Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[N:4][CH:5]=[C:6]([CH2:8]Br)[CH:7]=1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=1.[Al]>CC#N.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.[Ag-]=O>[Br:1][C:2]1[C:3]([F:10])=[N:4][CH:5]=[C:6]([CH2:8][O:18][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[CH:7]=1
Reactant: Fc1ncc(CBr)cc1Br
Reactant: COc1ccc(CO)cc1
Agent: O=[Ag-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Al]
Solvent: CC#N
Product: COc1ccc(COCc2cnc(F)c(Br)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
3-Bromo-5-(bromomethyl)-2-fluoropyridine (5.63 g, 20.9 mmol) was dissolved in MeCN (135 mL) and 4-methoxybenzyl alcohol (5.20 mL, 41.9 mmol), silver (I) oxide (7.169 g, 30.9 mmol), and tetrabutylammonium iodide (2.208 g, 5.98 mmol) were added. The reaction flask was covered with aluminum foil and the reaction was stirred under nitrogen at room temperature overnight. The reaction was filtered through a pad of Celite® (diatomaceous earth), washing with DCM, MeOH and MeCN. The filtrate was concentrated and purified on a silica gel column (3:1 to 2:1 to 3:2 hexanes/DCM to 3:2 DCM/hexanes to 2:1 DCM/hexanes to 3:1 DCM/hexanes to DCM) to give 3-Bromo-2-fluoro-5-((4-methoxybenzyloxy)methyl)pyridine (1.62 g, 24%). MS (ESI pos. ion) m/z 326/328 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][O:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][N:8]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=2)[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[CH:32][CH:31]=1
Reactant: COC(=O)c1ccc(CN(CCc2ccccc2O)C(=O)OC(C)(C)C)cc1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CN(CCc2ccccc2OCc2ccc(Br)cc2)C(=O)OC(C)(C)C)cc1
Yield: 96.3 %

Procedure:
A solution of 5 g (12.87 mmol) of methyl 4-({tert-butoxycarbonyl-[2-(2-hydroxyphenyl)ethyl]amino}methyl)benzoate from Example 3A in 100 ml of dry acetonitrile is mixed with 3.89 g (15.57 mmol) of 4-bromobenzyl bromide and 2.69 g (19.46 mmol) of anhydrous potassium carbonate and heated to reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The resulting organic phase is concentrated. The crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 20:1→10:1). 6.88 g (12.4 mmol, 89% yield) of a solid are obtained.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][C@@H:8]([C:35]#[N:36])[NH:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:34])[CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)[CH2:13]1)=[O:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:24]1[CH2:25][CH2:26][CH:21]([CH2:20][CH2:19][C:18]([N:14]2[CH2:15][CH2:16][CH2:17][C@@H:12]([C:10]([NH:9][C@H:8]([C:35]#[N:36])[CH2:7][C:6]([OH:37])=[O:5])=[O:11])[CH2:13]2)=[O:34])[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)C[C@@H](C#N)NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#C[C@H](CC(=O)O)NC(=O)[C@@H]1CCCN(C(=O)CCC2CCNCC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.2 %

Procedure:
To a solution of N-[(R)-1-{3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-3(S)-cyano-β-alanine tert-butyl ester (460.9 mg) in dichloromethane (5 ml) was added trifluoroacetic acid (4.6 ml). After stirring at ambient temperature for 2 hours, the mixture was concentrated in vacuo. The residue was dissolved in water and desalted by HP-20 eluting with (IPA:water=1:1). The eluting solution was concentrated in vacuo and freeze-dried to give N-[(R)-1-{3-(4-piperidyl)propionyl}-3-piperidylcarbonyl]-3(S)-cyano-β-alanine (0.12 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[C:10]([C:14]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([F:25])[CH:19]=3)=[O:17])=[O:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:31][S:32]([O-:34])=[O:33].[Na+].O>CN(C)C=O>[CH3:31][S:32]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[C:10]([C:14]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([F:25])[CH:19]=3)=[O:17])=[O:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1)(=[O:34])=[O:33]
Reactant: CS(=O)[O-]
Reactant: Cc1ccc(C(=O)C(=O)c2cccc(-c3ccc(F)cc3)c2-c2cccs2)cc1F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)C(=O)c2cccc(-c3ccc(S(C)(=O)=O)cc3)c2-c2cccs2)cc1F
Temperature: 90 °C
Reaction time: 16 h
Yield: 23.4 %

Procedure:
A mixture of the benzil from Step 3 (2 g, 6.8 mmol) and sodium methylsulfinate (775 mg, 7.1 mmol) in dimethylformamide (10 ml) was stirred at 90° C. for 16 hours. The reaction was cooled, poured into water (120 ml) and the mixture was extracted with methylene chloride. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated. The residue was recrystallized from ethyl acetate and hexane to give 760 mg (45%) of the desired sulfone: mp 130-132° C. Anal. Calc'd. for C16H13FO4S2 (MW 352.41): C, 54.53; H, 3.72; S, 18.20. Found: C, 54.20; H, 3.51; S, 18.40.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[C:11]([C:17]([OH:19])=O)[NH:12]3)[CH:2]=1.Cl.Cl.Cl.[N:24]1([CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:31][CH2:32][N:33]2[CH2:34][CH2:35][CH:36]([NH:39][C:17]([C:11]3[NH:12][C:13]4[C:9]([CH:10]=3)=[C:8]([O:7][C:3]3[CH:2]=[C:1]([CH3:20])[CH:6]=[CH:5][CH:4]=3)[CH:16]=[CH:15][CH:14]=4)=[O:19])[CH2:37][CH2:38]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Reactant: Cc1cccc(Oc2cccc3[nH]c(C(=O)O)cc23)c1
Agent: Cl
Product: Cc1cccc(Oc2cccc3[nH]c(C(=O)NC4CCN(CCN5CCCCCC5)CC4)cc23)c1

Procedure:
This compound is synthesized analogously to Example 1 from 4-m-tolyloxy-1H-indole-2-carboxylic acid 133 (preparation see below) and amine 5.
Reaction SMILES: [Br:1][C:2]([F:16])([F:15])[C:3]([F:14])([F:13])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11]C.C(O)(=O)C.Br>O>[Br:1][C:2]([F:15])([F:16])[C:3]([F:13])([F:14])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11]
Reactant: COc1ccccc1OC(F)(F)C(F)(F)Br
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccccc1OC(F)(F)C(F)(F)Br
Temperature: 20 °C
Reaction time: 43 h
Yield: 83.9 %

Procedure:
A solution of 54.42 g of 1-(2-bromo-1,1,2,2-tetrafluoroethoxy)-2-methoxybenzene in 500 ml of an acid mixture of acetic acid (96% by weight)/hydrobromic acid (48% by weight) 2.5:1 was stirred for 43 hours under reflux, the completeness of the reaction being monitored by gas chromatography (GC). The reaction mixture was then cooled to 20° C. and poured into water. The organic phase was separated off and the aqueous phase was extracted twice with dichloromethane. The extracts were added to the organic phase, and the mixture was dried over magnesium sulfate and evaporated in vacuo. Distillation of the residue gave 43.55 g (83.9% of theory) of 2-(2-bromo-1,1,2,2-tetrafluoroethoxy)-phenol of boiling point 84° C./20 mbar.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[O:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[N:28]([CH2:32][CH:33](OC)[O:34]C)[N:27]=[CH:26]3)=[O:12])[N:7]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].I[Si](C)(C)C>ClCCl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[O:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[N:28]([CH2:32][CH:33]=[O:34])[N:27]=[CH:26]3)=[O:12])[N:7]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(Cn1ncc2cc(Oc3ccc(F)cc3CNC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)ccc21)OC
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)NCc2cc(F)ccc2Oc2ccc3c(cnn3CC=O)c2)cc1
Yield: 116.1 %

Procedure:
1-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-((2-(1-(2,2-dimethoxyethyl)-1H-indazol-5-yloxy)-5-fluorophenyl)methyl)urea (0.500 g, 0.8324 mmol) was dissolved in dichloromethane at room temperature and iodotrimethylsilane (0.3554 mL, 2.497 mmol) added dropwise to the stirred solution. The reaction mixture was monitored by HPLC analysis and when no starting material was detected, the mixture was diluted with dichloromethane and washed with 10% aqueous Na2S2O4, saturated aqueous NaHCO3, brine, dried (MgSO4) and concentrated under reduced pressure to afford 536 mg (quant. yield) of the crude product, which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 7.97 (s, 1H), 6.78-7.30 (m, 10H), 6.17 (s, 1H), 5.99 (br, 1H), 5.44 (q, 1H, J=6.1 Hz), 4.46 (m, 4H), H 2.35 (s, 3H), 1.34 (s, 9H).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4]/[C:5](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:32])[C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:25])[CH:18]=2)=[CH:13][CH:12]=1)/[C:6]([O:8]C)=[O:7].C(O)(=O)C>O1CCCC1>[CH3:3][O:4]/[C:5](=[CH:10]\[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:32])[C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:25])[CH:18]=2)=[CH:15][CH:16]=1)/[C:6]([OH:8])=[O:7]
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)OC)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)O)cc2)c1
Temperature: 68 °C
Reaction time: 4 h
Yield: 83.6 %

Procedure:
2.9 mL (2.9 mmol) of aqueous 1 N sodium hydroxide solution are added to a solution of 0.8 g (1.9 mmol) of methyl (Z)-2-methoxy-3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]acrylate in 15 mL of tetrahydrofuran. The reaction medium is heated at 68° C. and stirred for 4 hours. The reaction medium is acidified with 3 mL of 1 N acetic acid solution and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated. The residue obtained is recrystallized from hot ethyl acetate. 630 mg (82%) of (Z)-2-methoxy-3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]acrylic acid are obtained in the form of a white solid with a melting point of 144° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:34]=[CH:33][C:12]([C:13]([NH:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][C:25]=2[NH:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:19]([O:21][CH3:22])=[O:20])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:34]=[CH:33][C:12]([C:13]2[N:26]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:25]3[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=3[N:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(NC2CCCCC2)c(NC(=O)c2ccc(OCc3ccccc3)cc2)c1
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Temperature: 100 °C
Reaction time: 15 h
Yield: 47.9 %

Procedure:
A solution of compound 47 (0.558 g, 1.11 mmol) in acetic acid (3 mL) was refluxed for 1 h and then stirred at 100° C. for 15 h. The reaction mixture was cooled to rt and concentrated on a rotary evaporator. The residue was coevaporated with toluene (1×) and then purified by column chromatography (silica gel, 8% acetone/toluene (v/v)) to give compound 48 as a white solid (0.234 g, 53%). ESI-MS m/e 441.3 (M+1).
Reaction SMILES: FC(F)(F)C1C=CC([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17]CC)=[O:16])[CH2:11][CH2:10]2)=NC=1.[OH-].[K+]>CO.O>[NH:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1
Reactant: CCOC(=O)C1CCN(c2ccc(C(F)(F)F)cn2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1CCNCC1

Procedure:
The crude ethyl 1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylate was dissolved in 15 ml of methanol and 2.5 ml of water. 535 mg (9.54 mmol) of potassium hydroxide were added and the mixture was reacted at 40° C. for 30 min. The mixture was evaporated, the residue was dissolved in water, pH 3 was adjusted with 2N hydrochloric acid and the solid formed was filtered off and dried in vacuo to yield 471 mg (54% yield) of 1-[5-trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylic acid.
Reaction SMILES: [C:1]1(=O)[O:5][CH2:4][CH2:3][O:2]1.[F:7][C:8]([F:32])([F:31])[C:9]1[N:13]2[N:14]=[C:15]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28]C(O)=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:32][C:8]([F:7])([F:31])[C:9]1[N:13]2[N:14]=[C:15]([N:18]3[CH2:19][CH2:20][CH:21]([C:24]4[CH:29]=[CH:28][C:1]([O:2][CH2:3][CH2:4][OH:5])=[CH:26][CH:25]=4)[CH2:22][CH2:23]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1
Reactant: Oc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A solution of ethylene carbonate (121 g, 1376.13 mmol) in DMF (200 mL) was added dropwise to a stirred suspension of 4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenol (100 g, 275.23 mmol) and potassium carbonate (76 g, 550.45 mmol) in DMF (200 mL) at 80° C. over a period of 15 minutes under nitrogen. The resulting mixture was stirred at 80° C. for 20 hours. The reaction mixture was cooled to room temperature, then concentrated and diluted with DCM (2 L), and washed sequentially with water (1 L) and saturated brine (500 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 70 to 100% EtOAc in isohexane. Fractions containing the desired product were evaporated to dryness then triturated with EtOAc (150 mL). The resulting solid was washed with further EtOAc (50 mL) and ether then dried to give 2-(4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethanol. The filtrate was evaporated and further purified by flash silica chromatography, elution gradient 70 to 100% EtOAc in isohexane. Fractions containing the desired product were evaporated to dryness then triturated with ether, dried and combined with the material previously collected to afford 2-(4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethanol (89 g, 79%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH:10]=[CH:9][C:5]2=[N+:6]([O-])[CH:7]=1.C[CH2:14][N:15](CC)CC.C[Si](C#N)(C)C>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH:10]=[CH:9][C:5]2=[N:6][C:7]=1[C:14]#[N:15]
Reactant: CCN(CC)CC
Reactant: Cn1ccc2c1cc(Br)c[n+]2[O-]
Agent: C[Si](C)(C)C#N
Solvent: ClCCCl
Product: Cn1ccc2nc(C#N)c(Br)cc21
Temperature: 80 °C
Reaction time: 5 h
Yield: 75.6 %

Procedure:
To a stirred mixture of 6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridine 4-oxide (3.8 g 14 mmol), Et3N (19.51 mL, 140 mmol) and DCE (20 mL) was added trimethylsilyl cyanide (9.38 mL, 70.0 mmol). The reaction mixture was stirred at 80° C. for 5 h, subsequently concentrated in vacuo, and purified by silica gel chromatography eluting with EtOAc/DCM (1:1) to give the title compound as an off-white solid (2.50 g, 76%, 2 steps). ESI-MS m/z [M+H]+ calc'd for C9H6BrN3, 236, 238; found 236, 238.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[CH2:20][CH2:19][C:18]([CH2:27][C:28]([OH:30])=[O:29])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:17][C:16]2=[O:31])[CH:10]=1.S(Cl)(Cl)=O.[CH3:36]O>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[CH2:20][CH2:19][C:18]([CH2:27][C:28]([O:30][CH3:36])=[O:29])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:17][C:16]2=[O:31])[CH:10]=1
Reactant: CO
Reactant: O=C(O)CC1(c2ccccc2)CCN(c2cccc(-c3ccc(F)cc3F)c2)C(=O)O1
Solvent: O=S(Cl)Cl
Product: COC(=O)CC1(c2ccccc2)CCN(c2cccc(-c3ccc(F)cc3F)c2)C(=O)O1
Reaction time: 8 h
Yield: 23 %

Procedure:
A 100-mL of flask was charged with 2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetic acid (1.02 g, 2.4 mmol) dissolved in MeOH (15 mL). Then thionyl chloride (418 mg, 3.5 mmol) was added dropwise slowly at 0° C. under N2 protection. The mixture was stirred overnight under reflux. The mixture was concentrated to give the crude product, which was purified by chromatography to give the pure product (230 mg, 23%).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[C:23]([CH3:32])=[C:24]2[C:29](=[CH:30][CH:31]=1)[O:28][CH2:27][CH2:26][CH2:25]2)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[F:39][C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][C:47]=1[CH3:48])[CH2:43]Br>C(#N)C.O.Cl>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:43][C:42]3[CH:45]=[CH:46][C:47]([CH3:48])=[C:40]([F:39])[CH:41]=3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[C:23]([CH3:32])=[C:24]2[C:29](=[CH:30][CH:31]=1)[O:28][CH2:27][CH2:26][CH2:25]2)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(CBr)cc1F
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2C)CCCO3)c2cc[nH]c2c(=O)n1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2C)CCCO3)c2ccn(Cc3ccc(C)c(F)c3)c2c(=O)n1C
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 82.6 %

Procedure:
A solution of methyl 2-(tert-butoxy)-2-(6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (20 mg, 0.046 mmol) in Acetonitrile (0.45 mL) was treated with Cs2CO3 (59.4 mg, 0.182 mmol), 3-fluoro-4-methylbenzyl bromide (13.89 mg, 0.068 mmol), and then stirred at 70° C. for 90 min. The reaction was cooled to rt, diluted with water and 1N HCl, extracted with EtOAc, washed Brine, dried with Na2SO4, filtered, and concentrated. Purification with column chromatography (0-60% EtOAc/Hexane) gave methyl 2-(tert-butoxy)-2-(1-(3-fluoro-4-methylbenzyl)-6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (21.5 mg, 0.038 mmol, 84% yield) as clear oil: LCMS (m/z) ES+=561 (M+1). The intermediate was dissolved in Methanol (0.5 mL) and Tetrahydrofuran (THF) (0.5 mL), treated with LiOH (0.100 mL, 0.200 mmol), and stirred overnight at 60° C. The reaction was concentrated and purified with reverse phase HPLC (20-100% MeCN/H2O-0.1% TFA) to give title compound (13.5 mg, 0.024 mmol, 64.7% yield) as white solid: 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.36-7.29 (m, 0.4H), 7.12 (t, J=7.8 Hz, 1H), 7.04-6.87 (m, 3.6H), 6.80-6.66 (m, 1H), 5.97-5.59 (m, 3H), 5.46-5.40 (m, 0.4H), 5.21-5.11 (m, 0.6H), 4.27-4.10 (m, 2H), 3.71-3.61 (m, 3H), 2.77-2.58 (m, 2H), 2.27-2.19 (m, 3H), 2.16-2.05 (m, 2H), 2.02 (s, 2H), 1.94 (s, 1H), 1.19-1.11 (m, 6H), 1.05-0.99 (m, 3; LCMS (m/z) ES+=547 (M+1).
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH:11][CH2:12][C:13]3[CH:29]=[CH:28][C:16]([CH2:17][NH:18][S:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)(=[O:21])=[O:20])=[CH:15][CH:14]=3)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:30][Si:31]([CH3:48])([CH3:47])[CH2:32][CH2:33][O:34][CH2:35][N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=[C:37]1[CH:45]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[N:1]1[C:10]2[CH:9]([N:11]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([CH2:17][NH:18][S:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)(=[O:20])=[O:21])=[CH:28][CH:29]=3)[CH2:45][C:37]3[N:36]([CH2:35][O:34][CH2:33][CH2:32][Si:31]([CH3:30])([CH3:47])[CH3:48])[C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=4[N:38]=3)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1c(C=O)nc2ccccc21
Reactant: O=S(=O)(NCc1ccc(CNC2CCCc3cccnc32)cc1)c1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: C[Si](C)(C)CCOCn1c(CN(Cc2ccc(CNS(=O)(=O)c3ccccn3)cc2)C2CCCc3cccnc32)nc2ccccc21
Yield: 40.8 %

Procedure:
Using general procedure B: Reaction of pyridine-2-sulfonic acid 4-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzylamide (AMD9426) (150 mg, 0.37 mmol), 1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole-2-carbaldehyde (102 mg, 0.37 mmol), and NaBH(OAc)3 (233 mg, 1.10 mmol) for 1 h at room temperature followed by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH 198:1:1) gave the title compound (101 mg, 41%) as a yellow foam. 1H NMR (300 MHz, CD3OD) δ 0.00 (s, 9H), 0.75 (dd, 2H, J=8.1, 8.1 Hz), 1.58-1.75 (m, 2H), 2.22 (br s, 2H), 2.66-2.85 (m, 2H), 3.25 (dd, 2H, J=8.1, 8.1 Hz), 3.66 (d, 1H, J=14.1 Hz), 3.78 (d, 1H, J=14.1 Hz), 4.02 (d, 1H, J=6.0 Hz), 4.06-4.16 (m, 1H) 4.20 (brs, 2H), 4.81 (br s, 1H), 5.68 (d, 1H, J=12.0 Hz), 5.91 (d, 1H, J=12.0 Hz), 6.92 (d, 2H, J=7.8 Hz), 7.06 (dd, 1H, J=7.5, 4.8 Hz), 7.17-7.23 (m 4H), 7.30-7.35 (m, 2H), 7.45 (ddd, 1H, J=7.5, 4.5, 1.1 Hz), 7.61-7.64 (m, 1H), 7.87 (ddd, 1H, J=7.8, 7.8,1.7 Hz), 7.98 (d, 1H, J=7.8 Hz), 8.55 (d, 1H, J=3.6 Hz), 8.68 (d, 1H, J=3.9 Hz).ES-MS m/z 669 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](B3OC(C)(C)C(C)(C)O3)[CH:8]=2)[C:3]1=[O:21].Br[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C([O-])(O)=O.[Na+]>CS(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][N:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:8]=2)[C:3]1=[O:21]
Reactant: Brc1ccccn1
Reactant: Cn1ccc2cc(B3OC(C)(C)C(C)(C)O3)ccc2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CS(C)=O
Product: Cn1ccc2cc(-c3ccccn3)ccc2c1=O
Yield: 46.1 %

Procedure:
A mixture of 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one (420 mg, 1.47 mmol), 2-bromopyridine (698 mg, 4.42 mmol), Pd(dppf)Cl2 (107 mg, 0.15 mmol) and saturated aqueous NaHCO3 (3.5 mL) in DMSO (25 mL) was microwaved at 150° C. for 45 min. After extractive work up with ethyl acetate, purification by silica gel chromatography (PE:EA=3:1 to 3:2) gave the title compound (160 mg, 46.0%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.76 (d, J=4.8 Hz, 1H), 8.53 (d, J=8.0 Hz, 1H), 8.20 (d, J=1.2 Hz, 1H), 8.07 (dd, J1=8.4 Hz, J2=1.6 Hz, 1H), 7.85-7.82 (m, 2H), 7.34-7.30 (m, 1H), 7.11 (d, J=7.2 Hz, 1H), 6.6 (d, J=7.2 Hz, 1H), 3.64 (s, 3H). LCMS: 237.2 (M+H)+
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[CH2:6]1)=O.[CH3:26][NH2:27]>C(O)C>[CH3:26][NH:27][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[CH2:6]1)=[O:2]
Reactant: CN
Reactant: COC(=O)C1CC(=O)N(c2ccc(OCc3ccc(F)cc3)cc2)C1
Solvent: CCO
Product: CNC(=O)C1CC(=O)N(c2ccc(OCc3ccc(F)cc3)cc2)C1

Procedure:
In an analogous manner to that described in Example 1e), the aminolysis of the (RS)-1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester with methylamine in a sealed tube at 80° C. in ethanol during 18 h yields the (RS)-1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide as a white powder; MS: m/e=343 (M+H)+.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].CS[C:8]1[N:9]([CH3:18])[C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[N+:12]=1[CH3:13].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCOCC1>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[C:8]1[N:9]([CH3:18])[C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[N+:12]=1[CH3:13]
Reactant: C1CCNCC1
Reactant: CSc1n(C)c2ccccc2[n+]1C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cn1c(C2CCCCN2)[n+](C)c2ccccc21

Procedure:
Heat 0.01 mol of 2-methylmercapto-1,3-dimethylbenzimidazolium perchlorate with 0.01 mol of piperidine for 4th at reflux in 250 ml of dioxane. Remove the solids by suction and recrystallise from ethanol.