Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24]([C:26]1[CH:27]=[N:28][CH:29]=[C:30]([C:32](O)=[O:33])[CH:31]=1)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:25])[C:26]1[CH:31]=[C:30]([C:32](=[O:33])[NH:20][C:10]2[CH:11]=[N:12][C:13]([O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH:9]=2)[CH:29]=[N:28][CH:27]=1)[CH3:22]
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: CCOC(=O)c1cncc(C(=O)O)c1
Product: CCOC(=O)c1cncc(C(=O)Nc2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)c1

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 3,5-pyridinedicarboxylic acid 3-ethyl ester (CAN 84254-37-5) as starting materials; MS (EI) 480.1(M+H)+.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([NH:30][CH2:31][CH:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[C:16]4[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.Cl>CO>[O:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([NH:12][C:13]3[N:14]=[C:15]([NH:30][CH2:31][CH:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:10][CH:11]=2)=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(NCC3CCOCC3)c2C1
Agent: Cl
Solvent: CO
Product: c1ncc(-c2ccc(Nc3nc4c(c(NCC5CCOCC5)n3)CNCC4)cc2)o1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 2-(4-(oxazol-5-yl)phenylamino)-4-((tetrahydro-2H-pyran-4-yl)methylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (330 mg, 0.65 mmol) was dissolved in methanol (3 mL). Hydrochloric acid (0.020 mL, 0.65 mmol) was added and the reaction mixture was stirred at 80° C. for 30 minutes. The solvent was evaporated and the crude was used as such in the subsequent step. MS (ES+) m/z 407.2 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([C:13]2[CH:14]=[N:15][C:16]([O:19]C)=[CH:17][CH:18]=2)=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl>O1CCOCC1>[F:8][C:6]1[CH:5]=[C:4](/[CH:9]=[CH:10]/[C:11]([C:13]2[CH:18]=[CH:17][C:16](=[O:19])[NH:15][CH:14]=2)=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COc1ccc(C(=O)/C=C/c2cc(F)cc(F)c2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(/C=C/c1cc(F)cc(F)c1)c1ccc(=O)[nH]c1

Procedure:
In analogy to example 162, step 2, (E)-3-(3,5-difluorophenyl)-1-(6-methoxypyridin-3-yl)prop-2-en-1-one was reacted with concentrated aqueous HCl in 1,4-dioxane to give the title compound as a colourless solid, MS (ESI+): m/z=262.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][CH:17]=[C:18]([CH2:20][CH2:21]Cl)[N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][OH:24]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][CH:17]=[C:18]([CH2:20][CH2:21][O:24][CH3:23])[N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: ClCCc1c[nH]c(-c2ccc(OCc3ccccc3)cc2)n1
Product: COCCc1c[nH]c(-c2ccc(OCc3ccccc3)cc2)n1
Reaction time: 15 h
Yield: 94 %

Procedure:
Under N2, Na (0.7 g, 0.029 mol) was added to CH3OH (100 ml) and heated at reflux. After the Na had reacted, a solution of 70 (2.0 g, 0.0064 mol) in CH3OH (75 ml) was added dropwise with stirring. After 15 hours, the suspension was concentrated to dryness to yield 1.85 g (94%) of 71, m.p. 154°-6° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14](=O)[CH3:15])[CH:5]=[C:6]([CH3:13])[C:7]=1[O:8][CH2:9][CH:10]([F:12])[F:11].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:15])[CH:5]=[C:6]([CH3:13])[C:7]=1[O:8][CH2:9][CH:10]([F:12])[F:11]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cc(C)c(OCC(F)F)c(Cl)c1
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cc(Cl)c1OCC(F)F
Yield: 93 %

Procedure:
The title compound is prepared in 93% yield (0.85 g, yellow oil) from 1-(3-chloro-4-(2,2-difluoroethoxy)-5-methylphenyl)ethanone (0.65 g, 2.61 mmol, Step-1) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH3:10])=[CH:5][CH:4]=1)#[N:2].C([O-])=O.[NH4+:15].C(O)(=O)C>[Ir].CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH2:15])[CH3:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: [NH4+]
Reactant: CC(=O)c1ccc(C#N)cc1
Agent: [Ir]
Agent: O=C[O-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(N)c1ccc(C#N)cc1
Temperature: 60 °C

Procedure:
726 mg (5.0 mmol) of 4′-cyanoacetophenone (MW: 145.16), 946 mg (15.0 mmol) of ammonium formate (MW: 63.06) and 5.90 mg (0.01 mmol, S/C=500) of the iridium catalyst Ir-7 (MW: 590.13) were introduced in a 20-mL Schlenk tube, and subjected to argon-gas replacement. To this, 5 mL of dehydrated methanol and 286 μL (5.0 mmol) of acetic acid were added and stirred while heating at 60° C. for 3 hr. After distillation of the solvent, a saturated sodium hydrogen carbonate solution was added, then a product was extracted with methylene chloride, the organic layer was washed with water, and the product was dried with sodium sulfate. The drying agent was removed by filtration and the methylene chloride was distilled away to give a crude product DL-1-(4′-cyanophenyl)ethylamine. Its conversion rate was 100% based on NMR measurement, with 95% of DL-1-(4′-cyanophenyl)ethylamine, 1% of 1-(4′-cyanophenyl)ethanol, and 4% of other by-products. Since no compound in which reduction of cyano groups occurred was generated, we confirmed that reductive amination reaction was carried out in a functional-group-selective manner.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:22](COCC[Si](C)(C)C)[C:21]([O:31][C@H:32]3[C@H:36]4[O:37][CH2:38][C@@H:39]([OH:40])[C@H:35]4[O:34][CH2:33]3)=[N:20][C:5]2=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:31][C@H:32]3[C@H:36]4[O:37][CH2:38][C@@H:39]([OH:40])[C@H:35]4[O:34][CH2:33]3)=[N:20][C:5]2=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(N3CCC(c4ccccc4)CC3)c(Cl)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(N3CCC(c4ccccc4)CC3)c(Cl)cc2[nH]1

Procedure:
To a r.t. solution of (3R,3aR,6R,6aR)-6-((6-chloro-5-(4-phenylpiperidin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol (77 mg, 0.131 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). The reaction was concentrated after 4 hours and diluted with ethyl acetate and saturated aqueous NaHCO3. This mixture was then extracted with ethyl acetate, and the combined the organic layers were washed with brine, dried over Na2SO4, and concentrated. This material was then purified via reverse phase HPLC on a 19×50 mm Waters Sunfire C18 column (5μ particle size) using a linear gradient with acetonitrile/water and buffering with 0.16% TFA at a flow rate 25 mL/min. The desired fractions were concentrated to obtain the title compound as a white sticky solid. LC-MS: calculated for C23H25ClN4O4 456.16 observed m/e: 457.33 (M+H)+ (Rt 1.08/2 min). 1H NMR δ (ppm) (DMSO): 7.76 (s, 1H), 7.30-7.28 (m, 4H), 7.19 (m, 1H), 5.38 (q, 1H), 4.80 (t, 1H), 4.33 (t, 1H), 4.14-4.09 (m, 2H), 3.85 (m, 1H), 3.74 (m, 1H), 3.59 (d, 2H), 3.40 (t, 1H), 2.85 (t, 2H), 2.68 (m, 1H), 1.85 (m, 4H).
Reaction SMILES: Br[CH2:2][CH3:3].[CH:4]1[C:17]2[C:8](=[CH:9][C:10]3[C:15]([C:16]=2[CH2:18][NH:19][CH2:20][CH2:21][CH2:22][OH:23])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH:14]1[C:15]2[C:10](=[CH:9][C:8]3[C:17]([C:16]=2[CH2:18][N:19]([CH2:2][CH3:3])[CH2:20][CH2:21][CH2:22][OH:23])=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:11]=[CH:12][CH:13]=1
Reactant: OCCCNCc1c2ccccc2cc2ccccc12
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CCCO)Cc1c2ccccc2cc2ccccc12
Temperature: 75 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
Bromoethane (616 mg, 5.65 mmol) was dissolved in anhydrous acetonitrile and was added to the stirring mixture of compound 14a (500 mg, 1.9 mmol) and anhydrous K2CO3 (781 mg, 5.7 mmol). The mixture was then stirred overnight at 75° C. under a N2 atmosphere. After confirmation of the disappearance of 14a by TLC, the solution was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (20 mL) and washed three times with aqueous sodium carbonate. The organic layer was separated, dried with anhydrous Na2SO4, filtered and concentrated under vacuum. Flash column chromatography of the residue gave 14b as a light yellow oil. Yield 82%; Rf=0.35 (3% MeOH/CHCl3); 1H NMR (CDCl3) δ 8.28 (m, 3H), 7.86 (d, 2H), 7.44 (m, 2H), 7.36 (m, 2H), 4.29 (s, 2H), 3.15 (t, 2H), 2.65 (q, 2H), 2.52 (t, 2H), 1.43 (q, 2H), 1.16 (t, 3H); 13C NMR (CDCl3) δ 131.2, 131.1, 129.3, 129.0, 127.6, 125.8, 124.8, 124.4, 63.4, 52.6, 50.5, 47.7, 28.1, 11.6. HRMS (FAB) m/z calcd. for C20H23NO (M+H)+ 294.1852; found 294.1859.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:12][C:11]=1[CH:26]([OH:30])[CH:27]([CH3:29])[CH3:28].C(N(CC)CC)C.Cl>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:12][C:11]=1[C:26](=[O:30])[CH:27]([CH3:28])[CH3:29]
Reactant: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C(O)C(C)C)c2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C(=O)C(C)C)c2)cc1
Reaction time: 24 h
Yield: 84.9 %

Procedure:
Under a nitrogen atmosphere, to a solution of 1-(2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)-[1,1′-biphenyl]-2-yl)-2-methylpropan-1-ol (256.9 mg) in DMSO (4.2 mL) were added triethylamine (523 μL) and sulfur trioxide pyridine complex (299 mg) at room temperature, and the mixture was stirred for 24 hr. To the reaction mixture was added 0.5N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (217 mg) as a pale-yellow oil.
Reaction SMILES: CN1CCNCC1.BrC1SC(C=O)=CC=1.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[S:27][C:26]([CH:28]=O)=[CH:25][CH:24]=2)[CH2:19][CH2:18]1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH2:35][C:36]#[N:37]>>[CH3:30][O:31][C:32]1[CH:33]=[C:34](/[C:35](=[CH:28]/[C:26]2[S:27][C:23]([N:20]3[CH2:19][CH2:18][N:17]([CH3:16])[CH2:22][CH2:21]3)=[CH:24][CH:25]=2)/[C:36]#[N:37])[CH:38]=[CH:39][C:40]=1[O:41][CH3:42]
Reactant: CN1CCN(c2ccc(C=O)s2)CC1
Reactant: COc1ccc(CC#N)cc1OC
Agent: CN1CCNCC1
Agent: O=Cc1ccc(Br)s1
Product: COc1ccc(/C(C#N)=C/c2ccc(N3CCN(C)CC3)s2)cc1OC
Yield: 66.9 %

Procedure:
Through the procedure as employed in Production step 1, an amine moiety derived from 1-methylpiperazine (6.01 g) was introduced into 5-bromothiophene-2-carboxaldehyde (3.82 g), to thereby yield 5-(4-methyl-piperazin-1-yl)-thiophene-2-carbaldehyde (yield: 3.71 g, 88%). The produced 5-(4-methyl-piperazin-1-yl)-thiophene-2-carbaldehyde (2.10 g) was condensed with 3,4-dimethoxybenzyl cyanide (1.77 g) through Method A (production step 2), to thereby yield the target product (yield: 2.47 g, 67%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[Cl-].[Ca+2].[Cl-].[CH3:18]O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:18])=[O:13]
Reactant: CO
Reactant: O=C(O)CCCCCCCCCCBr
Agent: [Ca+2]
Agent: [Cl-]
Product: COC(=O)CCCCCCCCCCBr
Yield: 84 %

Procedure:
11-Bromoundecanoic acid (commercial material, 25.0 g, 94 mmol), Duolite H+ resin (10 g), calcium chloride (26.2 g, 94 mmol) and methanol (700 ml) were stirred for 15 h. The methanol was removed and dichloromethane was added. The mixture was washed with water, dried (Na2SO4) and concentrated. Distillation gave pure 103 (22.0 g, 84%) with b.p. 103°-104° (2×10-2 torr). 1H-NMR (CDCl3, Me4Si) δ 3.67 (s, 3H, MeO), 3.41 (t, 2H, J=6.8 Hz, Br--CH2), 2.31 (t, 2H, J=7.3 Hz, CH2CO).
Reaction SMILES: [H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[F:18][C:19]1[C:24](F)=[CH:23][CH:22]=[C:21]([N+:26]([O-:28])=[O:27])[C:20]=1[O:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1>C1COCC1>[F:18][C:19]1[C:20]([O:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][CH:31]=2)=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[CH:23][C:24]=1[CH:4]([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1Oc1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])c(Oc2cccc3ccccc23)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 115.4 %

Procedure:
Sodium hydride (60% oil dispersion) (4.07 g, 102 mmol) was added in portions to a solution of di-t-butyl malonate (11.01 g, 50.9 mmol) in THF (200 mL) at room temperature. After gas evolution ceased, 1-[(2,3-difluoro-6-nitrophenyl)oxy]naphthalene (13.94 g, 46.3 mmol), dissolved in THF (100 mL), was added. The reaction mixture was stirred at room temperature for 2 hrs and then poured on to ice and extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The solvent was evaporated to give the title compound (26.59 g, 102%) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 8.33-8.44 (m, 1H), 7.83-7.95 (m, 2H), 7.51-7.65 (m, 4H), 7.23-7.34 (m, 1H), 6.60 (d, 1H), 4.82 (s, 1H), 1.49 (s, 18H). ESMS: m/z 497.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].[OH-].[Na+].[C:9]1([C:15]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>CO>[OH:5][C:4]1[CH:3]=[N:2][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=1
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Reactant: NCC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Oc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a stirred suspension of glycinamide hydrochloride (1.1 gm, 10 mmol) in 20 mL MeOH at 0° C. was added 20% NaOH (10 mL, 50 mmol). A clear solution formed and was treated slowly portionwise with benzil (2.1 gm, 10 mmol) as a solid. The yellow solution was stirred at 0° C. for 2 hours and then neutralized to approximately pH=7 with concentrated HCl. The bright yellow color disappeared and a tan precipitate formed. The material was isolated by filtration with MeOH and triturated with EtOAc to give 2-hydroxy-5,6-diphenylpyrazine (2 gm, 80%). 1H-NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 7.42-7.31 (m, 4H), 7.39-7.21 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]([NH2:29])[CH3:28].C(N(CC)CC)C.O>C(#N)C>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]([NH:29][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH3:28]
Reactant: CC(N)c1ccccc1-c1ccc(F)cc1F
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)NC(C)c2ccccc2-c2ccc(F)cc2F)cc1
Reaction time: 2 h
Yield: 78.2 %

Procedure:
4-Methoxybenzenesulfonyl chloride (341 mg, 1.7 mmol) was added to a solution of 1-(-2′,4′-difluoro-biphenyl-2-yl)ethylamine (350 mg, 1.5 mmol) and triethylamine (418 μL, 3 mmol) in acetonitrile. The reaction progress was monitored by LCMS and after 2 hours the reaction appeared to be complete. Water was added and the resulting solid was collected by filtration. The solid was dissolved in dichloromethane and purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 30%-50% methyl tert-butyl ether in hexane (35 min), to afford the title compound (473 mg, 78%) as a white solid, m.p. 154-155° C.;
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:11]2[N:12]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13](=O)[NH:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].P(Cl)(Cl)([Cl:26])=O.C(=O)([O-])O.[Na+]>>[Cl:26][C:13]1[N:12]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11]2[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][CH:8]=[CH:9][C:10]=2[N:14]=1
Reactant: CCOC(=O)CCCn1c(=O)[nH]c2cccc(C(CC)CC)c21
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)CCCn1c(Cl)nc2cccc(C(CC)CC)c21
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 46 %

Procedure:
The mixture of ethyl 4-[7-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]butanoate (Reference Example 31; 1.94 g, 6.09 mmol) and phosphorus oxychloride (4.33 mL) was stirred at 100° C. for 2.5 hr. After cooling, the mixture was poured into ice water and neutralized with sodium hydrogen carbonate. The precipitate was removed by filtration and the filtrate was extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-15% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless oil (942.6 mg, 2.80 mmol, 46%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[C:15](Cl)[N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[O:29]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30]1.CC#N.C(O)(C(F)(F)F)=O>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[C:15]([C:31]3[CH:32]=[CH:33][O:29][CH:30]=3)[N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: OB(O)c1ccoc1
Reactant: CC(Nc1nc(Cl)cc(-n2cnc3ccccc32)n1)c1cccc([N+](=O)[O-])c1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(Nc1nc(-c2ccoc2)cc(-n2cnc3ccccc32)n1)c1cccc([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 2-[1-(3-nitrophenyl)ethylamino]-4-[benzimidazol-1-yl]-6-chloropyrimidine and furan-3-boronic acid according to the precedure described in EXAMPLE 306, Step C and using [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(H) as catalyst. Mass spectrum (CH3CN/TFA/NH4O2CH/ESI) 427.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:19][CH:20]1[CH:27]2[CH2:28][C:23]3([OH:30])[CH2:24][CH:25]([CH2:29][CH:21]1[CH2:22]3)[CH2:26]2>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([NH:19][CH:20]2[CH:21]3[CH2:29][CH:25]4[CH2:24][C:23]([OH:30])([CH2:28][CH:27]2[CH2:26]4)[CH2:22]3)=[O:15])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(OCc2ccc(Cl)nc2)c1
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Product: O=C(NC1C2CC3CC1CC(O)(C3)C2)c1cccc(OCc2ccc(Cl)nc2)c1

Procedure:
Prepared from 3-(6-chloro-pyridin-3-ylmethoxy)-benzoic acid and 4-amino-1-hydroxyadamantane. 1H NMR (400 MHz, CDCl3): δ 8.49 (d, 1H), 7.78 (dd, 1H), 7.42-7.44 (m, 1H), 7.38 (t, 2H), 7.32 (d, 1H), 7.10 (dd, 1H), 6.32 (d, 1H), 5.12 (s, 2H), 4.19-4.24 (m, 1H), 3.13 (br. s., 2H), 2.26 (br. s., 2H), 2.21 (br. s., 1H), 1.95 (d, 2H), 1.73-1.85 (m, 6H), 1.59 (d, 2H).
Reaction SMILES: [CH2:1]([N:7]([CH3:27])[C:8]([CH:10]1[CH2:14][CH:13]([OH:15])[CH2:12][CH:11]1[C:16]([NH:18][C:19]1([C:24](O)=[O:25])[CH2:21][CH:20]1[CH:22]=[CH2:23])=[O:17])=[O:9])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].CCN=C=NCCCN(C)C.[CH:39]1([S:42]([NH2:45])(=[O:44])=[O:43])[CH2:41][CH2:40]1.C1CCN2C(=NCCC2)CC1>CN(C=O)C.CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:39]1([S:42]([NH:45][C:24]([C:19]2([NH:18][C:16]([CH:11]3[CH2:12][CH:13]([OH:15])[CH2:14][CH:10]3[C:8]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6])[CH3:27])=[O:9])=[O:17])[CH2:21][CH:20]2[CH:22]=[CH2:23])=[O:25])(=[O:44])=[O:43])[CH2:41][CH2:40]1
Reactant: NS(=O)(=O)C1CC1
Reactant: C=CCCCCN(C)C(=O)C1CC(O)CC1C(=O)NC1(C(=O)O)CC1C=C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCCCCN(C)C(=O)C1CC(O)CC1C(=O)NC1(C(=O)NS(=O)(=O)C2CC2)CC1C=C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.8 %

Procedure:
The crude acid 10d (410 mg, 1.09 mmol) was dissolved in DMF (1.5 ml) and DCM (4.5 ml) followed by addition of EDAC (417 mg, 2.18 mmol) at room temperature. The mixture was allowed to incubate with stirring at room temperature. After 10 min, DMAP (133 mg, 1.09 mmol) was added followed by another 20 min incubation at room temperature. Subsequently, a pre-mixed solution of cyclopropanesulfonic acid amide (527 mg, 4.36 mmol) and DBU (663 mg, 4.36 mmol) in DMF (2 ml) and DCM (2 ml) was added followed by heating in the microwave to 100° C. for 30 min. The resulting red solution was concentrated in vacuo and re-dissolved in EtOAc (20 ml). The organic phase was washed with 1 M HCl (aq) (3×10 ml) and brine (10 ml), dried (MgSO4) and filtered. The solvent was evaporated in vacuo to yield the crude sulfonamide which was further purified by chromatography (Silica, EtOAc:MeOH, 97.5:2.5) which gave the title compound (403 mg, 77%); LC/MS >95%, m/z (ESI+)=482 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:7][CH2:6][CH:5]([CH2:8][C:9](OCC)=[O:10])[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[CH3:1][C:2]1([CH3:14])[CH2:3][CH2:4][CH:5]([CH2:8][CH2:9][OH:10])[CH2:6][CH2:7]1
Reactant: CCOC(=O)CC1CCC(C)(C)CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC1(C)CCC(CCO)CC1
Temperature: 25 °C
Yield: 92.8 %

Procedure:
To a solution of ethyl 2-(4,4-dimethylcyclohexyl)acetate (Preparation 14, 2.0 g, 10 mmol) in tetrahydrofuran (20 ml) under an atmosphere of nitrogen at 0° C. was added lithium aluminium hydride (1.0M solution in tetrahydrofuran, 11 ml, 11 mmol) and the reaction mixture was allowed to warm to room temperature overnight. The mixture was poured onto ice (300 g), acidified to pH 1 with 1N aqueous hydrochloric acid and extracted with dichloromethane (200 ml). The organic extract was dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a pale yellow oil (1.45 g, 93%).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[F:14][C:15]([F:32])([F:31])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1>>[CH3:1][C:2]1[N:6]2[CH:7]=[C:8]([NH:11][C:28]([C:25]3[CH:24]=[CH:23][C:22]([C:19]4[CH:20]=[CH:21][C:16]([C:15]([F:14])([F:31])[F:32])=[CH:17][CH:18]=4)=[CH:27][CH:26]=3)=[O:29])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Cc1cnc2ccc([N+](=O)[O-])cn12
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Product: Cc1cnc2ccc(NC(=O)c3ccc(-c4ccc(C(F)(F)F)cc4)cc3)cn12

Procedure:
Conducting the operations similar to those of Example 1 using 3-methyl-6-nitroimidazo[1,2-a]pyridine and 4′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylic acid, the title compound was obtained as white solid.