Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.I[CH:24]([CH3:26])[CH3:25]>>[CH:24]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:11][CH:10]=2)=[N:6][CH:7]=1)([CH3:26])[CH3:25]
Reactant: CC(C)I
Reactant: CC(=O)N[C@@H](C)CCc1ccc(Oc2ccc(O)cn2)cc1
Product: CC(=O)N[C@@H](C)CCc1ccc(Oc2ccc(OC(C)C)cn2)cc1

Procedure:
N—{(S)-3-[4-(5-Hydroxypyridin-2-yloxy)phenyl]-1-methylpropyl}acetamide (153 mg, 0.51 mmol) was reacted with 2-iodopropane in analogy to example 1a. Yield: 61 mg (35%), M+H+: 343.15.
Reaction SMILES: [O:1]=[C:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29]>O1CCCC1>[CH2:26]([NH:30][C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][C:2](=[O:1])[CH3:10])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCN
Reactant: CC(=O)CCCCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCCCNC(=O)CCCCC(C)=O

Procedure:
The title compound was prepared by the method described for 6-oxoheptanoic acid p-toluide (IV, n=4, Y=p-methylanilino) using the following quantities: δ-acetyl-n-valeric acid (2.5 g, 1.75 mmol), N-methylmorpholine (1.9 ml, 17.5 mmol), isobutyl chloroformate (2.25 ml, 17.5 mmol), n-butylamine (1.7 ml, 17.5 mmol), tetrahydrofuran (15 ml). Recrystallization from ethyl acetate/hexanes gave 1.3 g of the desired compound as white needles, which were pure by thin layer chromatography (95:5:3 chloroform/methanol/acetic acid, Rf =0.52) m.p. 53°-54° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Br:38])[CH:33]=1)\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Br:38])[CH:33]=2)=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc(Br)c1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(Br)c2)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 29 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (843 mg, 0.005 mol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (2.64 g, 0.020 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(3-bromo-phenoxy)-but-2-enoic acid ethyl ester (1.50 g, 0.004 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-2-[4-(3-bromo-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid methyl ester (490 mg, 25%) as yellow oil.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([CH2:22][N:23]2C[CH:25]([C:27]([OH:29])=[O:28])[CH2:24]2)[CH:16]=[C:15]3[C:30]([F:33])([F:32])[F:31])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([CH2:22][NH:23][CH2:24][CH2:25][C:27]([OH:29])=[O:28])[CH:16]=[C:15]3[C:30]([F:33])([F:31])[F:32])[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(CN4CC(C(=O)O)C4)cc(C(F)(F)F)c3c2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(CNCCC(=O)O)cc(C(F)(F)F)c3c2)CC1

Procedure:
Synthesized as per 1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-trifluoromethyl-quinolin-2-ylmethyl]-azetidine-3-carboxylic acid (Example 168) using the appropriate amine. ESI-MS(M+H+): 453.2; 1H NMR (400 MHz, METHANOL-d4) Shift 8.15 (d, J=9.29 Hz, 1H), 7.85 (s, 1H), 7.56 (dd, J=2.26, 9.29 Hz, 1H), 7.38 (br. s., 1H), 4.65 (s, 2H), 4.28-4.45 (m, 1H), 3.48 (t, J=6.65 Hz, 2H), 2.88 (t, J=6.78 Hz, 2H), 2.27 (d, J=10.79 Hz, 2H), 1.74-2.03 (m, 2H), 1.38-1.54 (m, 2H), 1.18-1.32 (m, 2H), 1.04-1.18 (m, 1H), 0.79-0.94 (m, 9H). 1.6 TFA per molecule.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[C:72]([CH3:73])=[CH:71][CH:70]=[CH:69][N:68]=2)[C:56]=1[CH3:74].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.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]>[N:38]1([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[C:72]([CH3:73])=[CH:71][CH:70]=[CH:69][N:68]=4)[C:56]=3[CH3:74])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:39][CH2:40][O:35][CH2:36][CH2:37]1
Reactant: Cc1cccnc1-c1nc2cc(F)cc(F)c2c(Cl)c1C
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccnc1-c1nc2cc(F)cc(F)c2c(Nc2cc(N3CCOCC3)cnc2N2CCOCC2)c1C
Temperature: 120 °C

Procedure:
To a stirred solution of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.023 g, 0.047 mmol), 2,5-dimorpholinopyridin-3-amine (0.094 g, 0.354 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(3-methylpyridin-2-yl)quinoline (0.090 g, 0.295 mmol) and Pd2dba3 (10.8 mg, 0.012 mmol) in toluene (3.00 mL) was added sodium t-butoxide (0.071 g, 0.738 mmol). The reaction mixture was heated to 120° C. for 2 h. After which the reaction was cooled to rt and diluted with water (15 mL). The mixture was extracted with EtOAc (2×15 mL) and DCM (1×15 mL). The organic layers were combined and washed with brine (1×20 mL) and dried over magnesium sulfate. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product N-(2,5-di(4-morpholinyl)-3-pyridinyl)-5,7-difluoro-3-methyl-2-(3-methyl-2-pyridinyl)-4-quinolinamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.56 (1H, d, J=4.5 Hz), 7.71 (2H, m), 7.62 (2H, d, J=2.5 Hz), 7.35 (1H, m), 7.02 (1H, m), 6.39 (1H, br. s.), 3.93 (4H, br. s.), 3.76-3.87 (4H, m), 3.23 (4H, br. s.), 3.05 (4H, br. s.), 2.28 (3H, s), 1.95 (3H, br. s.). Mass Spectrum (ESI) m/e=533.2 (M+1).
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[N:14]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])[C:15](=[O:17])[NH:16][C:8]=12)[CH2:4][CH3:5])[CH3:2].[CH3:27][Si]([N-][Si](C)(C)C)(C)C.[Li+]>>[CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[N:14]([C:18]3[C:19]([CH3:26])=[CH:20][C:21]([CH3:25])=[CH:22][C:23]=3[CH3:24])[C:15](=[O:17])[N:16]([CH3:27])[C:8]=12)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1cc(C)nc2c1[nH]c(=O)n2-c1c(C)cc(C)cc1C
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CCC(CC)Oc1cc(C)nc2c1n(C)c(=O)n2-c1c(C)cc(C)cc1C

Procedure:
The title compound was prepared by reacting 7-(1-ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one with lithium bis(trimethylsilyl)amide, followed by quenching with methyl iodide. Mp. 151-153° C. Anal. For C22H29N3O2. ¼H2O calc. C, 71.03; H, 7.99; N, 11.30; found: C, 71.29; H, 8.01; N, 11.03.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:12]([C:13](O)=[O:14])=[CH:11][N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:24][O:25][C:26]([C:28]1([NH2:40])[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29]1)=[O:27].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:24][O:25][C:26]([C:28]1([NH:40][C:13]([C:12]2[C:6]3[C:7](=[N:8][CH:9]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[N:5]=3)[N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=2)=[O:14])[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[CH2:29]1)=[O:27]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Reactant: COC(=O)C1(N)CCN(C(=O)OC(C)(C)C)C1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(NC(=O)c2cn(COCC[Si](C)(C)C)c3ncc(C4CC4)nc23)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
In a round-bottomed flask were combined 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (180 mg, 0.54 mmol), 3-amino-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (214 mg, 0.87 mmol), EDC (114 mg, 0.59 mmol), and HOBt (80 mg, 0.59 mmol). Then added DMF (2.4 mL) followed by i-Pr2NEt (0.14 mL, 0.80 mmol). The reaction mixture was stirred at room temperature overnight then quenched with H2O and extracted with Et2O (2×). The combined organics were washed with H2O (2×) and brine then dried over Na2SO4 and concentrated. The residue was purified by chromatography over 24 g of SiO2 using EtOAc/hexanes (gradient: 0-40% EtOAc) to afford 276 mg (91%) of 3-{[2-Cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester as an off-white foam.
Reaction SMILES: I[C:2]1[C:3]([NH:11][C:12]2[CH:13]=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[N:4][C:5]([N:8]([CH3:10])[CH3:9])=[N:6][CH:7]=1.[CH3:20][C:21]1[N:26]=[C:25]([S:27][CH3:28])[N:24]=[C:23]([Sn](CCCC)(CCCC)CCCC)[N:22]=1.[F-].[Cs+].O1CCOCC1>O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][O:18][C:15]1[N:14]=[CH:13][C:12]([NH:11][C:3]2[C:2]([C:23]3[N:22]=[C:21]([CH3:20])[N:26]=[C:25]([S:27][CH3:28])[N:24]=3)=[CH:7][N:6]=[C:5]([N:8]([CH3:10])[CH3:9])[N:4]=2)=[CH:17][CH:16]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(C)nc(SC)n1
Reactant: COc1ccc(Nc2nc(N(C)C)ncc2I)cn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(N(C)C)ncc2-c2nc(C)nc(SC)n2)cn1
Temperature: 140 °C
Yield: 31.4 %

Procedure:
A glass microwave reaction vessel was charged with 5-iodo-N4-(6-methoxypyridin-3-yl)-N2,N2-dimethylpyrimidine-2,4-diamine (98 mg, 0.264 mmol), 2-methyl-4-(methylthio)-6-(tributylstannyl)-1,3,5-triazine (114 mg, 0.264 mmol), cesium fluoride (80 mg, 0.528 mmol), copper(I) iodide (10 mg, 0.053 mmol), tetrakis(triphenylphosphine)palladium(0) (30.5 mg, 0.026 mmol) and dioxane (2 mL). The reaction mixture was stirred and heated in a Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 140° C. for 30 min. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as an orange solid. The crude product was purified by silica gel chromatography eluting with 60% EtOAc/hexanes to give N4-(6-methoxypyridin-3-yl)-N2,N2-dimethyl-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyrimidine-2,4-diamine (32 mg, 0.083 mmol, 31.5% yield). 1H NMR (300 MHz, CDCl3) δ 11.66 (s, 1H); 9.43 (s, 1H); 8.42 (s, 1H); 8.05 (dd, J=8.70, 2.27 Hz, 1H); 6.77 (d, J=8.92 Hz, 1H); 3.95 (s, 3H); 3.25 (s, 6H); 2.59 (s, 3H); 2.57 (s, 3H). m/z (ESI, +ve ion) 385.1 (M+H)+.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][NH:10][C@H:9]([C:12]([OH:14])=[O:13])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:15]>C(O)C.[Pt]=O>[ClH:15].[CH:1]1([C@H:7]2[CH2:11][NH:10][C@H:9]([C:12]([OH:14])=[O:13])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)[C@@H]1C[C@@H](c2ccccc2)CN1
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: O=C(O)[C@@H]1C[C@@H](C2CCCCC2)CN1
Yield: 98.4 %

Procedure:
A slurry of (trans)-4-phenyl-L-proline (50 g, 0.262 moles) and platinum oxide (10 g) in absolute ethanol (1200 ml) was treated with 5.62 N ethanolic HCl (46.5 ml, 0.261 moles) and shaken until all the solid had gone into solution. The solution was then purged with argon and hydrogenated on a Parr apparatus at 50 psi overnight. After this time, the untake of hydrogen had ceased and NMR indicated complete reduction. The reaction mixture was filtered through a pad of Cellite and concentrated in vacuo. The residue was triturated with diethylether and filtered to yield 60.0 g of (trans)-4-cyclohexyl-L-proline hydrochloride as snow white crystals, m.p. 170°-171° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:21])[NH:11][CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.N>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.O>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:21])[N:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2]
Reactant: N#Cc1ccccc1-c1cc(-c2ccccn2)c[nH]c1=O
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
A suspension of 0.11 g of 3-(2-cyanophenyl)-5-(2-pyridyl)-2 (1H)-pyridone, 0.12 g of phenyl boronic acid 0.1 g of copper acetate and 0.3 ml of triethylamine in 10 ml of methylene chloride was stirred at room temperature for overnight. To this were added 5 ml of concentrated aqueous ammonia, 10 ml of water and 40 ml of ethyl acetate and the organic layer was separated, washed with water and a saturated saline solution and dried over magnesium sulfate. The solvent was concentrated in vacuo and the residue was purified by a silica gel column chromatography (ethyl acetate:hexane=1:2) to give 0.06 g of the title product as pale yellow powder.
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[C:10](=[O:12])[CH3:11].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[CH:10]([OH:12])[CH3:11]
Reactant: CC(=O)c1cc2cnccc2s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)c1cc2cnccc2s1
Reaction time: 1 h

Procedure:
To a solution of 1-(thieno[3,2-c]pyridin-2-yl) ethanone (D′-3) (3.5 g, 1 mmol) in anhydrous THF (50 mL) was added LiAlH4 (1.13 g, 1.5 mmol) in portions at 0° C. The suspension was stirred under this temperature for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution and filtered. The filtrate was washed with brine, concentrated, and then used for the next step without any further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH2:16][CH2:17][CH2:18][O:19][CH3:20])[C:14]3[CH:21]=[C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](OC)=[O:32])[CH:23]=[CH:24][C:13]=3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][O:36][CH2:37][CH2:38][CH2:39][NH2:40]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH2:16][CH2:17][CH2:18][O:19][CH3:20])[C:14]3[CH:21]=[C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([NH:40][CH2:39][CH2:38][CH2:37][O:36][CH3:35])=[O:32])[CH:23]=[CH:24][C:13]=3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCCn1c(-c2ccc(C(C)(C)C)cc2)nc2ccc(OCCCCCC(=O)OC)cc21
Reactant: COCCCN
Product: COCCCNC(=O)CCCCCOc1ccc2nc(-c3ccc(C(C)(C)C)cc3)n(CCCOC)c2c1

Procedure:
2-(4-tert-Butyl-phenyl)-6-[(5-(methoxycarbonyl)pentyl)oxy]-1-(3-methoxy-propyl)-benzimidazole is reacted with 3-methoxypropylamine according to general operating instructions 7. 2-(4-tert-Butyl-phenyl)-1-(3-methoxy-propyl)-6-[(5-((3-methoxy-propyl)amino-carbonyl)-pentyl)oxy]-benzimidazole is obtained as a yellow solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:17][C:18](=[O:30])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=2[O:26][CH:27]([CH3:29])[CH3:28])[CH2:14][C:13]2[C:8](=[CH:9][C:10]([CH3:16])=[C:11]([CH3:15])[CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH:27]([O:26][C:20]1[C:21]([CH3:25])=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]([NH:17][C:6]1([C:4]([OH:5])=[O:3])[CH2:7][C:8]2[C:13](=[CH:12][C:11]([CH3:15])=[C:10]([CH3:16])[CH:9]=2)[CH2:14]1)=[O:30])([CH3:29])[CH3:28]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC(C)C)Cc2cc(C)c(C)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc2c(cc1C)CC(NC(=O)c1cccc(C)c1OC(C)C)(C(=O)O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
The mixture of 2-(2-isopropoxy-3-methyl-benzoylamino)-5,6-dimethyl-indan-2-carboxylic acid ethyl ester (90) (440 mg, 1.07 mmol) and KOH (1 g, 18 mmol) is dissolved in EtOH (8 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (30 mL) and acidified with conc. HCl until no more precipitate formed. The precipitate is filtered to give the pure product (91) as a pale brown solid (374 mg, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:10]([N:13]=[C:14]([NH:22][CH2:23][CH3:24])[N:15]2[CH2:19][CH:18]([CH2:20][CH3:21])[CH:17]=[N:16]2)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([S:10]([N:13]=[C:14]([NH:22][CH2:23][CH3:24])[N:15]2[CH2:19][CH:18]([CH2:20][CH3:21])[CH:17]=[N:16]2)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCNC(=NS(=O)(=O)c1ccc(OC)c(Cl)c1)N1CC(CC)C=N1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCNC(=NS(=O)(=O)c1ccc(O)c(Cl)c1)N1CC(CC)C=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
In 25 mL DCM, 1.09 g 3-chloro-N-[ethylamino-(4-ethyl-4,5-dihydro-pyrazol-1-yl)-methylene]-4-methoxy-benzenesulfonamide was dissolved, and 11.69 mL of a 1M solution of BBr3 in DCM was added. The mixture was stirred overnight at room temperature, extracted with 5% aqueous NaHCO3, dried over MgSO4 and evaporated to dryness. The residue was purified by flash chromatography (DCM/EA 95:5) to yield 0.89 g (84%) of 3-Chloro-N-[ethylamino-(4-ethyl-4,5-dihydro-pyrazol-1-yl)-methylene]-4-hydroxy-benzenesulfonamide as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 0.97 (t, J=7.52 Hz, 3H), 1.16 (t, J=7.22 Hz, 3H), 1.46-1.70 (m, 2H), 3.05-3.18 (m, 1H), 3.43-3.54 (m, 2H), 3.69 (dd, J=11.14, 7.52 Hz, 1H), 4.04-4.12 (m, 1H), 6.05 (br.s., 1H), 6.83 (br.s., 1H), 6.93 (d, J=1.50 Hz, 1H), 7.06 (d, J=8.43 Hz, 1H), 7.75 (dd, J=8.73, 2.11 Hz, 1H), 7.94 (d, J=2.11 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[N:9]2[C:10]([CH2:14][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][CH2:17][CH2:18][NH:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][CH:6]=1)(OC)=[O:2].[BH4-].[Li+].Cl>C1COCC1.CO>[OH:2][CH2:1][C:5]1[N:9]2[C:10]([CH2:14][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][CH2:17][CH2:18][NH:19][S:20]([C:23]([F:25])([F:24])[F:26])(=[O:21])=[O:22])=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][CH:6]=1
Reactant: COC(=O)c1cnc2cccc(CN(CCCNS(=O)(=O)C(F)(F)F)C(=O)OC(C)(C)C)n12
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCCNS(=O)(=O)C(F)(F)F)Cc1cccc2ncc(CO)n12
Temperature: 25 °C
Yield: 72.1 %

Procedure:
To a solution of 396 mg (0.80 mmol) of 3-carbomethoxy-5-[N-tert-butoxycarbonyl-N-(3-trifluoromethane-sulfonamidopropan-1-yl)aminomethyl]imidazo[1,2-a]pyridine in a mixture of 5.0 ml of THF and 1.0 ml of methanol was added, at room temperature, 87.12 mg (4.00 mmol) of lithium borohydride with small portions. The mixture was heated for 30 minutes under reflux. The reaction mixture was cooled to room temperature, and poured into ice-water. The mixture was neutralized with 1N HCl, and extracted with 50 ml of chloroform. The organic layer was washed with 50 ml of a saturated aqueous saline solution, which was dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol=20:1) to afford 269 mg of the desired compound (72%, a pale yellow liquid).
Reaction SMILES: [C:1](#[N:3])C.[F:4][C:5]([F:23])([F:22])[CH:6]([C:15]1[CH:20]=[CH:19][N+:18]([O-])=[CH:17][CH:16]=1)[O:7][Si:8]([CH2:13][CH3:14])([CH2:11][CH3:12])[CH2:9][CH3:10].C[Si](C#N)(C)C>C(N(CC)CC)C>[F:4][C:5]([F:23])([F:22])[CH:6]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:1]#[N:3])[CH:16]=1)[O:7][Si:8]([CH2:13][CH3:14])([CH2:11][CH3:12])[CH2:9][CH3:10]
Reactant: CC[Si](CC)(CC)OC(c1cc[n+]([O-])cc1)C(F)(F)F
Reactant: CC#N
Agent: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Product: CC[Si](CC)(CC)OC(c1ccnc(C#N)c1)C(F)(F)F
Temperature: 90 °C
Reaction time: 20 h

Procedure:
To 40 ml of acetonitrile were added 5 g of 4-[2,2,2-trifluoro-1-(triethylsilyloxy)ethyl]pyridine N-oxide, 5.26 ml of triethylamine, and 5.62 g of trimethylsilyl cyanide, and the mixture was stirred at 90° C. for 20 hours. Thereafter, the reaction solution was allowed to cool to room temperature, and concentrated. The residue was subjected to silica gel column chromatography to obtain 3 g of 4-[2,2,2-trifluoro-1-(triethylsilyloxy)ethyl]pyridine-2-carbonitrile.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14](O)=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][N:19]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2[CH:38]=[CH:39][CH:40]=[N:41][C:36]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N1CCCC1>CN(C=O)C>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14]([N:41]4[CH2:40][CH2:39][CH2:38][CH2:36]4)=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][N:19]=2)[CH2:3][CH2:2]1
Reactant: CCOc1ccc(Cc2nc3cc(C(=O)O)ccc3n2CC2CC2)nc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(Cc2nc3cc(C(=O)N4CCCC4)ccc3n2CC2CC2)nc1
Reaction time: 0.17 h
Yield: 45.5 %

Procedure:
Following the general procedure 20E, 1-(cyclopropylmethyl)-2-[(5-ethoxy-2-pyridinyl)methyl]-1H-benzimidazole-5-carboxylic acid (80 mg, 0.228 mmol) was dissolved in DMF (2 mL) and HATU (104 mg, 0.274 mmol) was added followed by DIPEA (48 μl, 0.274 mmol), After being stirred for 10 min, pyrrolidine was added and the resulting mixture was stirred overnight. The crude residue obtained after work-up was purified using reverse phase preparative HPLC to give a TFA salt as white solids (42 mg, 37%). 1H NMR (400 MHz, CD3OD): δ 8.18 (d, J=2.8 Hz, 1H), 7.98 (d, J=9.2 Hz, 1H), 7.87 (s, 1H), 7.72 (dd, J=9.2 Hz, J=2.0 Hz, 1H), 7.52 (d, J=9.2 Hz, 1H), 7.46 (dd, J=9.2 Hz, J=2.8 Hz, 1H), 4.89 (s, 2H), 4.43 (d, J=6.8 Hz, 2H), 4.09 (q, J=7.2 Hz, 2H), 3.60 (t, J=7.6 Hz, 2H), 3.44 (t, J=7.6 Hz, 2H), 2.02–1.94 (m, 2H), 1.92–1.86 (m, 2H), 1.37 (t, J=7.2 Hz, 3H), 1.30–1.22 (m, 1H), 0.64–0.58 (m, 2H), 0.48–0.44 (m, 2H). MS (ESI) (M+H)+=405. Anal. Calcd for C24H28N4O2.0.8TFA.0.2H2O: C, 55.32; H, 5.12; N, 9.49. Found: C, 55.30; H, 4.91; N, 9.23.