Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:16]([OH:18])=[O:17])[C:3]1[CH:4]=[CH:5][C:6]([C:10]2[CH:11]=[CH:12]C=CC=2)=[C:7](F)[CH:8]=1.[CH2:19](O)C>>[OH:18][C:16]([CH:2]([C:3]1[CH:8]=[CH:7][C:6]([CH2:10][CH:11]([CH3:12])[CH3:19])=[CH:5][CH:4]=1)[CH3:1])=[O:17]
Reactant: CCO
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Temperature: 60 °C

Procedure:
Three grams of flurbiprofen and 30 g of poloxamer 237 were heated at 110° C. for 10 minutes to obtain a liquified mixture and cooled to 60° C. Into this mixture, 5 g of polyethylene glycol 300, 10 g of ethanol and 52 g of pH 4 buffer solution were added at 60° C. to obtain an ibuprofen gel.
Reaction SMILES: [Br-].[C:2]([C:5]1[CH:6]=[N+:7]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:21][CH3:22])[CH:18]=2)[C:13]1=[O:23])(=[O:4])[CH3:3].C1C(C(N)=O)=CN(CC2C=CC=CC=2)C=C1>>[C:2]([C:5]1[CH:10]([CH2:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:21][CH3:22])[CH:18]=3)[C:13]2=[O:23])[CH:9]=[CH:8][N:7]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH:6]=1)(=[O:4])[CH3:3]
Reactant: COc1ccc2c(c1)CC(Cc1cc[n+](Cc3ccccc3C)cc1C(C)=O)C2=O
Agent: NC(=O)C1=CN(Cc2ccccc2)C=CC1
Agent: [Br-]
Product: COc1ccc2c(c1)CC(CC1C=CN(Cc3ccccc3C)C=C1C(C)=O)C2=O

Procedure:
The title compound 164 is prepared according to the procedure reported in Example 39.1 with compound 138 (100 mg, 0.21 mmol) and BNAH (45 mg, 1 equiv) as reactants. Yellow solid. (Yield 34.5 mg, 41%).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)CCC.Br[C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[C:26](=[O:30])[N:25]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)[CH2:24]2>C1(C)C=CC=CC=1.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>[CH3:38][C:35]1[CH:34]=[CH:33][C:32]([CH2:31][N:25]2[CH2:24][C:23]3[C:27](=[CH:28][CH:29]=[C:21]([C:8]4[CH:7]=[CH:6][CH:11]=[CH:10][N:9]=4)[CH:22]=3)[C:26]2=[O:30])=[CH:37][CH:36]=1
Reactant: Cc1ccc(CN2Cc3cc(Br)ccc3C2=O)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(CN2Cc3cc(-c4ccccn4)ccc3C2=O)cc1
Yield: 169 %

Procedure:
4-Tributylstannanylpyridine (37 mg, 0.032 mmol), 5-bromo-2-(4-methyl-benzyl)-2,3-dihydro-isoindol-1-one (50.0 mg, 0.16 mmol) and Pd(PPh3)4 (37 mg, 0.032 mmol) were dissolved in anhydrous toluene (4 mL). The mixture was immersed in a 100° C. oil bath. After eighteen hours, the reaction was cooled and the solvent was removed under reduced pressure. The compound was purified by column chromatography (50% EtOAc/Hexanes) to provide the title compound as a brown solid (17.0 mg, 35%). 1H NMR (300 MHz, CDCl3): δ 8.72 (br s, 2H), 8.01 (d, 1H), 7.75 (dd, 1H), 7.62 (s, 1H), 7.53 (br s, 2H), 7.20 (q, 4H), 4.81 (s, 2H), 4.35 (s, 2H), 2.35 (s, 3H)
Reaction SMILES: C[O-].[Na+].[C:4]([O:11][CH3:12])(=[O:10])[CH2:5][C:6](OC)=O.BrC[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH:23]([CH3:27])[CH2:24]CO.P(=O)(O)(O)O.[OH-].[K+].ClCC(O)CO.C[O-].[K+]>CO.OCC(CO)O.O.O.COC(C)(C)C>[CH3:24][CH:23]1[CH2:27][CH2:12][O:11][C:4](=[O:10])[CH2:5][CH2:6][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: COC(=O)CC(=O)OC
Reactant: CC(CCO)CCOCCCCCCBr
Agent: C[O-]
Agent: O=P(O)(O)O
Agent: OCC(O)CCl
Solvent: CO
Solvent: COC(C)(C)C
Solvent: OCC(O)CO
Product: CC1CCOCCCCCCCC(=O)OCC1
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 46.8 %

Procedure:
A solution of 30 g (520 mmol) of 95 percent sodium methylate in 220 ml of dry methanol was heated to reflux. Thereupon, 60 ml (520 mmol) of dimethyl malonate were allowed to drop in, the reaction mixture was heated under reflux for a further 15 min. and then 182 g of 66 percent 12-bromo-3-methyl-6-oxadodecan-1-ol from the preceding batch were added thereto. After heating under reflux for 14 hours the reaction mixture was added to 1.6 l of water/tert-butyl methyl ether (1:1) and made acid with concentrated phosphoric acid. The organic phase was separated and the aqueous phase was extracted twice with 500 ml of tert-butyl methyl ether each time. The combined organic phases were dried over magnesium sulphate, concentrated to dryness on a rotary evaporator, taken up in 400 ml of methanol and treated with 99 g (1.5 mol) of 85 percent potassium hydroxide. Methanol and byproducts were distilled off at 180° C./20-23mbar during 1 h. Thereupon, the reaction mixture was treated with 200 ml (2.4 mol) of 3-chloro-1,2-propanediol and heated to 140° C. for 1 h. After distilling off the excess 3-chloro-1,2-propanediol the reaction vessel was fitted with a condenser and separator and treated with 6.0 g (86 mmol) of potassium methylate in 450 ml of anhydrous glycerol. After stirring at 140° C./20-30 mbar for 15 minutes the mixture was heated to reflux at 155° C./4-6 mbar for 3 days under the separator, with 6.0 g (86 mmol) of potassium methylate being added every 24 hours. The separated glycerol was poured into 800 ml of water and extracted three times with 500 ml of tert-butyl methyl ether each time. After drying the combined organic extracts over magnesium sulphate, concentration on a rotary evaporator and distillation at 95-97° C./0.04 mbar there were obtained 59 g (52%) of 12-methyl-9-oxa-14-tetradecanolide (1) as a colorless liquid with the following characteristics.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14]C(=O)OC(C)(C)C)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C1COCC1.CO.[ClH:29]>O1CCOCC1>[ClH:29].[ClH:29].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Cc1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)nc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cc1ccc(N2CCC(N)CC2)nc1
Reaction time: 17 h
Yield: 86.8 %

Procedure:
A solution of tert-butyl [1-(5-methylpyridin-2-yl)piperidin-4-yl)carbamate (0.23 g, 0.79 mmol) in HCl in Dioxane (4M, 2 ml), THF (1 ml) and MeOH (1 ml) was stirred at room temperature. After 17 h, the reaction mixture was filtered, and the residue washed with EtOAc and dried to give the title compound (181 mg, 86.8%) as a solid. 1H NMR (500 MHz, D2O): 7.80 (d, 1H), 7.60 (s, 1H), 7.15 (d, 1H), 4.10-4.03 (m, 2), 3.53-3.44 (m, 1H), 3.21 (t, 2H), 2.16-2.10 (m, 5H), 1.65 (dq, 2H); 13C NMR (D2O): 150.8, 146.8, 133.9, 123.9, 112.9, 47.7, 44.7, 28.8; Mass Spectrum: M+H 192
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[O:12][CH:13]=2)=[CH:5][CH:4]=1.[Br:27]N1C(=O)CCC1=O>ClCCl.C(Cl)(Cl)Cl>[Br:27][C:13]1[O:12][C:11]([CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)=[N:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1ccc(-c2coc(C3CCN(C(=O)OC(C)(C)C)CC3)n2)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CSc1ccc(-c2nc(C3CCN(C(=O)OC(C)(C)C)CC3)oc2Br)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.1 %

Procedure:
tert-butyl 4-{4-[4-(methylsulfanyl)phenyl]-1,3-oxazol-2-yl}piperidine-1-carboxylate (585 mg, 1.56 mmol) was dissolved in dichloromethane (15.6 mL) under argon atmosphere. N-bromosuccinimide (306 mg, 1.72 mmol) was added portionwise as a solid to the stifling solution. The resulting solution stirred at 25° C. for 6 hours. The solution was then diluted with chloroform and washed with aqueous sodium bisulfite. The organics were dried over sodium sulfate and concentrated in vacuo to yield 680 mg of the desired product as yellow oil. LCMS (M+1)=453.40
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.[F:22][C:23]([F:40])([F:39])[C:24]1[N:29]=[C:28]([N:30]2[CH2:34][C@@H:33]3[C@@H:35]([NH2:38])[CH2:36][CH2:37][C@@H:32]3[CH2:31]2)[CH:27]=[CH:26][CH:25]=1.C(N=C=NCCCN(C)C)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:38][C@@H:35]2[C@@H:33]3[C@@H:32]([CH2:31][N:30]([C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([C:23]([F:40])([F:39])[F:22])[N:29]=4)[CH2:34]3)[CH2:37][CH2:36]2)=[O:8])=[CH:9][CH:10]=1
Reactant: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Reactant: O=C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=C(N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
p-Fluorobenzoic acid (56.8 mg, 0.405 mmol), 1-hydroxybenzotriazole hydrate (62.1 mg, 0.405 mmol 1), and (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine from Example 264 Step A (100 mg, 0.369 mmol) were combined in dichloromethane (1.2 mL) to give a colorless solution. After 20 minutes, N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.072 mL, 0.405 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with 2×2 mL of dichloromethane. The combined extracts were applied directly to a 12 g silica gel cartridge and purified with a gradient of 1-10% methanol in (2 N ammonia)/dichloromethane over 20 minutes to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.90 (d, J=6.9, 1H), 8.29-8.19 (m, 2H), 7.56-7.47 (m, 1H), 7.17 (ddd, J=9.7, 5.9, 2.5, 2H), 6.99 (d, J=7.2, 1H), 6.53 (d, J=8.6, 1H), 4.64-4.52 (m, 1H), 3.80 (dd, J=11.0, 3.7, 1H), 3.63 (dd, J=10.9, 8.2, 1H), 3.51 (dd, J=10.8, 8.4, 1H), 3.30 (dd, J=10.9, 4.6, 1H), 2.90-2.77 (m, 1H), 2.77-2.64 (m, 1H), 2.23 (ddd, J=19.5, 7.1, 4.7, 1H), 1.93 (dtd, J=12.7, 8.0, 4.6, 1H), 1.81 (ddd, J=16.4, 12.7, 8.1, 1H), 1.40 (dt, J=13.2, 7.6, 1H); MS (ESI+) m/z 394 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:23]=[CH:22][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.O[C@H]1CC[C@H](C2C=CC(OCCCN3CCC[C@H](C)C3)=CC=2)CC1.C([O-])(=O)C([O-])=O>>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:23]=[CH:22][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=C1CCC(c2ccc(OCCCN3CCCCC3)cc2)CC1
Agent: C[C@H]1CCCN(CCCOc2ccc([C@H]3CC[C@H](O)CC3)cc2)C1
Agent: O=C([O-])C(=O)[O-]
Product: O[C@H]1CC[C@H](c2ccc(OCCCN3CCCCC3)cc2)CC1

Procedure:
Reduction of 1-{3-[-4-(4-oxocyclohexyl)phenoxy]propyl}piperidine (1.57 g) as described for (3S)-1-{3-[trans-4-(4-hydroxycyclohexyl)phenoxy]propyl}-3-methyl-piperidine gives 600 mg of 1-{3-[trans-4-(4-hydroxycyclohexyl)phenoxy]-propyl}piperidine, oxalate as a white powder melting at 182° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH:12]([CH3:14])[CH3:13])OC(C(F)(F)F)=[C:3]1[C:19]([O:21][CH3:22])=[O:20].[C:23]([C:27]#[N:28])([Cl:26])([Cl:25])[F:24].C1CCN2C(=NCCC2)CC1.Cl>COCCOC>[Cl:25][C:23]([Cl:26])([F:24])[C:27]1[C:3]([C:19]([O:21][CH3:22])=[O:20])=[C:2]([OH:1])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH:12]([CH3:14])[CH3:13])[N:28]=1
Reactant: COC(=O)c1c(C(C)C)oc(C(F)(F)F)c(C(=O)OC)c1=O
Reactant: N#CC(F)(Cl)Cl
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: COC(=O)c1c(C(C)C)nc(C(F)(Cl)Cl)c(C(=O)OC)c1O
Temperature: 25 °C
Yield: 100.1 %

Procedure:
To a solution of 17.80 g (0.073 mol) of dimethyl 2-(isobutyryl)-3-oxo-1,5-pentendioate (Step B of Example 208) in 300 mL of DME at -78° C. was added 18 g (0.4 mol) of CFCl2CN followed by 11.1 g (11 ml, 0.073 mol) of DBU. The reaction was warmed up to 25° C., poured into 3.7% HCl, and extracted twice with EtOAc. The EtOAc extract was washed again with 3.7% HCl, saturated NaCl and dried (MgSO4). The solvent was removed in vacuo to give 25.88 g of a dark brown solid. The crude was purified by HPLC using 2% HOAc/16% EtOAc/82% cyclohexane as eluting solvent, affording 21 g (81%) of product as a beige solid. For elemental analysis a portion of this solid was washed with hexane affording the product as a white solid: mp 75°-76° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[CH:6]2[CH3:14].[OH-].[Na+].Cl[CH2:18][C:19]#[N:20]>C1(C)C=CC=CC=1>[C:19]([CH2:18][C:6]1([CH3:14])[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:8]([CH3:12])[C:7]1=[O:13])#[N:20]
Reactant: COc1ccc2c(c1)C(C)C(=O)N2C
Reactant: N#CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(C)(CC#N)C(=O)N2C
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 90.7 %

Procedure:
To a mixture containing 50 g of 5-methoxy-l,3-dimethyloxindole, 10.57 g of Aliquat 366 in 375 ml of toluene and 100 ml of 50% NaOH was added dropwise under nitrogen, a solution containing 21.73 g of chloroacetonitrile in 125 ml of toluene over 30 min. A slightly exothermic reaction ensued (50° C.). The reaction mixture was stirred for another 10 minutes, and then cooled to 10° C. To this cooled reaction mixture was added 400 ml of ice-cold water. The reaction mixture was transferred to a separatory funnel. The layers were separated and the organic layer was extracted with 3N HCl (2×250 ml) and water (1×250 ml). The toluene extract was concentrated under reduced pressure and the resultant dark oil was filtered through silica gel (500 g) eluting with 3% methanol-methylene chloride mixture. The eluate (2 L) was concentrated to give the target compound as an oil (54.61 g; 91% yield) which slowly crystallized upon seeding. This material was sufficiently pure and was reduced to (±)-1,3-dimethyl-5-methoxy-oxindolylethylamine without further purification. A small sample of (±)-cyanomethyl-5-methoxy-1,3-dimethyloxindole was recrystallized from isopropyl ether, m.p.=75.5°-76° C. (lit: 75°-76° C.).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.[CH3:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=O.C(O)(=O)C.[BH3-]C#N.[Na+]>CN1C(=O)N(C)CC1.CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: CCCCCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CN1CCN(C)C1=O
Product: CCCCCCNc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12

Procedure:
Analogously to Example 34, 261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6), 150 mg (1.5 mmol) of capronaidehyde and 180 mg of acetic acid are stirred in 39 ml of DMEU/methanol (1:2) and then reacted with 440 mg (7 mmol) of NaCNBH3. Stirring in DIPE yields 4-(3-chloro-phenyl-amino)-3-(n-hexyl-amino)-1H-pyrazolo[3,4-d]pyrimidine; HPLC: tRet(grad20-100)=9.9; FAB-MS: (M+H)+=345.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([C:15](=[O:17])[CH3:16])[CH2:14][CH2:13][CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10]>ClCCl.CO>[Br:1][CH2:16][C:15]([C:11]1([C:6]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=2)[CH2:14][CH2:13][CH2:12]1)=[O:17]
Reactant: BrBr
Reactant: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Solvent: CO
Solvent: ClCCl
Product: O=C(CBr)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of bromine (10.2 ml) in dichloromethane (50 ml) was added dropwise over 3.5 hours at 10-15° C. under nitrogen to a stirred solution of 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethanone (47 g) in a mixture of methanol (75 ml) and dichloromethane (15 ml). After the addition was complete, the mixture was stirred at ambient temperature for 2.5 hours, then poured onto ice-water (500 ml). The aqueous layer was separated and washed with dichloromethane (3×100 ml), then the combined organic solutions were washed with saturated aqueous sodium hydrogen carbonate solution (2×100 ml) and water (100 ml), dried (CaCl2), and the solvents removed in vacua. The residue was distilled to give 2-bromo-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethanone as a pale yellow oil (40.2 g), b.p. 156-164° C. at 0.8 mbar.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][CH2:33][C:34]1[CH:35]=[N:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)=[CH:15][C:10]=2[N:9]=[CH:8]1.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][CH2:33][C:34]1[CH:35]=[N:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:15][C:10]=2[N:9]=[CH:8]1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(C5CCN(C(=O)OC(C)(C)C)CC5)ccc43)cc2OC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(COc2ccc(Cn3cnc4cc(C5CCNCC5)ccc43)cc2OC)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.7 %

Procedure:
To a stirred and cooled (5° C.) solution of tert-butyl 4-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate (0.28 g, 0.51 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was allowed to warm room temperature and stir. After 2 h, the mixture was treated with 1 N sodium hydroxide solution to achieve a pH −10 and was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with brine (3×10 mL), dried over sodium sulfate, concentrated. The residue was purified by prep-HPLC to afford 0.018 g (8%) of the product as a white solid: 1H NMR (500 MHz, MeOD-d4) δ 8.25 (s, 1H), 8.16 (d, J=2.5 Hz, 1H), 7.76 (dd, J=8.5, 2.5 Hz, 1H), 7.55 (s, 1H), 7.40 (d, J=8.5 Hz, 1H), 7.20 (dd, J=8.5, 1.0 Hz, 1H), 7.00-6.97 (m, 2H), 6.82-6.79 (m, 2H), 5.41 (s, 2H), 5.01 (s, 2H), 3.91 (s, 3H), 3.79 (s, 3H), 3.24-3.21 (m, 2H), 2.86-2.81 (m, 3H), 1.93-1.90 (m, 2H), 1.78-1.75 (m, 2H) ppm; (M+1)=459.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH3:8].[Cl:9][C:10]1[CH:11]=[C:12]([OH:31])[CH:13]=[CH:14][C:15]=1[CH:16]([CH3:30])[C:17]([OH:29])([C:22]1[CH:27]=[N:26][C:25]([CH3:28])=[CH:24][N:23]=1)[C:18]([F:21])([F:20])[F:19]>>[Cl:9][C:10]1[CH:11]=[C:12]([O:31][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH3:8])[CH:13]=[CH:14][C:15]=1[CH:16]([CH3:30])[C:17]([C:22]1[CH:27]=[N:26][C:25]([CH3:28])=[CH:24][N:23]=1)([OH:29])[C:18]([F:21])([F:19])[F:20]
Reactant: COCCOCCBr
Reactant: Cc1cnc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn1
Product: COCCOCCOc1ccc(C(C)C(O)(c2cnc(C)cn2)C(F)(F)F)c(Cl)c1

Procedure:
The title compound was prepared in analogy to Example 74 from 1-bromo-2-(2-methoxyethoxy)ethane and 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenol (Example 72). MS (m/e)=449.0 (MH+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]1[N:18]=[C:17]([CH2:19][OH:20])[CH:16]=[C:15]([NH:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[N:14]=1.C(N(CC)CC)C>C(Cl)Cl.O>[CH3:11][O:12][C:13]1[N:18]=[C:17]([CH:19]=[O:20])[CH:16]=[C:15]([NH:21][CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[N:14]=1
Reactant: COc1ccc(CCNc2cc(CO)nc(OC)n2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CCNc2cc(C=O)nc(OC)n2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
A solution of oxalyl chloride (305 μL, 3.55 mmol) in DCM (10 mL) is chilled to −78° C. To the chilled solution is added dropwise, dimethyl sulfoxide (492 μL, 6.92 mmol). After 10 minutes of stirring a solution of {2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-methanol [500 mg, 1.73 mmol, Intermediate (58)] in DCM (7 mL) is added via syringe. The mixture is stirred at −78° C. for 30 minutes before adding, triethylamine (1.95 mL, 13.84 mmol) via syringe. After stirring for an additional 40 minutes at −78° C. the reaction is poured into water (30 mL) and this mixture is extracted twice with 30 ml DCM. The combined extracts are dried over magnesium sulfate, filtered and concentrated by rotary evaporator. The residue is taken up in toluene and re-concentrated and dried under high vacuum to afford 2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidine-4-carbaldehyde [450 mg, 90.5%, Intermediate (59)].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]1[CH2:14][NH:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(NCC1C[N:26]([C:28](=N)[NH:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])C1)=O)(C)(C)C>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]1[CH2:12][N:13]([C:28](=[NH:26])[NH:29][C:30]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC1CNC1
Reactant: CC(C)(C)OC(=O)NCC1CN(C(=N)NC(=O)OCc2ccccc2)C1
Product: CC(C)(C)OC(=O)NCCC1CN(C(=N)NC(=O)OCc2ccccc2)C1

Procedure:
The title compound was prepared from 3-(N-tert-butyloxycarbonylaminoethyl) azetidine according the procedure for 3-(N-tert-butyloxycarbonylaminomethyl)-1-(N-benzyloxycarbon ylamidino) azetidine, in a yield of 0.090 g (34%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:34])[CH:5]=[C:6]([Cl:33])[C:7]=1[CH2:8][C@@H:9]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[C:20]([O:28][CH2:29][CH:30]2[CH2:32][CH2:31]2)[CH:19]=1)[O:10][C:11]([C@H:13]1[NH:17][CH2:16][CH2:15][S:14]1)=[O:12].[CH:35]([C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](O)=[O:41])=[O:36].C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C.Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:34])[CH:5]=[C:6]([Cl:33])[C:7]=1[CH2:8][C@@H:9]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[C:20]([O:28][CH2:29][CH:30]2[CH2:32][CH2:31]2)[CH:19]=1)[O:10][C:11]([C@H:13]1[N:17]([C:40](=[O:41])[C:39]2[CH:43]=[CH:44][CH:45]=[C:37]([CH:35]=[O:36])[CH:38]=2)[CH2:16][CH2:15][S:14]1)=[O:12]
Reactant: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)[C@H]1NCCS1
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=Cc1cccc(C(=O)N2CCS[C@H]2C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (Int 4, 208 mg, 0.389 mmol), 3-formylbenzoic acid (87 mg, 0.583 mmol), EDC (149 mg, 0.777 mmol), and DMAP (57.0 mg, 0.466 mmol) were dissolved in DMF (2 ml). The reaction was stirred at RT for 8 hours to achieve completion. The reaction mixture was diluted with HCl 1N, and the precipitate was filtered, washed with HCl 1N, dissolved in DCM and extracted with HCl 1N, Na2CO3 sat and brine. The organic phase was dried over Na2SO4 and concentrated under vacuum to give 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-3-(3-formylbenzoyl)thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (108 mg, 0.162 mmol, 41.6% yield). The compound was used in the next step without any further purification.