Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [PH:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Li]P(C1C=CC=CC=1)C1C=CC=CC=1.[Cl:33][CH2:34][CH2:35][CH2:36]Cl>C(OCC)C.O.O1CCCC1>[P:1]([CH2:36][CH2:35][CH2:34][Cl:33])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: ClCCCCl
Agent: [Li]CCCC
Agent: [Li]P(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: ClCCCP(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 500 mL round bottom flask there was added 400 mL of dry tetrahydrofuran followed by 0.081 mole of HPPh2. The mixture was cooled to 0° C. and 0.081 mole of n-butyl lithium was slowly added to generate LiPPh2 ; this was slowly warmed to room temperature and stirred for about one hour. The solution was transferred to a dropping funnel and added dropwise to a flask containing 100 mL of 1,3-dichloropropane dissolved in 100 mL of diethyl ether. After stirring overnight the mixture was hydrolyzed with 25 mL of water. The organic layer was separated and the solvent removed by vacuum to leave Ph2P(CH2)3Cl that was stored under nitrogen until needed.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.Br[CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1>>[CH3:1][C:2]1[N:3]([CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1c[nH]c(C)n1
Reactant: BrCc1ccc2ccccc2c1
Product: CCOC(=O)c1cn(Cc2ccc3ccccc3c2)c(C)n1
Yield: 65 %

Procedure:
4.6 g (29.8 mmol) of ethyl 2-methylimidazole-4-carboxylate and 6.6 g (29.8 mmol) of 2-bromomethylnaphthalene were reacted analogously to procedure 8a. 5.7 g (65%) of the product were obtained.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.Cl[C:17]1[N:18]([C:22]2[CH2:26][CH2:25][CH2:24][N:23]=2)[CH2:19][CH2:20][CH:21]=1>ClCCCl>[NH:23]1[CH2:24][CH2:25][CH:26]=[C:22]1[N:18]1[CH2:19][CH2:20][CH:21]=[C:17]1[N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: c1ccc2c(c1)Cc1ccccc1N2
Reactant: ClC1=CCCN1C1=NCCC1
Agent: Cl
Solvent: ClCCCl
Product: C1=C(N2CCC=C2N2c3ccccc3Cc3ccccc32)NCC1

Procedure:
A mixture of acridan (3.6 g., 0.02 mole) and 2-chloro-1-(1-pyrrolin-2-yl)-2-pyrroline hydrochloride (5.1 g., 0.025 mole), obtained according to the method of H. Brederick, et al., Chem. Ber., 94, 2292 (1961), in 50 ml. of 1,2-dichloroethane is refluxed for a period of 15 hr. The mixture is sequentially extracted with50 ml. of 1.5N hydrochloric acid and three 50 ml. portions of water. The combined acid-water extracts are basified with 5N potassium hydroxide, extracted with ether and the ethereal extract concentrated. Crystallization of the residue thus obtained from ethanol affords the free base 10-[1-(2-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]ACRIDAN, m.p. 179°-181° C. which is converted according to the procedure of Example 1 to 10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]ACRIDAN HYDROCHLORIDE, m.p. 212.5°-216.5° C. (dec.)(corr.)., from ethanol-ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@H:12]([CH3:15])[N:11](C(=O)C(F)(F)F)[C@@H]2C(C)C)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[F:25][C:26]([F:37])([F:36])[O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl-].[NH4+].[OH-].[K+].OS(O)(=O)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.CC(O)C.CCOC(C)=O>[NH2:11][C@@:12]([CH2:32][C:31]1[CH:34]=[CH:35][C:28]([O:27][C:26]([F:37])([F:36])[F:25])=[CH:29][CH:30]=1)([CH3:15])[C:13]([NH:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:14]
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: CC(C)[C@@H]1N(c2cc(Cl)cc(Cl)c2)C(=O)[C@@H](C)N1C(=O)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: O
Product: C[C@@](N)(Cc1ccc(OC(F)(F)F)cc1)C(=O)Nc1cc(Cl)cc(Cl)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S,5R)-3-(3,5-dichloro-phenyl)-2-isopropyl-5-methyl-1-(2,2,2-trifluoro-acetyl)-imidazolidin-4-one (50.0 g, 130.0 mmol) and 4-trifluoromethoxybenzyl bromide (33.94 g, 133.0 mmol) in THF (200 mL) was added lithium bis(trimethylsilyl)amide (136.5 mL of 1.0 M solution in THF, 136.5 mmol) at 0° C. over 20 min keeping the internal temperature below 0° C. The resulting mixture was stirred at for 30 min. 10% Aqueous ammonium chloride (160 mL) and EtOAc (100 mL) were added. The layers were separated and the organic layer was concentrated to dryness. To the residue was added 2-propanol (250 mL) and potassium hydroxide (9.89 g, 176 mmol), and the mixture was heated at 50° C. for 4 h. 3 M H2SO4 (32 mL) was then added and the mixture was heated at 70° C. for 2 h. 2-Propanol was distilled and isopropyl acetate (200 mL) was added. The organic solution was washed with 2 N NaOH (200 mL) and water (150 mL) and then concentrated to dryness. Acetonitrile (150 mL) was added to the residue followed by 4-toluenesulfonic acid monohydrate (25.9 g, 136.5 mmol). The mixture was stirred at room temperature for 10 h. The title compound was collected by filtration (69.3 g, 92%), mp>200° C. 1H NMR (400 MHz, (D3C)2SO) δ 10.44 (s, 1H, ArNH), 8.30 (bs, 2H, NH2), 7.71 (d, J=1.6 Hz, 2H, ArH), 7.51 (ABq, J=6.4 Hz, 2H, ArH), 7.37 (t, J=1.6 Hz, 1H, ArH), 7.30 (ABq, J=7.4 Hz, 2H, ArH), 7.28 (ABq, J=7.4 Hz, 2H, ArH), 7.11 (ABq, J=6.4 Hz, 2H, ArH), 3.40 (ABq, J=14.0, 1H. ArCH2), 3.20 (ABq, J=14.0 Hz, ArCH2), 2.27 (s, 3H, CH3), 2.27 (s, 3H, CH3), 1.66 (s, 3H, CH3); MS: m/z 406 (M+); Anal. calcd for C24H23Cl2F3N2O5S: C, 49.75; H, 4.00; Cl, 12.24; N, 4.88. Found: C, 49.87; H, 3.99; Cl, 12.40; N, 4.84.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[N:18]=2)=[CH:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][OH:16])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.C(N(CC)CC)C.[S:39](Cl)([CH3:42])(=[O:41])=[O:40]>C(Cl)Cl>[CH3:42][S:39]([O:16][CH2:15][C@H:12]1[CH2:11][CH2:10][C@H:9]([NH:8][C:5]2[CH:4]=[C:3]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=4)[N:18]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:14][CH2:13]1)(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@H]1CC[C@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CC[C@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a round-bottom flask containing (trans-4-(5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridin-2′-yl-amino)cyclohexyl)methanol (obtained following example 2) (102 mg, 0.231 mmol) at 0° C. was added DCM (2 ml) and triethylamine (0.048 ml, 0.347 mmol), followed by dropwise addition of Mesyl Chloride (0.023 ml, 0.301 mmol). The ice bath was removed and the reaction mixture was stirred at rt for 2 hr. The reaction mixture was diluted with DCM and washed with sat NaHCO3 and then sat NaCl. The organic layer was dried over Na2SO4, filtered and concentrated to yield (trans-4-(5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridin-2′-yl-amino)cyclohexyl)methyl methanesulfonate (110 mg, 92% yield), LCMS (m/z): 519.2 (MH+), retention time=0.80 min. The resulting residue was used in next step without further purification.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:14][N:13](CC3C=CC=CC=3)[CH2:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[H][H]>[Pd].CO>[ClH:1].[F:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:10][CH2:11][CH2:12][NH:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: Fc1cccc(C2=CCCN(Cc3ccccc3)C2)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Fc1cccc(C2CCCNC2)c1
Yield: 100 %

Procedure:
A mixture of 6.5 parts of 5-(3-fluorophenyl)-1,2,3,6-tetrahydro-1-(phenylmethyl)pyridine hydrochloride and 120 parts of methanol was hydrogenated at normal pressure and at 50° C. with 1 part of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 4.5 parts (100%) of 3-(3-fluorophenyl)piperidine hydrochloride as a residue (intermediate 93).
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([O:21][CH2:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]>>[Cl:20][C:18]1[CH:19]=[C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:28]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:29])[C:7]=3[CH2:8]2)[CH3:13])[CH:15]=[N:16][C:17]=1[O:21][CH2:22][CH2:23][C:24]([F:27])([F:26])[F:25]
Reactant: O=COc1ccccc1
Reactant: CC(c1cnc(OCCC(F)(F)F)c(Cl)c1)N1Cc2c(ccnc2Cl)C1=O
Product: CC(c1cnc(OCCC(F)(F)F)c(Cl)c1)N1Cc2c(ccnc2C(=O)Oc2ccccc2)C1=O
Yield: 79 %

Procedure:
The title compound is prepared in 79% yield (140 mg, pale brown solid) from 4-chloro-2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (150 mg, 0.36 mmol, Intermediate-78, single enantiomer) and phenyl formate (87 mg, 0.71 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([NH:12][CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[OH:15])[CH2:9]2)=[CH:4][CH:3]=1.OC1C=C2C(CCC(NCC(C3C=CC=C(Cl)C=3)O)C2)=CC=1.Br[CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47]>>[C:46]([CH2:45][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([NH:12][CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[OH:15])[CH2:9]2)=[CH:4][CH:3]=1)([O:48][CH2:49][CH3:50])=[O:47]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc2c(c1)CC(NCC(O)c1ccccc1)CC2
Agent: Oc1ccc2c(c1)CC(NCC(O)c1cccc(Cl)c1)CC2
Product: CCOC(=O)COc1ccc2c(c1)CC(NCC(O)c1ccccc1)CC2

Procedure:
Among the methods of preparation of the products of formula (A) hereinabove there is described an O-alkylation that, starting from the 2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-phenyl-ethanol or from the 2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-amino]-1-(3-chlorophenyl)ethanol, by reaction with ethyl bromoacetate gives the 2-[(7-carbethoxymethoxy-1,2,3,4-tetrahydronaphth-2-yl)-amino]-1-phenylethanol or the 2-[(7-carbethoxymethoxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-(3-chlorophenyl) ethanol. This reaction does not give yet good result because the yield of the final product is very low.
Reaction SMILES: [F:1][C:2]1[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])=[CH:28][CH:27]=[C:26]([F:37])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:15](I)=[CH:14][N:13]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:10]2=[N:11][CH:12]=1)=[O:5].[CH:38]([B-](F)(F)F)=[CH2:39].[K+].C(N(CC)CC)C>CC(O)C.C1COCC1.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]>[F:1][C:2]1[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])=[CH:28][CH:27]=[C:26]([F:37])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:15]([CH:38]=[CH2:39])=[CH:14][N:13]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:10]2=[N:11][CH:12]=1)=[O:5]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccccc2)c1F
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: C=Cc1cn(S(=O)(=O)c2ccccc2)c2ncc(NC(=O)c3c(F)ccc(NS(=O)(=O)CCC)c3F)cc12
Temperature: 70 °C
Yield: 57 %

Procedure:
2,6-Difluoro-N-(3-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (0.050 g, 0.076 mmol), potassium vinyltrifluoroborate (0.012 g, 0.091 mmol), triethylamine (d. 0.726; 0.011 mL, 0.076 mmol) and PdCl2(dppf)*DCM (0.0031 g, 0.0038 mmol) were dissolved in 3:1 IPA/THF (1.0 mL), degassed with argon for 10 minutes and heated to 70° C. overnight. The solution was partitioned between water and EtOAc. The organic portion was washed with water (3×), brine, dried over Na2SO4 and concentrated. The resulting residue was purified by column chromatography (2:1 hexane/EtOAc) giving 2,6-difluoro-N-(1-(phenylsulfonyl)-3-vinyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (57%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[N:33]1([C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:31])[F:32])=[CH:4][CH:5]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:30])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: C1CCNCC1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2cc(C(=O)N3CCCCC3)cnc2c1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (50 mg, 0.11 mmol) was combined with piperidine (10 mg, 0.11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 0.14 mmol), 1-hydroxybenzotriazole (17 mg, 0.13 mmol), and triethylamine (0.064 ml, 0.46 mmol) in 1 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was concentrated, the residue was suspended in water, and the solid was collected by vacuum filtration to afford 45 mg of the title compound as a colorless solid.
Reaction SMILES: C([S:4][C@@H:5]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:6]([NH:8][CH2:9][C:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([C:28]([OH:30])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][C:17]=2[F:31])[C:13]([O:32][CH2:33][CH3:34])=[N:12][C:11]=1[CH2:35][CH3:36])=[O:7])(=O)C.C(S)[C@@H](O)[C@H](O)CS.CC(O)=O.O>CO>[CH2:33]([O:32][C:13]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([C:28]([OH:30])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][C:17]=2[F:31])[C:10]([CH2:9][NH:8][C:6](=[O:7])[C@@H:5]([SH:4])[CH2:37][CH:38]([CH3:39])[CH3:40])=[C:11]([CH2:35][CH3:36])[N:12]=1)[CH3:34]
Reactant: CCOc1nc(CC)c(CNC(=O)[C@H](CC(C)C)SC(C)=O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1F
Agent: O[C@H](CS)[C@H](O)CS
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CCOc1nc(CC)c(CNC(=O)[C@@H](S)CC(C)C)n1Cc1ccc(-c2ccccc2C(=O)O)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
Crystalline 4′-{5-[((S)-2-acetylsulfanyl-4-methylpentanoylamino)methyl]-2-ethoxy-4-ethylimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylic acid (2.3 g, 4 mmol, 1 eq.) and DTT (62 mg, 0.4 mmol, 0.1 eq.) was dissolved in MeOH (30 mL). The resulting solution was degassed with nitrogen (3 times) and cooled at 0° C. NaOMe (25% in MeOH, 1.7 mL) was added and the mixture was stirred at 0° C. for 30 minutes. AcOH (3 g, 50 mmol, 4 eq.) was added to quench the reaction at 0° C. The mixture was warmed to 20° C. Deionized water (10 mL) was added slowly. The mixture was stirred at 20° C. for 3 hours and then stirred at 4° C. for 1 hour until precipitates were formed. The solids were filtered and washed with MeOH/H2O (2:1; 30 mL), then dried under nitrogen at 20° C. for 48 hours to yield the title crystalline compound (1.2 g).
Reaction SMILES: [CH3:1]I.[CH2:3]([N:10]1[C:14]([C:15]([F:18])([F:17])[F:16])=[C:13]([CH3:19])[C:12]([Br:20])=[C:11]1[C:21]([NH:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H-].[Na+]>C1COCC1>[CH2:3]([N:10]1[C:14]([C:15]([F:18])([F:16])[F:17])=[C:13]([CH3:19])[C:12]([Br:20])=[C:11]1[C:21]([N:23]([CH3:1])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:22])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: Cc1c(Br)c(C(=O)NCC(C)(C)C)n(Cc2ccccc2)c1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(Br)c(C(=O)N(C)CC(C)(C)C)n(Cc2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
HATU (12.6 g, 33.24 mmol) and DIPEA (12.4 ml, 69.25 mmol) were added to the ice cold solution of 1-benzyl-3-bromo-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic acid (10 g, 27.77) in DMF (110 mL) and it was stirred for 10 min at same temperature and then neopentyl amine (3.92 ml, 33.24 mmol) was added to the reaction mixture warmed to RT and then stirred for 15 h. Reaction mixture was diluted with EtOAc and H2O. The aqueous layer was extracted with EtOAc (2×300 mL). Combined organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure to yield crude mass of 1-benzyl-3-bromo-4-methyl-N-neopentyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide (11 g, 91.9% yield, white color solid) which directly used without further purification. Methyl iodide (3.17 mL, 51.04 mmol) was added to the ice cold solution of 1-benzyl-3-bromo-4-methyl-N-neopentyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide (11 g, 25.52 mmol), (100%) NaH (1.2 g, 51.04 mmol) in THF (100 mL) and stirred for 2 h at RT. The reaction mass was poured onto crushed ice, extracted with EtOAc (2×200 mL). Combined organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure to yield crude mass which was then purified by column chromatography (100-200 mesh Silica gel; 10% ethyl acetate/hexane Rf-value 0.6) to afford title compound (10 g, 88.05% yield, white solid).
Reaction SMILES: C([O:8][NH:9][C:10](=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)C1C=CC=CC=1>CO.[Pd]>[OH:8][NH:9][C:10](=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1
Reactant: O=C(CCCCCCCN1CCc2ccccc2C1)NOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(CCCCCCCN1CCc2ccccc2C1)NO

Procedure:
200 mg (0.53 mmol) 8-(3,4-dihydro-1H-isoquinolin-2-yl)-octanoic acid benzyloxy-amide in 30 ml methanol was hydrogenated for 1 h in the presence of palladium on barium sulfate at ambient temperature and pressure. The catalyst was removed by filtration and the solvent was evaporated. There was thus obtained 150 mg (98%) 8-(3,4-dihydro-1H-isoquinolin-2-yl)-octanoic acid hydroxyamide as an amorphous solid. MS: 291 (M+H+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:27])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1.I[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH:31]1[O:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:13][O:14][C:15](=[O:27])[CH:16]([C:17]1[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:21][CH:22]=1)[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH:31]1[O:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1
Reactant: ICC1CCCC1OC1CCCCO1
Reactant: COC(=O)Cc1ccc(S(C)(=O)=O)cc1
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1OC1CCCCO1)c1ccc(S(C)(=O)=O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45.1 %

Procedure:
A solution of diisopropylamine (846 μL, 6.04 mmol) in dry tetrahydrofuran (4.4 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.4 mL) was cooled to −78° C. and then treated with a 2.5M solution of n-butyllithium in hexanes (2.4 mL, 6.04 mmol). The reaction mixture was stirred at −78° C. for 30 min and then was treated with a solution of (4-methanesulfonyl-phenyl)-acetic acid methyl ester (prepared as in Example 8, 1.06 g, 4.64 mmol) in dry tetrahydrofuran (4.4 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.4 mL). The resulting reaction mixture was allowed to stir at −78° C. for 45 min and then the reaction mixture was treated with a solution of 2-(2-iodomethyl-cyclopentyloxy)-tetrahydropyran (prepared as in Example 24, 1.87 g, 6.04 mmol) in a small amount of dry tetrahydrofuran. The reaction mixture was stirred at −78° C. and then allowed to warm to 25° C., where it was stirred for 68 h. The reaction mixture was quenched with water (100 mL) and then concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 7/3 hexanes/ethyl acetate) afforded the 2-(4-methanesulfonyl-phenyl)-3-[2-(tetrahydropyran-2-yloxy)-cyclopentyl]-propionic acid methyl ester (859.2 mg, 45%) as a light yellow oil: FAB-HRMS m/e calcd for C21H30O6S (M+H)+ 411.1841. found 411.1831.
Reaction SMILES: C(=O)(OC(C)(C)C)N.[CH3:9][O:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2([NH:22][C:23]([CH:25]3[CH2:30][C:29]([CH3:32])([CH3:31])[CH2:28][CH2:27][N:26]3C(OC(C)(C)C)=O)=[O:24])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1)=[O:12]>>[CH3:31][C:29]1([CH3:32])[CH2:28][CH2:27][NH:26][CH:25]([C:23]([NH:22][C:19]2([C:16]3[CH:15]=[CH:14][C:13]([C:11]([O:10][CH3:9])=[O:12])=[CH:18][CH:17]=3)[CH2:21][CH2:20]2)=[O:24])[CH2:30]1
Reactant: COC(=O)c1ccc(C2(NC(=O)C3CC(C)(C)CCN3C(=O)OC(C)(C)C)CC2)cc1
Agent: CC(C)(C)OC(N)=O
Product: COC(=O)c1ccc(C2(NC(=O)C3CC(C)(C)CCN3)CC2)cc1
Yield: 78.2 %

Procedure:
The title compound (D93) (150 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from tert-butyl 2-((1-(4-(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)-4,4-dimethylpiperidine-1-carboxylate (D58) (250 mg)
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:8]=[CH:7]2.[CH3:16][N:17](C=O)C>[Li+].[Cl-].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>[C:16]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:8]=[CH:7]2)#[N:17]
Reactant: NS(=O)(=O)c1ccc2cccc(I)c2c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Product: N#Cc1cccc2ccc(S(N)(=O)=O)cc12
Temperature: 125 °C
Yield: 30 %

Procedure:
A solution of 8-iodonaphthalene-2-sulfonamide (Intermediate 7, 100 mg, 0.30 mmol), ZnCN (11 μL, 0.180 mmol) and Pd(PPh3)4 (14 mg, 0.012 mmol) in DMF (1.5 mL) was purged with argon for 5 min. The reaction mixture was then heated to 125° C. in a microwave reactor for 30 min. Additional ZnCN (33 μL, 0.54 mmol) and Pd(PPh3)4 (280 mg, 0.24 mmol) were added, and the reaction mixture was heated at 125° C. for 12 h. The reaction mixture was cooled to room temperature, diluted with 10% aq. LiCl solution and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (22 mg, 30%). 1H NMR (CD3OD) δ 8.77 (d, J=0.9 Hz, 1H), 8.35 (d, J=8.4 Hz, 1H), 8.25 (d, J=8.8 Hz, 1H), 8.19 (d, J=7.3 Hz, 1H), 8.14 (d, J=1.8 Hz, 1H), 7.85-7.75 (m, 1H); MS(ESI+) m/z 250.1 (M+NH4)+.