDCl3) 0.60 (6H, d), 1.07 (9H, s), 7.47 (1H, m), 8.33 (1H, m), 8.52 (1H, m); 19F NMR (decoupled) −107.2, −72.4, −61.8; MS ES (+) 387.04 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[F:23])[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: OB(O)c1ccccc1F
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)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: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(-c2ccccc2F)c1
Yield: 73.8 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 2-fluorophenylboronic acid (0.026 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.051 g (73%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-3-carboxamide as a white solid.