Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([Cl:11])[N:5]=[CH:4][CH:3]=1.[CH2:12]([NH2:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.ClCCl>[NH2:1][C:2]1[C:7]([C:8]([NH:20][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])=[C:6]([Cl:11])[N:5]=[CH:4][CH:3]=1
Reactant: Nc1ccnc(Cl)c1C(=O)O
Reactant: NCCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1ccnc(Cl)c1C(=O)NCCc1ccccc1
Temperature: 20 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
4-Amino-2-chloro-nicotinic acid (1 g, 5.795 mmol) was dissolved in DMF (30 mL) and dichloromethane (50 mL). Phenethylamine (0.87 mL, 6.954 mmol, 1.2 equiv.) was added followed by TEA (1.21 mL, 8.693 mmol, 1.5 equiv.) and HBTU (2.64 g, 6.954 mmol, 1.2 equiv.) and the reaction stirred at 20° C. for 12 hours. The reaction mixture was then diluted with dichloromethane and the aqueous layer was extracted with 20% isopropyl alcohol/dichloromethane. The combined organic portions were washed with 0.5N NaOH solution, NH4Cl solution, water, brine, dried over anhydrous MgSO4, filtered and concentrated. The crude material was purified by column chromatography using 2:1 ethyl acetate:hexane to provide 1.23 g (77%) of product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:5]=[C:4](Cl)[N:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=[O:31])=[CH:28][CH:27]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[NH2:1][C:2]1[N:3]=[C:4]([C:26]2[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=[O:31])=[CH:28][CH:27]=2)[CH:5]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[N:7]=1
Reactant: N#Cc1ccc(-c2cc(Cl)nc(N)n2)cc1F
Reactant: CC1(C)OB(c2ccc(C(N)=O)cc2)OC1(C)C
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: C1COCCO1
Solvent: O
Product: N#Cc1ccc(-c2cc(-c3ccc(C(N)=O)cc3)nc(N)n2)cc1F
Temperature: 110 °C
Yield: 35.4 %

Procedure:
A mixture of 4-(2-amino-6-chloro-4-pyrimidinyl)-2-fluorobenzonitrile (400 mg, 1.61 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (397.0 mg, 2.41 mmol), Pd(PPh3)4 (185 mg, 0.16 mmol), and Na2CO3 (427 mg, 4.02 mmol) in 1,4-dioxane (60 mL) and water (20.0 mL) was stirred and heated at 110° C. for 1 hour under nitrogen. The mixture was cooled to room temperature and concentrated, and the resulting residue was portioned between EtOAc (100 mL) and water (100 mL). The aqueous phase was extracted with EtOAc (2×50 mL), and the combined organic layers were dried Na2CO3, filtered and concentrated to dryness. Purification by SiO2 chromatography using 4:1 petroleum ether/THF as eluent afforded the title compound (190 mg) as a white solid. LC-MS (ES) m/z=334 [M+H]+.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH3:2].[CH2:5]1COC[CH2:6]1.C(O[C:13](=[O:21])[CH2:14][CH2:15][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)C>CCOCC>[CH:16]1([CH2:15][CH2:14][C:13]([CH2:1][CH3:2])([OH:21])[CH2:5][CH3:6])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: C1CCOC1
Reactant: CCOC(=O)CCC1CCCC1
Reactant: CC[Mg]Cl
Solvent: CCOCC
Product: CCC(O)(CC)CCC1CCCC1
Temperature: 17.5 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
31.3 ml of a 2.8 M solution of EtMgCl in THF (87.7 mmol), diluted with 50 ml of anhydrous ether were placed into a 250 ml 4-neck round bottom flask, equipped with a mechanical stirrer and a reflux condenser. Upon cooling to 15-20° C., 6 g (35.16 mmol) of 3-cyclopentylpropionic acid ethyl ester (obtained according to Barret et al., J. Chem. Soc.; 1935, 1065) dissolved into 50 ml of anhydrous ether were added dropwise to the stirred solution at a rate which maintained the pot temperature between 15-25° C. The reaction mixture was then stirred at room temperature overnight and then quenched at 5° C. with the addition of 60 ml of water and neutralized at pH 7. The organic layer was separated and the ether and THF were stripped at reduced pressure. The resulting crude product was fractionally distilled with a bulb-to-bulb distillation (0.5 mbar, 120° C.) to give 4.5 g of pure 5-cyclopentyl-3-ethyl-3-pentanol (66% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12])=[CH:5]2.[H-].[Na+].FC(F)(F)S(O[CH2:27][C:28]([F:31])([F:30])[F:29])(=O)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:27][C:28]([F:31])([F:30])[F:29])[C:6]([C:11]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[O:12])=[CH:5]2
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=C(c1cc2cc(Br)ccc2[nH]1)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1cc2cc(Br)ccc2n1CC(F)(F)F)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.4 %

Procedure:
To a mixture of (5-bromo-1H-indol-2-yl)-morpholin-4-yl-methanone (6.64 g, 20 mmol) in tetrahydrofuran (60 mL) was added sodium hydride (60% dispersion in oil, 979 mg, 24 mmol) in several portions. The mixture was stirred 15 min at room temperature then 2,2,2-trifluroethyl trifluoromethanesulfonate (6.16 g, 27 mmol) was added and the reaction mixture was refluxed overnight. The reaction mixture was partitioned between ethyl acetate and an aqueous solution of sodium bicarbonate. The organic layer was washed with hydrochloric acid (1N) and brine, dried over sodium sulfate, filtered and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel with dichloromethane: ethyl acetate (98:2 to 94:6 v/v) as eluant, to give 4.65 g (58%) of the desired compound as an off-white solid.
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:17][C:18]1([CH3:24])[CH2:22][CH2:21][CH2:20][C:19]1=O.C(OCC)C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:17][C:18]1([CH3:24])[CH2:22][CH2:21][CH2:20]/[C:19]/1=[N:9]\[C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CC1(C)CCCC1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C[C@@H](/N=C1\CCCC1(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an ice cold solution of (R)-1-phenylethanamine (3.11 g, 25.7 mmol) and triethylamine (17.9 mL, 128 mmol) in dichloromethane (60 mL) was added dropwise neat titanium tetrachloride (10.7 mL, 10.7 mmol) to afford a light brown mixture. The cold bath was removed and 2,2-dimethylcyclopentanone (2.68 mL, 21.4 mmol) was added and the resulting mixture was allowed to stir at rt for ˜16 h. To this mixture was added 75 mL of diethyl ether and the resulting mixture was stirred at rt for 15 min then filtered thru a pad of Celite to remove the solids. The solids were rinsed with additional ether (30 mL×2) and the resulting clear yellow filtrate was concentrated on a rotovap to afford 4.86 g (quantitative) of the title compound as a yellow liquid. HPLC (condition B): retention time=1.58 min. LCMS (condition E): m/z 216+ve.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].Br.Br[CH2:19][CH2:20][CH2:21][NH2:22].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:7][N:8]([CH2:19][CH2:20][CH2:21][NH2:22])[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1(c2ccccc2)CCNCC1
Reactant: NCCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)C1(c2ccccc2)CCN(CCCN)CC1
Yield: 72.4 %

Procedure:
A mixture of 4-methoxycarbonyl-4-phenylpiperidine (8.5 g, 0.039 mol), 3-bromopropylamine hydrobromide (12.7 g, 0.058 mol), potassium carbonate (13.475 g, 0.0957 mole), and KI (3.24 g, 0.0195 mol) in 1,4-dioxane (200 mL) was stirred and refluxed for 24 hours. Dioxane was evaporated at reduced pressure, the residue was treated with ice-cold 6 N NaOH (400 mL) and extracted with CH2Cl2 (4×120 mL). Solvent was evaporated from the combined dried (K2CO3) extracts and the residue was purified by column chromatography on silica gel using CHCl3/MeOH/2 M NH3 in MeOH (20:2:1) as the eluent to afford the product as a viscous oil (7.8 g, 72%).
Reaction SMILES: [O:1]=[C:2]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][C:4](O)=[O:5].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[F:29][C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][C:36]=1[O:37][C:38]1[CH:43]=[CH:42][N:41]=[C:40]2[CH:44]=[C:45]([I:47])[S:46][C:39]=12)[NH2:33].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:29][C:30]1[CH:31]=[C:32]([NH:33][C:4](=[O:5])[CH2:3][C:2]([NH:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:1])[CH:34]=[CH:35][C:36]=1[O:37][C:38]1[CH:43]=[CH:42][N:41]=[C:40]2[CH:44]=[C:45]([I:47])[S:46][C:39]=12
Reactant: O=C(O)CC(=O)Nc1ccccc1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1)Nc1ccccc1
Reaction time: 0.25 h
Yield: 54.1 %

Procedure:
A solution of the acid 1 (465 mg, 2.59 mmol) and BOPCl (666 mg, 2.59 mmol) was mixed in DCM (5 mL) at 0° C. and stirred at the same temperature for 15 min. The reaction mixture was then treated with a solution of 410 (500 mg, 1.29 mmol) and iPr2NEt (1.3 mL, 1 g, 7.79 mmol) in DCM (5 mL) at 0° C. and allowed to stir at room temperature for overnight. The mixture was diluted in DCM (30 mL), washed with saturated NaHCO3 solution (30 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography using the gradient 75-100% EtOAc in hexanes as an eluent, to provide 411 (382 mg, 54% yield). 1H NMR δ(400 MHz, CD3OD): 8.33 (d, 5.7 Hz), 7.79 (dd, 1H, J=2.4 Hz, J=12.3 Hz), 7.54 (m, 5H), 7.2-7.4 (m, 4H), 7.09 (t, 1H, J=7.2 Hz), 6.50 (d, 1H, J=5.5 Hz), 3.51 (s, 2H), 7.75 (s, 1H). MS (m/z): (M+1) 547.9 (100%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:30])[N:14]([CH3:29])[N:15]=[C:16]([CH3:28])[C:17]=1S(C1C=CC(C)=CC=1)(=O)=O)[CH3:2].[OH-:31].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:30])[N:14]([CH3:29])[N:15]=[C:16]([CH3:28])[C:17]=1[OH:31])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(=O)(=O)c2ccc(C)cc2)c(C)nn(C)c1=O
Reactant: [OH-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1-c1c(O)c(C)nn(C)c1=O
Temperature: 25 °C
Yield: 35.8 %

Procedure:
To a 10 ml volume two-necked flask with Dean-Start, 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-(4-methylphenylsulfonyl)-2,3-dihydro-3-pyridazinone ((2-36)-(1)-39) (699 mg), toluene (2.45 ml), tetrabutylammonium bromide (27 mg), and 48 w/w % of aqueous sodium hydroxide solution (550 mg) were added. Water was removed by azeotropic distillation under reflux for 33 hours. After the mixture was cooled to room temperature, water was added, and the organic layer was removed. To the aqueous layer, 20 w/w % of sulfuric acid was added to adjust pH to 4, and extracted with toluene 2 times. The organic layers were combined, and concentrated under reduced pressure. The residue was subjected to column chromatography (hexane: ethyl acetate=5:1) to give 169 mg of 4-(2,6-diethyl-4-methylphenyl)-5-hydroxy-2,6-dimethyl-2,3-dihydro-3-pyridazinone ((1-4)-(1)-39).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([N+:11]([O-])=O)[C:5]=1[OH:14].C(O)(=O)C>CO.[Fe]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([NH2:11])[C:5]=1[OH:14]
Reactant: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(Cl)cc(N)c1O
Temperature: 25 °C

Procedure:
5-Chloro-2-hydroxy-3-nitro-benzoic acid methyl ester 1 g (4.31 mmol) is dissolved in methanol (30 mL) and acetic acid (30 mL) and then iron powder is added (4.8 g, 86 mmol) at room temperature. The resulting suspension is stirred and heated to reflux for 1 hour. The reaction is allowed to cool to room temperature and then gravity filtered though a pad of celite. The celite cake is washed 3× with ethyl acetate (50 mL) and then the combined washings evaporated in vacuo. The oil is then taken up in ethyl acetate (250 mL) and washed with water (100 mL) and saturated sodium bicarbonate (100 mL). The organic layer is dried (MgSO4), decolorized with charcoal, filtered and evaporated to give the title compound that is used without further purification (730 mg, 3.6 mmol, 84%). LCMS (ESMS): m/z 202.5 (M+H+).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[N:8][NH:9]2)=[CH:5][CH:4]=1.[OH-].[K+].[I:16]I.C(OCC)(=O)C>CN(C=O)C>[I:16][C:7]1[C:6]2[C:10](=[CH:11][C:3]([C:2]([F:1])([F:12])[F:13])=[CH:4][CH:5]=2)[NH:9][N:8]=1
Reactant: FC(F)(F)c1ccc2cn[nH]c2c1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc2c(I)n[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
A mixture of 6-(trifluoromethyl)-1H-indazole (0.5 g, 2.69 mmol), KOH (0.45 g, 8.1 mmol) and I2 (1.37 g, 5.38 mmol) in dry DMF (20 mL) was stirred for 16 hours at room temperature. Ethyl acetate (100 mL) was added and the mixture was washed with water (3×10 mL) and brine (2×10 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was then washed with ether (2 mL) and filtered to afford 3-iodo-6-(trifluoromethyl)-1H-indazole (688 mg, crude) as a yellow solid. LCMS: (M+H)+=313.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]([F:13])([F:12])[F:11])=[C:6]([NH2:8])[CH:7]=1.[N:14]#[C:15][NH2:16].Cl>CCO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]([F:11])([F:12])[F:13])=[C:6]([NH:8][C:15]([NH2:16])=[NH:14])[CH:7]=1
Reactant: Nc1cc(Br)ccc1OC(F)(F)F
Reactant: N#CN
Agent: Cl
Solvent: CCO
Solvent: O
Product: N=C(N)Nc1cc(Br)ccc1OC(F)(F)F
Temperature: 25 °C
Yield: 89.5 %

Procedure:
To a suspension of 5-bromo-2-trifluoromethoxy-phenylamine (5.0 g, 19.5 mmol) in EtOH (15 mL), cyanamide (1.64 g, 39 mmol) dissolved in 5 mL of EtOH and 1 mL H2O, and HCl 37% (3.25 mL) diluted in 10 mL EtOH were added drop wise into the mixture under stirring. The mixture was refluxed for 72 h. The mixture was cooled down to room temperature, concentrated then diluted with water; NaOH 1N was added to basic pH and extracted several times with ethyl acetate, dried over sodium sulfate and concentrated to afford 5.2 g of the title compound (89% yield).
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:16][NH:17][C:18](=[O:36])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27](=[O:35])[NH:28][C:29]2[NH:30][CH2:31][CH2:32][CH2:33][N:34]=2)=[CH:21][CH:20]=1)[C:13]([OH:15])=[O:14])=O)C1C=CC=CC=1.C(O)(=O)C.CO>O1CCOCC1.[Pd]>[NH2:11][C@@H:12]([CH2:16][NH:17][C:18](=[O:36])[C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][C:27](=[O:35])[NH:28][C:29]2[NH:34][CH2:33][CH2:32][CH2:31][N:30]=2)=[CH:23][CH:24]=1)[C:13]([OH:15])=[O:14]
Reactant: O=C(CCc1ccc(C(=O)NC[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1)NC1=NCCCN1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1COCCO1
Product: N[C@@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)C(=O)O
Reaction time: 2 h

Procedure:
100 mg (0.2 mmol) of (2S)-2-benzyloxycarbonylamino-3-(4-(2-(1,4,5,6-tetra-hydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propionic acid (Example 3e) were dissolved in 15 ml of dioxane, treated with 0.012 ml of glacial acetic acid and hydrogenated at RT and 1 bar H2 over Pd/C (5%). After 2 h, 15 ml of methanol were added and the mixture was hydrogenated at RT and 1 bar H2 for a further 5 h. It was filtered and the solvent was evaporated in vacuo. Yield: 67.4 mg (93%). MS: ES+, m/e=362.2 (M+H+, 30%); 173.0 (100).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][NH:17][C:14]2=[CH:15][N:16]=1)[CH3:2].I[C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(N)CN>O1CCOCC1.CCOC(C)=O.[Cu]I>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][N:17]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=3)[C:14]2=[CH:15][N:16]=1)[CH3:2]
Reactant: CC(C)c1ccc(I)cc1
Reactant: CCc1cccc(CC)c1-c1cc2cc[nH]c2cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: NCCN
Product: CCc1cccc(CC)c1-c1cc2ccn(-c3ccc(C(C)C)cc3)c2cn1
Temperature: 60 °C
Yield: 48.5 %

Procedure:
A mixture of 5-(2,6-diethyl-phenyl)-1H-pyrrolo[2,3-c]pyridine (700 mg, 2.8 mmol), 1-iodo-4-isopropyl-benzene (2.0 g, 8.1 mmol), CuI (1.0 g, 5.3 mmol), cesium carbonate (1.8 g, 5.5 mmol) and ethylenediamine (336 mg, 5.6 mmol) in dioxane (10 mL) is heated at 60° C. overnight. The reaction mixture is cooled, diluted with EtOAc, and filtered through Celite. The filtrate is concentrated under reduced pressure. The residue is purified by chromatography on silica gel (Hexane/EtOAc, 4:1) to afford 500 mg of 2.7 g of 5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridine as a solid. 1H NMR: (CDCl3) 8.97 (s, 1H), 7.41-7.52 (m, 6H), 7.28 (t, 1H), 7.15 (d, 2H), 6.68 (d, 1H), 3.03 (m, 1H), 2.36 (m, 4H), 1.34 (d, 6H), 1.01 (t, 6H).
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]([NH:15][OH:16])=[NH:14])[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[C:17]1([C:23]2[CH:31]=[CH:30][C:26]([C:27]([Cl:29])=O)=[CH:25][CH:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[ClH:29].[CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]2[N:14]=[C:27]([C:26]3[CH:30]=[CH:31][C:23]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:24][CH:25]=3)[O:16][N:15]=2)[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)N1CCC(CC(=N)NO)CC1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: CCC(CC)N1CCC(Cc2noc(-c3ccc(-c4ccccc4)cc3)n2)CC1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 12, starting from 2-((1-ethylpropyl)piperidin-4-yl)-N-hydroxyacetamidine and 4-phenylbenzoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[F:14][C:15]([F:30])([F:29])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:26][C:25]([CH:27]=O)=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH2:45]>ClC(Cl)C>[F:14][C:15]([F:30])([F:29])[C:16]([OH:12])=[O:45].[F:30][C:15]([F:14])([F:29])[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[S:26][C:25]([CH2:27][NH:1][C:2]3[CH:3]=[CH:4][C:5]([C@@H:8]4[CH2:10][C@H:9]4[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=3)=[CH:24][CH:23]=2)=[CH:20][CH:21]=1
Reactant: O
Reactant: Nc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(NCc2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1
Reaction time: 12 h
Yield: 15 %

Procedure:
To a mixture of racemic-(trans)-2-(4-aminophenyl)cyclopropanecarboxylic acid (I-1) (0.058 g, 0.327 mmol) in dichloroethane (2.5 mL) was added 5-[4-(trifluoromethyl)phenyl]-2-thiophenecarbaldehyde (0.071 0.277 mmol). The mixture was stirred for 12 h followed by addition of sodium triacetoxyborohydride (0.090 g, 0.425 mmol). The mixture was stirred for 7 h at RT. Water was added (10 mL), and the layers were separated. The aqueous phase was extracted with EtOAc (3×10 mL). The combined organics were dried with MgSO4 and concentrated. The crude material was purified by preparative HPLC (10% to 100% CH3CN/H2O with 0.05% TFA) to give the title compound as a yellow solid (0.048 g, 15%). 1H NMR (400 MHz, DMSO-d8): δ7.77 (d, J=8.2 Hz, 2H), 7.69 (d, J=8.4 Hz, 2H), 7.51 (d, J=3.7 Hz, 1H), 7.06 (d, J=3.7 Hz, 1H), 6.85 (d, J=8.4 Hz, 2H), 6.55 (d, J=8.6 Hz, 2H), 4.43 (s, 2H), 2.19 (m, 1H), 1.59 (m, 1H), 1.28 (m, 1H), 1.18 (m, 1H). ES-MS m/z 416.03 (MH−).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[Br:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Brc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Br)cc2)CC1
Temperature: 110 °C

Procedure:
tert-Butyl piperidin-4-ylcarbamate (500 mg), 1-bromo-4-iodobenzene (710 mg) and Cs2CO3 (1.2 g) are dissolved in 1,4-dioxane (15 mL) and purged for 10 minutes with argon. 4,5-Bis-(diphenylphosphino)-9,9-dimethylxanthen (Xantphos, 115 mg) and tris-(dibenzylideneacetone)-dipalladium-(0) (Pd2(dba)3, 45 mg) are added and the mixture is heated for 12 hours at 110° C. Then the mixture is partitioned between saturated aqueous NH4Cl solution and ethylacetate and the organic phase is washed with brine and dried (MgSO4). The solvents are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→70:30) to give the title compound. LC (method 2): tR=1.14 min; Mass spectrum (ESI+): m/z=355 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[F:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[CH:21]=3)=[O:32])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1cccc(F)c1
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Product: CC(=O)c1csc(Cn2ncc(NC(=O)c3ncoc3-c3cccc(F)c3)n2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-fluoro-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.[I:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>CN(C)C=O>[I:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:3]2[C:4](=[O:15])[C:5]3[C@H:6]4[C:11]([CH3:12])([CH3:13])[C@:9]([CH3:14])([CH2:8][CH2:7]4)[C:10]=3[N:2]2[CH3:1])=[CH:19][CH:18]=1
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Reactant: BrCc1ccc(I)cc1
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1ccc(I)cc1)[C@@H]1CC[C@@]2(C)C1(C)C
Temperature: 80 °C
Reaction time: 72 h
Yield: 68.2 %

Procedure:
A mixture of (4R,7S)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 104 mg, 0.50 mmol) and 4-iodo-benzyl bromide (163.5 mg, 0.55 mmol) in N,N-dimethylformamide (5 mL) was heated at 80° C. over the weekend and then allowed to stand at room temperature for three days. The reaction mixture was evaporated and the residue was purified using a Biotage 40S system, eluting with 0-1% methanol/chloroform, followed by drying under high vacuum to give (4R,7S)-2-(4-iodo-benzyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (144 mg, 68%) as an off-white solid. APCI-MS (M+H) 423.