Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:7]=1[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1)O)=[O:5])[CH3:2].[NH2:24][C:25]1[CH:26]=[C:27]([Cl:41])[C:28](=[O:40])[N:29]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[CH:30]=1.C(OC(C1C=CN(C(C)C)C=1C(C1C=CC(Cl)=CC=1)O)=O)C.NC1C(=O)N(C)C=C(Cl)C=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:7]=1[CH:14]([NH:24][C:25]1[CH:26]=[C:27]([Cl:41])[C:28](=[O:40])[N:29]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[CH:30]=1)[C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccn(C(C)C)c1C(O)c1ccc(C#N)cc1
Reactant: COc1ccc(Cn2cc(N)cc(Cl)c2=O)cc1
Agent: CCOC(=O)c1ccn(C(C)C)c1C(O)c1ccc(Cl)cc1
Agent: Cn1cc(Cl)cc(N)c1=O
Product: CCOC(=O)c1ccn(C(C)C)c1C(Nc1cc(Cl)c(=O)n(Cc2ccc(OC)cc2)c1)c1ccc(C#N)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for Step L3, but 2-[(4-cyano-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester (Step H4) and 5-amino-3-chloro-1-(4-methoxy-benzyl)-1H-pyridin-2-one (Step O4) were used instead of 2-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester and 3-amino-5-chloro-1-methyl-1H-pyridin-2-one respectively. The title compound was obtained as a white solid. ESI-MS: tR=1.20 min, [M+H]+ 559/561 (LC-MS 1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[NH:10][C@@H:11]([CH3:25])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[C:20]=2[CH:22]=O)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[CH2:38]([O:37][C:35]([C:34]1[O:24][C:19]2=[CH:18][CH:17]=[C:16]3[C:21]([N:13]([CH2:12][C@@H:11]([NH:10][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:26])[CH3:25])[N:14]=[CH:15]3)=[C:20]2[CH:22]=1)=[O:36])[CH3:39]
Reactant: CCOC(=O)CBr
Reactant: C[C@@H](Cn1ncc2ccc(O)c(C=O)c21)NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(ccc3cnn(C[C@H](C)NC(=O)OCc4ccccc4)c32)o1
Yield: 42.4 %

Procedure:
To a stirred solution of the product from Step C (0.20 g, 0.56 mmol) in DMF (10 mL) was added potassium carbonate (0.23 g, 1.68 mmol) followed by ethyl 2-bromoacetate (0.07 mL, 0.62 mmol) at room temperature and the resultant solution was heated at 70° C. for 20 h. Saturated aqueous ammonium chloride (20 mL) was added followed by ethyl acetate (50 mL). The organic layer was separated and the aqueous was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (30 mL), dried and evaporated. The residue was purified by chromatography (silica, 50% ethyl acetate in hexane) to give an oil (0.10 g, 42%): MS(ES) m/z 422 (M+); 1H NMR (CDCl3) δ 8.17 (s, 1H), 8.05 (s, 1H), 7.72 (d, 1H, J=8.8 Hz), 7.43 (d, 1H, J=8.8 Hz), 7.33 (m, 5H), 5.05-5.09 (m, 2H), 4.58 (m, 1H), 4.30 (m, 2H), 1.45 (t, 3H, J=7.2 Hz), 1.17 (d, 3H, J=6.8 Hz).
Reaction SMILES: [Na].[CH3:2][C:3]1[NH:4][O:5][C:6](=[O:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].IC[CH2:16][CH:17]([CH3:19])[CH3:18]>>[CH3:2][C:3]1[N:4]([CH2:16][CH:17]([CH3:19])[CH3:18])[O:5][C:6](=[O:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CC(C)CCI
Reactant: CCOC(=O)c1c(C)[nH]oc1=O
Agent: [Na]
Product: CCOC(=O)c1c(C)n(CC(C)C)oc1=O

Procedure:
The title compound was prepared by alkylation of ethyl 3-methyl-5-oxo-2,5-dihydroisoxazole-4-carboxylate sodium salt with 1-iodo-3-methylbutane in a manner similar to step 1 of example 28. 1H NMR (CDCl3) δ ppm 4.12 (q, 2H, J=7.1 Hz), 3.47 (t, 2H, J=6.8 Hz), 2.35 (s, 3H), 1.97-2.07 (m, 1H), 1.16 (t, 3H, J=7.0 Hz), 0.77 (d, 6H, J=6.8 Hz). LCMS (APCI, M+H+): 228.2.
Reaction SMILES: [C-]1[C:14]2[C:5](=C[C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[Li+:15].[I-].[Ca+2].[I-].[Ca].Cl[Si](C)(C)C>>[C:12]1([C:13]2[CH:2]=[CH:3][CH:4]=[CH:5][C-:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][C-:7]=1.[Li+:15].[Li+:15]
Reactant: [c-]1cccc2cc3ccccc3cc12
Agent: C[Si](C)(C)Cl
Agent: [Ca+2]
Agent: [Ca]
Product: [c-]1ccccc1-c1[c-]cccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Preformed lithium anthracenide was reacted with calcium iodide to prepare a soluble calcium species. This calcium species was added to chloromethylated polystyrene (DF=0.11) and stirred for 24 hours at room temperature. The corresponding calcium-substituted reagent was then reacted with chlorotrimethylsilane at room temperature to yield the silylated product; however, the yield was not optimized and was lower than the yield obtained from preformed lithium biphenylide (Table III, entry 4). Reaction of the calcium species with chloromethylated polystyrene at 0° C. for 6 hours resulted in a 100% loss of chlorine from the polymer. Subsequent reaction with benzaldehyde gave the corresponding secondary alcohol in 80% yield, compared to the 100% yield when calcium biphenylide was used (Table III, entry 6).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][N:6]1[C:14](=S)[CH2:15][C:16](=O)[CH3:17])=[O:4].[CH2:20]([NH:27][NH2:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][N:6]1[C:14]1[N:27]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:28]=[C:16]([CH3:17])[CH:15]=1)=[O:4]
Reactant: NNCc1ccccc1
Reactant: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1C(=S)CC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1c1cc(C)nn1Cc1ccccc1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-methanesulfonyl-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 448c) was reacted with benzylhydrazine (CAS Reg. No. 555-96-4) to give the title compound. MS (ESI): m/z=378.5 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[CH:20]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[N:30]1[CH:34]=[N:33][CH:32]=[N:31]1)[C:25]#[N:26])=O.OOS([O-])=O.[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]3[N:14]([C:15]([CH3:16])([CH3:18])[CH3:17])[C:20]([C:22]4[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=4[N:30]4[CH:34]=[N:33][CH:32]=[N:31]4)[C:25]#[N:26])=[N:19][C:10]=3[CH:9]=2)=[CH:4][N:3]=1
Reactant: N#Cc1ccc(-n2cncn2)c(C=O)c1
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Agent: O=S([O-])([O-])=S
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)n1c(-c2cc(C#N)ccc2-n2cncn2)nc2cc(-c3cnc(N)nc3)ccc21
Reaction time: 3 h
Yield: 27.1 %

Procedure:
To a solution of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (100 mg, 0.39 mmol) in DMF (5 mL) is added 3-formyl-4-1,2,4-triazol-1-yl-benzonitrile (115 mg, 0.58 mmol) at room temperature. Oxone (239 mg, 0.39 mmol) in H2O (1 mL) is added and the solution is stirred for 3 hours. Saturated sodium thiosulfate solution (5 mL) is added and the mixture is extracted with EtOAc (3×15 mL) and H2O (10 mL). The combined organic layer is dried (MgSO4), filtered and concentrated. The residue is purified by silica gel flash column chromatography eluting with 10% MeOH in CH2Cl2 eluent to afford the title compound (46 mg, 27%) as a white foam. LCMS (ESMS): m/z 436.72 (M++1)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([CH3:28])=[C:12]([NH:16][C:17]([C:19]3[S:23][C:22]4[CH2:24][CH2:25][CH2:26][CH2:27][C:21]=4[CH:20]=3)=[O:18])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].Cl[C:30]1[N:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)=[CH:32][CH:31]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:9][O:8][C:7]1[N:6]=[CH:5][C:4]([C:10]2[C:11]([CH3:28])=[C:12]([NH:16][C:17]([C:19]3[S:23][C:22]4[CH2:24][CH2:25][CH2:26][CH2:27][C:21]=4[CH:20]=3)=[O:18])[CH:13]=[CH:14][CH:15]=2)=[CH:3][C:2]=1[NH:1][C:30]1[CH:31]=[CH:32][C:33]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)=[CH:34][N:35]=1
Reactant: COc1ncc(-c2cccc(NC(=O)c3cc4c(s3)CCCC4)c2C)cc1N
Reactant: CN1CCN(c2ccc(Cl)nc2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ncc(-c2cccc(NC(=O)c3cc4c(s3)CCCC4)c2C)cc1Nc1ccc(N2CCN(C)CC2)cn1
Temperature: 95 °C
Yield: 49.2 %

Procedure:
In a 48-mL seal tube equipped with a magnetic stirring bar was placed N-(3-(5-Amino-6-methoxypyridin-3-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide (17) (0.20 g, 0.5 mmol), 1-(6-chloro-pyridin-3-yl)-4-methyl-piperazine (0.11 g, 0.5 mmol), Pd2(dba)3 (0.046 g, 0.050 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.040 g, 0.070 mmol), and Cs2CO3 (0.33 g, 1.0 mmol) in dioxane (10 mL). After the mixture was degassed for 15 min., it was heated at 95° C. for 16 h. Then, the reaction mixture was cooled to room temperature and poured into H2O (10 mL). To this was added dichloromethane (10 mL) and the layers were separated. The aqueous phase was extracted with dichloromethane (3×10 mL), and the combined organic extracts were washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and concentrated. The crude mixture was purified by column chromatography, gradient 0-33% MeOH in dichloromethane, to afford 0.140 g (50%) of N-(3-(6-Methoxy-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)pyridine-3-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-carboxamide (18) as a solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([N:15]1[CH2:20][CH2:19][O:18][CH:17]([CH2:21][OH:22])[CH2:16]1)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([N:15]1[CH2:20][CH2:19][O:18][CH:17]([CH:21]=[O:22])[CH2:16]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N1CCOC(CO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)N1CCOC(C=O)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.4 %

Procedure:
A solution of oxalyl chloride (0.097 mL) in dichloromethane (10 mL) was cooled to −78° C. under argon. A solution of dimethylsulfoxide (0.201 mL) in dichloromethane (5 mL) was added dropwise and the mixture was stirred for 5 minutes. A solution of (4-tert-butylmorpholin-2-yl)methanol (175 mg) in dichloromethane (3 mL) was added and the mixture was stirred for 15 minutes. Triethylamine (0.845 mL) was added and the mixture was warmed to room temperature. The reaction was quenched with water and partitioned between water and dichloromethane. The organic layer was dried (Na2SO4), filtered and concentrated to give an orange oil (165 mg). This material was used immediately in the next stage without further purification or analysis.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[N:6][N:5]=[C:4]2[N:9]([CH3:18])[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:3]=12.[C:19]1(B2OC(C)(C)C(C)(C)O2)[CH2:23][CH2:22][CH2:21][CH:20]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:19]2[CH2:23][CH2:22][CH2:21][CH:20]=2)=[N:6][N:5]=[C:4]2[N:9]([CH3:18])[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:3]=12
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Reactant: Cn1nc(-c2ccccc2)c2c(Cl)c(I)nnc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccccc2)c2c(Cl)c(C3=CCCC3)nnc21
Temperature: 30 °C
Yield: 20.1 %

Procedure:
Nitrogen was bubbled through a suspension of 4-chloro-5-iodo-1-methyl-3-phenyl-pyrazolo[3,4-c]pyridazine (60 mg, 0.16 mmol), 2-(cyclopenten-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (35 mg, 0.18 mmol) and K3PO4 (103 mg, 0.48 mmol) in DMF (1 mL) and water (0.3 mL) for 15 min. 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (13 mg, 0.016 mmol) was added and the tube sealed and heated to 30° C. for 16 h. The reaction mixture was diluted with CH2Cl2 and water. The aqueous phase was extracted with CH2Cl2 and the combined organic phases were dried (phase separator cartridge) and concentrated in vacuo. The resultant residue was purified using chromatography (silica gel, CH2Cl2/isohexane 1:1 to 1:0), to provide Compound IIIb as a solid (10 mg).
Reaction SMILES: C([Li])CCC.[C:6]1([O:12][CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:14]([N:21]1[CH2:29][CH:28]2[CH:23]([CH2:24][CH:25]([CH3:31])[CH2:26][C:27]2=[O:30])[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>CCCCCC.COC(C)(C)C.CN(C)CCN(C)C.O1CCCC1>[CH2:14]([N:21]1[CH2:29][CH:28]2[CH:23]([CH2:24][CH:25]([CH3:31])[CH2:26][C:27]2([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:12][CH3:13])[OH:30])[CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC1CC(=O)C2CN(Cc3ccccc3)CC2C1
Reactant: COc1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccccc1C1(O)CC(C)CC2CN(Cc3ccccc3)CC21
Temperature: -72 °C
Reaction time: 1 h

Procedure:
135 cm3 of 1.6M n-butyllithium solution in hexane are added to 31.3 cm3 of anisole diluted in 400 cm3 of t-butyl methyl ether and 33 cm3 of tetramethylethylenediamine, while maintaining the temperature below 30° C. After one hour at 20° C., the reaction mixture is cooled to -72° C. and 24 g of (3aRS,6SR,7aSR)-2-benzyl-6-methyl-4-perhydroisoindolone dissolved in 200 cm3 of tetrahydrofuran are added at this temperature over thirty minutes. After stirring for thirty minutes, 200 cm3 of aqueous 26% ammonium chloride solution are poured in over thirty minutes and the reaction mixture is warmed to room temperature and decanted. The organic phase is washed with water (3 times 150 cm3) and then with saturated sodium chloride solution (150 cm3), dried over magnesium sulphate, filtered and concentrated under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a column of silica gel (0.060-0.200 mm, diameter 6 cm, height 55 cm), eluting under a pressure of 0.7 bar with a mixture of ethyl acetate and cyclohexane [by volume: 30/70 (3 dm3) then 50/50 (2 dm3) and 100/0 (3 dm3)] and collecting 200 cm3 fractions. Fractions 9 to 26 are combined, concentrated to dryness under reduced pressure (2.7 kPa) and crystallized in isopropyl ether. 20.5 g of (3aRS,4RS,6SR,7aSR)-2-benzyl-4-(2methoxyphenyl)-6-methyl-4-perhydroisoindolol are obtained in the form of white crystals, m.p.=120° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:26]=[CH:25][C:10]2[S:11][C:12]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[C:13]([C:14](=[O:17])[NH:15][CH3:16])[C:9]=2[CH:8]=1)(=O)=O.B([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35]([OH:37])=[O:36])(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:12]2[S:11][C:10]3[CH:25]=[CH:26][C:7]([C:32]4[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=4)[C:35]([OH:37])=[O:36])=[CH:8][C:9]=3[C:13]=2[C:14](=[O:17])[NH:15][CH3:16])=[CH:19][CH:20]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)sc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)sc2ccc(-c3cccc(C(=O)O)c3)cc12
Temperature: 95 °C
Reaction time: 1 h

Procedure:
To a degassed solution containing 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzo[b]thiophen-5-yl trifluoromethanesulfonate (0.32 g, 0.74 mmol), 3-boronobenzoic acid (0.18 g, 1.1 mmol), cesium carbonate (0.36 g, 1.1 mmol), dioxane (6.2 mL) and water (1.2 mL) was added tetrakis(tiphenylphosphine)palladium(0) (0.02 g, 0.016 mmol). The solution was maintained at 95° C. for 90 min. The solution was cooled to room temperature, concentrated and suspended in ethyl acetate (20 mL) with stirring for 1 h. The mixture was filtered, washed with water (3×20 mL) and air dried to afford 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzo[b]thiophen-5-yl)benzoic acid as a grey solid which was used without further purification. LCMS: retention time: 2.132 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 406 (MH+).
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([CH2:10][OH:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.Br[CH2:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]#[N:22])=[O:15]>>[OH:11][CH2:10][C:5]12[CH2:8][CH2:9][C:2]([NH:1][CH2:13][C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[C:21]#[N:22])=[O:15])([CH2:3][CH2:4]1)[CH2:7][CH2:6]2
Reactant: N#C[C@@H]1CCCN1C(=O)CBr
Reactant: NC12CCC(CO)(CC1)CC2
Product: N#C[C@@H]1CCCN1C(=O)CNC12CCC(CO)(CC1)CC2
Yield: 68.8 %

Procedure:
Using 4-amino-1-hydroxymethylbicyclo[2,2,2]octane (50.5 mg) and (2S)-1-(2-bromoacetyl)pyrrolidine-2-carbonitrile (61.7 mg), the same procedure was followed as in Example 5 to obtain (2S)-1-[[N-(4-hydroxymethylbicyclo[2,2,2]oct-1-yl)amino]acetyl]pyrrolidine-2-carbonitrile (57.0 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:20])[CH:15]2[CH2:19][CH2:18][O:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:20][N:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH:15]1[CH2:19][CH2:18][O:17][CH2:16]1
Reactant: CN(C1CCN(C(=O)OC(C)(C)C)CC1)C1CCOC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C1CCNCC1)C1CCOC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-[methyl(tetrahydrofuran-3-yl)amino]piperidine-1-carboxylic acid tert-butyl ester (132 mg, 0.46 mmol) and TFA (2 mL) in DCM (5 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording Methyl(piperidin-4-yl)(tetrahydro-furan-3-yl)amine as a white solid (84 mg, quant.). 1H NMR (CDCl3, 300 MHz): δ 3.98-3.91 (m, 1 H); 3.88-3.83 (m, 1 H); 3.80-3.73 (m, 1 H); 3.61-3.53 (m, 1 H); 3.42-3.35 (m, 1 H); 3.26-3.14 (m, 2 H); 2.71-2.53 (m, 2 H); 2.57-2.46 (m, 1 H); 2.23 (s, 3 H); 2.05-1.97 (m, 1 H); 1.93-1.77 (m, 1 H); 1.78-1.72 (m, 2 H); 1.64-1.49 (m, 2 H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][CH2:9][NH:10][CH:11]=O)=[CH:5][CH:4]=1.B.C1COCC1.Cl.[OH-].[Na+]>C1COCC1.O>[CH3:11][NH:10][CH2:9][CH2:8][O:7][C:6]1[CH:13]=[CH:14][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:4][CH:5]=1
Reactant: O=CNCCOc1ccc(C(F)(F)F)cc1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CNCCOc1ccc(C(F)(F)F)cc1
Reaction time: 8 h
Yield: 55.3 %

Procedure:
N-[2-(4-trifluoromethylphenoxy)ethyl]-formamide (2.02 g, 8.66 mmol) prepared in Reference Example 160 was dissolved in THF (20 ml). Borane-THF complex (1 M) THF solution (21.7 ml, 21.7 mmol) was added dropwise to this solution while cooling in an ice-bath, and the mixture was stirred overnight. The reaction mixture was cooled, to which water and 6N hydrochloric acid were added, and the mixture was stirred for 20 minutes. The reaction mixture was neutralized with a sodium hydroxide aqueous solution, and the mixture extracted with methylene chloride. The extract was dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=200/1) to afford N-methyl-N-[2-(4-trifluoromethylphenoxy)ethyl]amine (1.05 g, yield 55%) as a white powder.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.OS(O)(=O)=O.[N+:20]([O-])([OH:22])=[O:21]>C(O)(=O)C>[N+:20]([C:5]1[CH:4]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:8]=[CH:7][C:6]=1[CH2:9][C:10]([OH:12])=[O:11])([O-:22])=[O:21]
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-trifluoromethylphenyl acetic acid (2.5 g, 12.25 mmol) in 8 mL of glacial acetic acid at 0° C. under an anhydrous atmosphere was added 5 mL of fuming H2SO4 (11% SO3) (caution !) followed by cautious addition of 90% HNO3 (3.5 mL, 73.14 mmol) within 10 min. The reaction mixture was then stirred at room temperature for 2 h and poured into ice-water. The resulting solid was filtered and washed with cold deionized water to give the desired product after drying as off-white solid, 2.5 g (82%); 1H NMR (200 MHz, CDCl3) δ 4.02 (s, 2H), 7.41 (d, J=8.0 Hz, 2H), 7.74 (d, J=8.0 Hz, 2H), 8.28 (s, 1H). The product was used directly into the following reactions.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]([C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[NH2:31])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[CH3:40][O:41][C:42](=[O:50])[CH2:43][CH2:44][CH2:45][CH2:46][C:47](Cl)=[O:48]>CCOC(C)=O>[CH3:40][O:41][C:42](=[O:50])[CH2:43][CH2:44][CH2:45][CH2:46][C:47](=[O:48])[NH:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=1[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([S:15]([C:13]2[CH:14]=[C:10]([C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:34])=[NH:9])[S:11][C:12]=2[S:32][CH3:33])(=[O:17])=[O:16])[CH:19]=1
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2N)c1
Reactant: COC(=O)CCCCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CCCCC(=O)Nc1cccc(C)c1-c1cccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
{[4-(2′-Amino-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (100 mg, 0.19 mmol, Example 25: step c) was dissolved into THF (3 mL). To this was added 5-Chlorocarbonyl-pentanoic acid methyl ester (41.5 mg, 0.23 mmol) and the reaction was stirred at RT for 2 hours. The reaction was dissolved into EtOAc and washed with brine. The combined organic layers were dried (MgSO4) followed by removal of solvents in vacuo resulted in the title compound that was used without further purification. ESI-MS (m/z): Calcd. for C31H37N3O7S3: 660.2 (M+1); found: 660.8.