Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([CH2:11][S:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:5]=1.Cl.[N:27]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.O>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][N:27]=[C:11]2[S:12]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)(=[O:13])=[O:14])=[O:25]
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc(N)c(CS(=O)(=O)c2cccc3ccccc23)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Temperature: 3 °C

Procedure:
A mixture of 4-amino-3-(naphthalene-1-sulfonylmethyl)benzoic acid methyl ester (0.9 g, 2.5 mmoles) in THF (5 mL), and 4M HCl (10 mL) was stirred in a round bottom flask, under nitrogen, at 3° C. A solution of sodium nitrite (0.18 g, 2.62 mmoles) in H2O (1 mL) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.82 g, 2.25 mmoles).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]([O-])=[O:15])[CH:6]=[C:7]([CH:13]=1)[C:8](OCC)=[O:9].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[OH:9][CH2:8][C:7]1[CH:13]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([CH2:14][OH:15])[CH:6]=1
Reactant: CCOC(=O)c1cc(OC)cc(C(=O)[O-])c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(CO)cc(CO)c1
Reaction time: 1 h

Procedure:
To a solution of 5.00 g (22.32 mmoles) of methyl,methyl 5-methoxyisophthalate in 100 ml dry THF is added dropwise, maintaining a gentle reflux, 67 ml (66.96 mmoles) of a 1M solution of lithium aluminum hydride in Et2O. After addition the reaction mixture is stirred for 1 hour and is then quenched with saturated NH4Cl. The reaction mixture is then extracted with Et2O (3 times). The Et2O layers are combined, washed with brine, dried with MgSO4, filtered and concentrated down in vacuo to yield 1,3-di-(hydroxymethyl)-5-methoxybenzene which is used directly in the next step.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[C:19](=[O:20])[C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[NH:16][S:15]2(=[O:26])=[O:25])[CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1.[ClH:33]>>[ClH:33].[O:26]=[S:15]1(=[O:25])[CH:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:19](=[O:20])[C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(C2C(=O)c3ccccc3NS2(=O)=O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1c2ccccc2NS(=O)(=O)C1C1CCNCC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
4-(2,2,4-Trioxo-1,2,3,4-tetrahydro-2,1-benzothiazin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (175 mg, 0.46 mmol) was dissolved in 4M hydrogen chloride in 1,4-dioxane (3.0 mL, 12.0 mmol). Reaction stirred at room temperature for 45 minutes. Reaction mixture was concentrated to dryness in vacuo. Title compound was obtained as pink solid in quantitative yield. MS m/e (M+H)+=281.1.
Reaction SMILES: FC(F)(F)C(O)=O.ClC1C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)=C2N=C(C3C=CC(CN4CCOCC4)=CC=3)NC2=NC=1.[NH2:42][C:43]1[C:48]([NH2:49])=[C:47]([NH:50][C@@H:51]2[C@@H:56]3[CH2:57][C@@H:53]([CH:54]=[CH:55]3)[C@@H:52]2[C:58]([NH2:60])=[O:59])[C:46]([Cl:61])=[CH:45][N:44]=1.[CH3:62][O:63][C:64]1[CH:69]=[CH:68][N:67]=[CH:66][C:65]=1[CH:70]=O>>[Cl:61][C:46]1[C:47]([NH:50][C@@H:51]2[C@@H:56]3[CH2:57][C@@H:53]([CH:54]=[CH:55]3)[C@@H:52]2[C:58]([NH2:60])=[O:59])=[C:48]2[N:49]=[C:70]([C:65]3[CH:66]=[N:67][CH:68]=[CH:69][C:64]=3[O:63][CH3:62])[NH:42][C:43]2=[N:44][CH:45]=1
Reactant: COc1ccncc1C=O
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: COc1ccncc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 89 %

Procedure:
In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 4-methoxy-pyridine-3-carbaldehyde were reacted to produce the title compound (89%). 1H NMR (d-6 DMSO): 13.16 (br s, 1H), 9.19 (s, 1H), 8.81 (s, 1H), 8.10 (s, 1H), 7.83 (s, 1H), 7.70 (m, 2H), 7.28 (s, 1H), 6.40 (s, 1H), 6.38 (s, 1H), 5.10 (t, J=7 Hz, 1H), 4.21 (s, 3H), 2.92 (s, 1H), 2.85 (s, 1H), 2.63 (d, J=8 Hz, 1H), 2.23 (d, J=8 Hz, 1H), 1.41 (d, J=8 Hz, 1H). MS: 411.14 (M+H). HPLC retention time: 1.60 minutes (G Method)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14](O)=[O:15])=[CH:5][CH:4]=1)#[N:2].[F:24][C:25]([F:34])([F:33])[C:26]1[N:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]([O:18][CH2:19][C:20]([F:22])([F:23])[F:21])=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14]([NH:32][CH2:31][C:29]2[O:28][N:27]=[C:26]([C:25]([F:24])([F:33])[F:34])[N:30]=2)=[O:15])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(-c2cc(C(=O)O)cnc2OCC(F)(F)F)cc1
Reactant: NCc1nc(C(F)(F)F)no1
Product: N#Cc1ccc(-c2cc(C(=O)NCc3nc(C(F)(F)F)no3)cnc2OCC(F)(F)F)cc1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-cyanophenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid (example BU) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; MS (ESI): 470.2 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[C:12]([OH:14])=O.[N:15]1([CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[CH:27][CH:26]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[C:12]([N:34]1[CH2:35][CH2:36][N:31]([C:28]2[CH:27]=[CH:26][C:25]([O:24][CH2:23][CH2:22][CH2:21][N:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)=[CH:30][CH:29]=2)[CH2:32][CH2:33]1)=[O:14]
Reactant: c1cc(N2CCNCC2)ccc1OCCCN1CCCCC1
Reactant: Cn1cc(C(=O)O)c2cc(F)ccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Product: Cn1cc(C(=O)N2CCN(c3ccc(OCCCN4CCCCC4)cc3)CC2)c2cc(F)ccc21
Temperature: 120 °C
Yield: 15.2 %

Procedure:
A solution of 5-fluoro-1-methyl-1H-indole-3-carboxylic acid [WO 0071537 A1] (35 mg) and 1-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine (D11) (50 mg) in dichloromethane (1 ml) was treated with benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (94.4 mg) and heated in a microwave (CEM™ Discover microwave) at 120° C. for 5 min. The reaction mixture was concentrated in vacuo and purified on a SCX cartridge (2 g) eluting with methanol-aqueous ammonia (10:1) followed by mass directed auto preparative HPLC to give the title compound (12 mg). LCMS RT=2.49 min, 478 (M+H)+
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:13]=[CH:12][C:8]2[NH:9]C=N[C:7]=2[CH:6]=1)[NH2:4].[NH:14]1[C:22]2C(=CC(C#N)=CC=2)C=N1>>[OH:1][N:2]=[C:3]([C:5]1[CH:6]=[C:7]2[C:8](=[CH:12][CH:13]=1)[NH:9][N:14]=[CH:22]2)[NH2:4]
Reactant: NC(=NO)c1ccc2[nH]cnc2c1
Reactant: N#Cc1ccc2[nH]ncc2c1
Product: NC(=NO)c1ccc2[nH]ncc2c1

Procedure:
The title compound was prepared following procedure described for Intermediate 1, step 2, but starting from 1H-indazole-5-carbonitrile (JW-Pharmalab, 0.50 g; 3.49 mmol) as a beige solid (560 mg, 91%). 1H NMR (DMSO-d6) δ 13.12 (s, 1H), 9.54 (s, 1H), 8.10 (s, 1H), 8.04 (s, 1H), 7.71 (d, J=8.7 Hz, 1H), 7.49 (d, J=8.7 Hz, 1H), 5.82 (bs, 2H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[N:15]([CH2:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([Cl:28])[CH:23]=4)[C:14]3=[O:29])[CH:11]=2)[C:6]([CH3:31])([CH3:30])[CH2:5]1)(=O)C.Cl>O1CCOCC1>[Cl:28][C:24]1[CH:23]=[C:22]([CH2:21][N:15]2[C:16]([CH3:20])([CH3:19])[C:17](=[O:18])[N:13]([C:10]3[CH:11]=[C:12]4[C:7]([C:6]([CH3:31])([CH3:30])[CH2:5][NH:4]4)=[CH:8][CH:9]=3)[C:14]2=[O:29])[CH:27]=[CH:26][N:25]=1
Reactant: CC(=O)N1CC(C)(C)c2ccc(N3C(=O)N(Cc4ccnc(Cl)c4)C(C)(C)C3=O)cc21
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)CNc2cc(N3C(=O)N(Cc4ccnc(Cl)c4)C(C)(C)C3=O)ccc21
Temperature: 70 °C
Yield: 95.9 %

Procedure:
To a solution of 2.65 g of 3-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-1-[(2-chloropyridin-4-yl)methyl]-5,5-dimethylimidazolidine-2,4-dione obtained in stage h) below in 30 mL of dioxane are added 33 mL of aqueous 1N hydrochloric acid solution. The reaction mixture is heated at 70° C. for 17 hours and concentrated under reduced pressure. The residue is diluted with 30 mL of water and poured into saturated aqueous sodium hydrogen carbonate solution, and the precipitate formed is filtered off, washed with four times 10 mL of water and dried to give 2.3 g of 1-[(2-chloropyridin-4-yl)methyl]-3-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-5,5-dimethylimidazolidine-2,4-dione in the form of a beige-coloured solid, the characteristics of which are as follows:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=3)[NH:4][N:3]=2)=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)n1nc(Br)c2cc([N+](=O)[O-])ccc21
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 95 °C
Yield: 95.9 %

Procedure:
The product from Step (b) (0.5 g, 1.5 mmol), 4-fluoro phenylboronic acid (0.31 g, 2.2 mmol) and Pd(dppf)2Cl2.CH2Cl2 (0.12 g, 0.15 mmol) were combined in 9 ml of 2:1 Dioxane/2 M K2CO3 The reaction mixture was sealed and heated to 95° C. for 18 h. The resulting biphasic mixture was cooled to room temperature. The phases were separated and the organic phase (top) was filtered. The aqueous layer was extracted once with EtOAc. The combined organic phases were washed with sat'd NaHCO3, water, brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (5% MeOH/CH2Cl2) to afford 0.37 g of the title compound, (100%); MS (ES+) m/e 259 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[NH2:28][CH:29]([CH2:39][CH3:40])[C@@H:30]([C:32]1[N:36]=[C:35]([CH2:37][CH3:38])[O:34][N:33]=1)[OH:31]>>[CH:1]1([CH2:7][C@H:8]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[C:9]([NH:28][C@H:29]([C:30]([C:32]2[N:36]=[C:35]([CH2:37][CH3:38])[O:34][N:33]=2)=[O:31])[CH2:39][CH3:40])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)CC1CCCCC1
Reactant: CCc1nc([C@@H](O)C(N)CC)no1
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc(C(=O)[C@H](CC)NC(=O)[C@@H](CC(=O)N2CCOCC2)CC2CCCCC2)no1

Procedure:
It is similarly prepared according to general procedure given for example 8 above but using (R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid and (S)-2-Amino-1-(5-ethyl-1,2,4-oxadiazol-3-yl)-butan-1-ol; compound with trifluoro-acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C([Li])CCC.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:26]3([OH:29])[CH2:25][CH2:24][N:23]([C:21]([O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:22])[CH2:28][CH2:27]3)=[CH:7][C:6]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Clc1ccc2sccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cc3cc(Cl)ccc3s2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
A solution of 0.60 gm (3.56 mMol) 5-chlorobenzothiophene 1.55 mL in 20 mL freshly distilled tetrahydrofuran was cooled to -78° C. under a nitrogen atmosphere. To this was then added a solution of 2.94 mL (3.56 mMol) n-butyllithium and the reaction mixture was stirred at -78° C. for 1 hour. To the resulting anion solution was added dropwise a solution of 0.779 gm (3.91 mMol) 1-tert-butoxycarbonyl-4-piperidone and then the reaction mixture was allowed to warm to 0° C. The reaction mixture was then quenched with saturated aqueous sodium bicarbonate, diluted with 1:1 hexanes:diethyl ether and the phases separated. The organic phase was washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica chromatography, eluting with toluene containing 10% ethyl acetate. Fractions shown to contain product were combined and concentrated under reduced pressure to give 1.09 gm of the desired compound as a colorless foam contaminated with 20% 1-tert-butoxycarbonyl-4-piperidone.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[C:10]([O:17][CH3:18])[CH:9]=2)=[CH:4][C:3]=1[C:19]1[N:20]=[N:21][N:22]([CH:24]([CH3:26])[CH3:25])[CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[O:13])=[C:10]([O:17][CH3:18])[CH:9]=2)=[CH:4][C:3]=1[C:19]1[N:20]=[N:21][N:22]([CH:24]([CH3:25])[CH3:26])[CH:23]=1
Reactant: COc1cc(-c2cnc(N)c(-c3cn(C(C)C)nn3)c2)ccc1C(=O)O
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2cnc(N)c(-c3cn(C(C)C)nn3)c2)ccc1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
To a solution of 4-(6-amino-5-(1-isopropyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-2-methoxybenzoic acid (260 mg, 0.735 mmol) and HATU (418 mg, 1.10 mmol) in DMF (10.0 mL) were added morpholine (77 mg, 0.88 mmol) and DIPEA (0.4 mL, 2.205 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was poured into ice cold water, extracted with EtOAc (100 mL). The organic layer was washed with brine solution (50 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure. Crude compound was purified by column using 100-200 mesh silica gel. The column was eluted with 100% EtOAc to afford 250 mg (yield: 80.64%) of the title compound as pale yellow solid.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)=[C:14]([CH:29]([NH2:31])[CH3:30])[CH:13]=1.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)=[C:14]([CH:29]([NH:31][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:30])[CH:13]=1
Reactant: CC(N)c1cc(Cl)c2ccccc2c1-c1cccc(F)c1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2ccccc2c1-c1cccc(F)c1
Temperature: 100 °C

Procedure:
A mixture of 6-bromo-9H-purine (0.077 g, 0.39 mmol), 1-[4-chloro-1- (3-fluorophenyl)-2-naphthyl]ethanamine (0.058 g, 0.19 mmol), and N,N-diisopropylethylamine (0.067 mL, 0.39 mmol) in ethanol (0.6 mL) was heated at 100° C., in a sealed tube overnight. The volatiles were removed under reduced pressure. The residue was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the desired product. LCMS calculated for C23H18ClFN5(M+H)+: m/z=418.1; Found: 418.1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5](=[O:17])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1>C(OCC)(=O)C.[Pd]>[OH:1][CH2:2][CH2:3][O:4][C:5](=[O:17])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1
Reactant: O=C(COc1ccc([N+](=O)[O-])cc1)OCCO
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(OCC(=O)OCCO)cc1
Reaction time: 1 h
Yield: 22.8 %

Procedure:
(4-Aminophenoxy)acetic acid methyl ester 41 (1 g, 4.15 mmol) was dissolved in ethyl acetate in a pressure vessel, palladium on carbon (5%, 0.5 g) was added and the mixture was stirred under an atmosphere of hydrogen (0.5 Kg) for one hour. The catalyst was removed by filtration, ethyl acetate was distilled off and hexane was added. The solid product was filtered and dried to give pure 46 (0.2 g, 22.8%) as a brown powder. M.p: 104-106.3° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:47])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4].[C:48]([NH:58][CH2:59][C:60](O)=[O:61])([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49]>>[C:48]([NH:58][CH2:59][C:60]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:47])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4])=[O:61])([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Product: CCCCCCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)CNC(=O)OCc1ccccc1

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-octadecyl-dodecanamide and N-carbobenzoxy-glycine.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.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]>[CH2:14]([O:13][C:11]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([N:19]3[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]3)[C:7]=2[CH:8]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cc2c(Cl)cccc2o1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)cccc2o1

Procedure:
Ethyl 4-bromobenzofuran-2-carboxylate (prepared in analogy with ethyl 4-chlorobenzofuran-2-carboxylate, (Example 1b), starting from 2-bromo-6-hydroxy-benzaldehyde) (7.7 g, 29 mmol), tert-butyl piperazine-1-carboxylate (5.33 g, 28.6 mmol), tris(dibenzylideneacetone)dipalladium(0) (1.31 g, 1.43 mmol), 2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl (1.36 g, 2.86 mmol) and cesium carbonate (12.1 g, 37.2 mmol) in dioxane (40 mL) was heated under argon to +95° C. overnight. The mixture was allowed to cool, diluted with ethyl acetate and filtered through a pad of Celite. The filtrate was collected and the solvent was removed by rotary evaporation. The crude product was added to a silica gel column and eluted with 0-50% ethyl acetate in heptane. The collected fractions were combined and the solvent was removed to give the title compound, which was used in the subsequent step ii). Yield: 4.92 g, 46%. MS m/z 375.8 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([S:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:13][CH2:12][CH2:11][O:10][C:9]1[CH:14]=[CH:15][C:6]([S:5][CH:2]([CH3:1])[CH2:3][CH3:4])=[CH:7][CH:8]=1)(=[O:26])=[O:25]
Reactant: CCC(C)Sc1ccc(OCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)Sc1ccc(OCCOS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 2-[4-(1-methylpropylthio)phenoxy]ethanol (4.26 g, 20.0 mmol) and triethylamine (4.2 ml, 30.0 mmol) in 100 ml methylene chloride at 0° is added dropwise methanesulfonyl chloride (1.7 ml, 22.0 mmol). The mixture is stirred at 0° for 20 min, after which it is poured into ice water. The methylene chloride layer is washed with ice water, with cold 10% sulfuric acid, with cold 5% sodium bicarbonate and with cold brine, dried and the solvent removed to give 2-[4-(1-methylpropylthio)phenoxy]ethyl methanesulfonate.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH2:8][CH3:9])[NH:4][C:3]=1[C:10]([OH:12])=O.Cl.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[S:22][C:23]([C:26]([NH2:28])=[O:27])=[CH:24][N:25]=2)[CH2:17][CH2:16]1>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH2:8][CH3:9])[NH:4][C:3]=1[C:10]([NH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[S:22][C:23]([C:26]([NH2:28])=[O:27])=[CH:24][N:25]=2)[CH2:17][CH2:16]1)=[O:12]
Reactant: NC(=O)c1cnc(N2CCC(N)CC2)s1
Reactant: CCc1[nH]c(C(=O)O)c(Cl)c1Cl
Agent: Cl
Product: CCc1[nH]c(C(=O)NC2CCN(c3ncc(C(N)=O)s3)CC2)c(Cl)c1Cl

Procedure:
Title compound was synthesized by an analogous method to Example 29 by coupling 3,4-dichloro-5-ethyl-1H-pyrrole-2-carboxylic acid (Intermediate 73) with 2-(4-aminopiperidin-1-yl)-1,3-thiazole-5-carboxamide hydrochloride (Intermediate 81).
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([NH:9]C(=O)C(C)(C)C)[CH:6]=[CH:5][CH:4]=1.C(OC([N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[CH2:32][NH:33][CH:34]1[C:43]2[N:42]=[CH:41][CH:40]=[CH:39][C:38]=2[CH2:37][CH2:36][CH2:35]1)=O)(C)(C)C.C(N(CC)C(C)C)(C)C.[I-].[K+]>CC#N>[NH2:9][C:7]1[N:8]=[C:3]([CH2:2][N:33]([CH2:32][C:24]2[NH:23][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[N:25]=2)[CH:34]2[C:43]3[N:42]=[CH:41][CH:40]=[CH:39][C:38]=3[CH2:37][CH2:36][CH2:35]2)[CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Reactant: CC(C)(C)C(=O)Nc1cccc(CBr)n1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)n1
Temperature: 60 °C
Reaction time: 3.75 h
Yield: 85.5 %

Procedure:
Using the general N-alkylation procedure: To a stirred solution of N-[6-(bromomethyl)-2-pyridyl]pivalamide (prepared as described by Harata, M.; Hasegawa, K.; Jitsukawa, K.; Masuda, H.; Einaga, H. Bull. Chem. Soc. Jpn 1998, 71, 1031-1038) (0.129 g, 0.45 mmol) in dry CH3CN (10 mL) was added (1-tert-butoxycarbonyl-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (0.176 g, 0.47 mmol), N,N-diisopropylethylamine (0.20 mL, 1.15 mmol) and potassium iodide (12 mg, 0.048 mmol). The mixture was stirred under an argon atmosphere at 60° C. for 3.75 h. Purification of the crude material by column chromatography on silica gel (CH2Cl2/MeOH, 98:2 followed by 96:4) gave the alkylated product (0.148 g, 54%) as a brown oil.