Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]3[C:18]4[C:17]([NH:19][C@H:20]([C:22]5[N:27]([C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=6)[C:26](=[O:34])[C:25]6=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]6[N:23]=5)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=4[N:12](COCC[Si](C)(C)C)[CH:11]=3)[CH:9]=[C:4]2[CH:3]=[CH:2]1.FC(F)(F)C(O)=O.N>>[NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]3[C:18]4[C:17]([NH:19][C@H:20]([C:22]5[N:27]([C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=6)[C:26](=[O:34])[C:25]6=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]6[N:23]=5)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=4[NH:12][CH:11]=3)[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cnc5[nH]ccc5c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cnc6[nH]ccc6c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 44.9 %

Procedure:
(S)-2-(1-((5-(1H-Pyrrolo[2,3-b]pyridin-5-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (51 mg, 0.08 mmol) was treated with trifluoroacetic acid (2 ml, 25 mmol) and a solution of ammonia (7N in methanol, 2 ml, 14 mmol) according to the method described in Example 27. The residue was purified using SP1® Purification System (0% to 50% dichloromethane-2-propanol) to obtain 18 mg (44% yield) of the title compound. Purity 100%.
Reaction SMILES: [C:1]([C:3]1[C:4](O)=[N:5][C:6]([CH3:10])=[CH:7][C:8]=1[CH3:9])#[N:2].P(Cl)(Cl)(Cl)(Cl)[Cl:13].C(=O)(O)[O-].[Na+]>>[Cl:13][C:4]1[C:3]([C:1]#[N:2])=[C:8]([CH3:9])[CH:7]=[C:6]([CH3:10])[N:5]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1cc(C)c(C#N)c(O)n1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C)c(C#N)c(Cl)n1
Temperature: 120 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
A stirred mixture of 3-cyano-4,6-dimethyl-2-hydroxypyridine (4.35 g, 29.39 mmol) and phosphorous pentachloride (6.92 g, 33.21 mmol) is heated to 120° C. The reaction mixture becomes clear and is stirred for an additional 1 hr. It is then poured onto ice/water (250 mL) and allowed to stand for 30 min. The solution is neutralized with sodium bicarbonate (pH 6) and extracted with dichloromethane (400 mL). The separated organic layer is dried, filtered and concentrated to yield 2-chloro-3-cyano-4,6-dimethylpyridine (4.60 g, 94% yield) as a tan solid containing ca 15% impurity. LC/MS: MS m/e=167/169 (M+H); RT 2.98 min; NMR (CDCl3, δ ppm) 7.08 (1H, s), 2.57 (3H, s), 2.55 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-])=O)=[C:4]([Cl:12])[N:3]=1.O>CCO.[Ni]>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH2:9])=[C:4]([Cl:12])[N:3]=1
Reactant: O=[N+]([O-])c1c(Cl)nc(Cl)nc1Cl
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: Nc1c(Cl)nc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 149.6 %

Procedure:
2,4,6-Trichloro-5-nitropyrimidine (1 g, 4.38 mmol) was suspended in EtOH (10 mL). Raney-Nickel®2800 in water (1.285 g, 21.89 mmol) was added and the vessel was purged with hydrogen gas and stirred at atmospheric pressure and room temperature overnight. After filtration through Celite® the filtrate was evaporated to give 1.3 g of crude 2,4,6-trichloropyrimidin-5-amine. MS [M+H] Found 200.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22]([CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23])=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH:24]1([C:22]([NH:21][NH:20][C:18]([C@@H:13]2[CH2:12][CH2:11][C@@H:10]3[CH2:17][N:14]2[C:15](=[O:16])[N:9]3[OH:8])=[O:19])=[O:23])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)C1CCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O)C1CCCC1
Yield: 94.8 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-N′-(cyclopentylcarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 191 (0.33 g, 0.84 ml) in methanol (20 mL) was added 10% Pd/C (0.30 g). The mixture was hydrogenated under 15 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered through Celite, and the filtrate was evaporated to give (2S,5R)—N′-(cyclopentylcarbonyl)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 192 (0.24 g, 98%) as a colorless foam.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](OC)=[O:13])=[C:6]([N+:16]([O-])=O)[CH:5]=1)([OH:3])=[O:2].CO.[OH-].[Na+]>[Pd].CO>[C:1]([C:4]1[CH:5]=[C:6]2[C:7]([CH2:10][CH2:11][C:12](=[O:13])[NH:16]2)=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: COC(=O)CCc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CCc2ccc(C(=O)O)cc2N1

Procedure:
5 Grams of methyl 3-(4-carboxy-2nitrophenyl)propionate, 8.87 ml of 2.226N-sodium hydroxide methanol solution, 100 ml of methanol and 1 g of 5%-Pd-C (50% in water) were well mixed together and this mixture was catalytically reduced at a normal temperature under a normal pressure. Then the catalyst was removed from the reaction mixture by filtration, and the pH of the filtrate was adjusted to about pH=1 by adding concentrated hydrochloric acid. The precipitated crystals were collected by filtration and recrystallized from methanol to obtain 3.62 g of 7-carboxy-3,4-dihydrocarbostyril in the form of colorless needle-like crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[C:13]([N:14]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[N:15]2)=[N:12][C:11](Br)=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[C:13]([N:14]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[N:15]2)=[N:12][C:11]([NH:28][C:27]2[CH:29]=[CH:30][C:24]([Cl:23])=[CH:25][CH:26]=2)=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(Cl)cc1
Reactant: Cc1cc(C)n(-c2nc(Br)cnc2NC(=O)OC(C)(C)C)n1
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1cc(C)n(-c2nc(Nc3ccc(Cl)cc3)cnc2NC(=O)OC(C)(C)C)n1
Temperature: 120 °C
Yield: 43.4 %

Procedure:
A mixture of give [5-bromo-3-(3,5-dimethyl-pyrazol-1-yl)-pyrazin-2-yl]-carbamic acid tert-butyl ester (511 mg, 1.25 mmol), 4-chloroaniline (223 mg, 1.75 mmol) and cesium carbonate (822 mg, 2.5 mmol) in dioxane (35 mL) was degassed with argon for 15 min. Tris(dibenzylideneaceton)dipalladium (0) 29 mg, 0.03 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (57 mg, 0.1 mmol) were added followed by degassing for 5 min. The reaction mixture was heated to 120° C. for overnight. Ethyl acetate, water and brine were added and the phases were separated. The aqueous phase was extracted with ethyl acetate (5×50 mL). The combined organic phases were washed with brine, dried over sodium sulphate, filtrated and concentrated in vacuo. The crude product purified by flash chromatography (ethyl acetate/heptane as eluent) to give [5-(4-chloro-phenylamino)-3-(3,5-dimethyl-pyrazol-1-yl)-pyrazin-2-yl]-carbamic acid tert-butyl ester (225 mg, 43%) as an yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[CH:10][C:11]([F:20])=[C:12]([N:14]3[CH2:18][CH2:17][CH2:16][C:15]3=[O:19])[CH:13]=2)=[CH:4][CH:3]=1.[CH3:23][N:24]1[CH:28]=[C:27]([S:29](Cl)(=[O:31])=[O:30])[N:26]=[CH:25]1.N1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]([C:8]2[CH:9]=[CH:10][C:11]([F:20])=[C:12]([N:14]3[CH2:18][CH2:17][CH2:16][C:15]3=[O:19])[CH:13]=2)[S:29]([C:27]2[N:26]=[CH:25][N:24]([CH3:23])[CH:28]=2)(=[O:31])=[O:30])=[CH:4][CH:3]=1
Reactant: O=C1CCCN1c1cc(NCc2ccc(Cl)cc2)ccc1F
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1cnc(S(=O)(=O)N(Cc2ccc(Cl)cc2)c2ccc(F)c(N3CCCC3=O)c2)c1
Yield: 42.1 %

Procedure:
1-[5-(4-Chloro-benzylamino)-2-fluoro-phenyl]-pyrrolidin-2-one (32 mg, 0.1 mmol), 1-methylimidazole-4-sulfonyl chloride (54 mg, 0.3 mmol) and pyridine (24 ul, 0.3 mmol) were refluxed in dry dichloromethane (3 ml) for 18 hrs. The reaction mixture was concentrated in vacuo and the residue purified by preparative HPLC to afford the title compound as a yellow oil (19.5 mg, 42%). HPLC retention time 4.3 min, Mass spectrum (ES+) m/z 464 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[O:16][CH2:17][C:18]([OH:20])=O)[CH3:2].[CH:21]([NH:24][NH:25][C:26](=[O:38])[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:29][CH:28]=1)([CH3:23])[CH3:22].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[F:15][C:13]1[CH:12]=[CH:11][C:10]([O:16][CH2:17][C:18]([N:24]([CH:21]([CH3:23])[CH3:22])[NH:25][C:26](=[O:38])[C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:31][CH:32]=2)=[O:20])=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:1][CH3:2])[CH:14]=1
Reactant: COCCOc1ccc(C(=O)NNC(C)C)cc1
Reactant: CCc1ccccc1-c1cc(F)ccc1OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1ccccc1-c1cc(F)ccc1OCC(=O)N(NC(=O)c1ccc(OCCOC)cc1)C(C)C
Yield: 7.8 %

Procedure:
A solution of (2′-ethyl-5-fluoro-biphenyl-2-yloxy)-acetic acid (38 mg, 0.1395 mmol), and 4-(2-methoxy-ethoxy)-benzoic acid-N′-isopropyl hydrazide (32 mg, 0.1268 mmol) in DMF (5 mL), was treated with triethylamine (0.053 ml, 0.38 mmol), HOBT (20 mg, 0.152 mmol), and EDCI (29 mg, 0.152 mmol) for 12 hours at room temperature. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 50-100% ethyl acetate/hexanes gradient to afford the product as a white solid (5 mg, 7%). MS m/e 509.42 (M+H+)
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][C@H:6]([NH:22][C:23](=[O:36])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1.[OH-].[Na+]>CO.C1COCC1>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C@@H:6]([NH:22][C:23](=[O:36])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:5][CH2:4][C:3]([OH:37])=[O:2])=[CH:9][CH:10]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)CC[C@@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)CCCCCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CC[C@@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)CCCCCCc1ccccc1

Procedure:
(S)-5-(4-Benzyloxy-phenyl)-4-(7-phenyl-heptanoylamino)-pentanoic acid methyl ester (0.86 g, 1.7 mmol) and NaOH solution (4 M, 0.85 mL, 3.4 mmol) in MeOH-THF (1:1, 6 mL) was stirred at room temperature overnight. The solvent was removed, and the residue diluted with water. The solution was washed with Et2O, acidified with 5% aqueous HCl, and extracted with EtOAc. The organic phase was then washed with brine, dried Na2SO4) and the solvent removed under reduced pressure to afford (63), 0.81 g (98%), m.p. 127.7-129.5° C. 1H NMR (DMSO-d6) δ 1.13-1.23 (6H, m, 3×CH2), 1.35-1.44 (2H, m, CH2), 1.47-1.54 (2H, m, CH2), 1.95-2.00 (2H, m, CH2), 2.14-2.22 (2H, m, CH2), 3.86 (1H, br s, H58□ 5.02 (2H, s, OCH2Ph), 6.89 (2H, d, J=8.6 Hz), 7.08 (2H, d, J=8.5 Hz), 7.15-7.44 (10H, m, 10×Ar—H), 7.50 (1H, br d, J=8.6 Hz, NH), 12.01 (1H, br s, CO2H). 13C NMR (DMSO-d6) δ 25.3, 28.4, 28.5, 29.3, 30.5, 31.0, 35.2, 35.5, 49.3, 114.3, 125.6, 127.7, 127.8, 128.2, 128.4, 130.1, 131.1, 137.2, 142.3, 156.7, 171.7, 174.3.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[CH3:26][S:27]([C:30]1[CH:31]=[C:32]([NH:36]N)[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28]>>[CH3:26][S:27]([C:30]1[CH:31]=[C:32]([N:36]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:24])[F:22])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:33]=[CH:34][CH:35]=1)(=[O:28])=[O:29]
Reactant: CS(=O)(=O)c1cccc(NN)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Product: CS(=O)(=O)c1cccc(-n2nccc2-c2nn(-c3ccc(OC(F)(F)F)cc3)ccc2=O)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and (3-methanesulfonyl-phenyl)-hydrazine according to the method described for example 91. MS: M=477.0 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[F:19][C@@H:20]1[CH2:24][CH2:23][NH:22][CH2:21]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:23][CH2:24][C@@H:20]([F:19])[CH2:21]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: F[C@@H]1CCNC1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Product: Fc1ccc(C2CCc3c2nc(Cl)nc3N2CC[C@@H](F)C2)cc1

Procedure:
2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) was reacted as described in Preparation Hp1 and Hp2 with (R)-3-fluoropyrrolidine. The solvent was removed and the residue applied to Silica gel and eluted with an EtOAc/Hex gradient to afford the combined two diasteriomers (Hq). Ha1: LC-MS (M+H)+=336.0.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](I)[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:13])[CH:3]=1.[C:14]([Cu])#[N:15].CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([F:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:10]([C:14]#[N:15])[CH:11]=1
Reactant: COC(=O)c1c(F)cc(Cl)cc1I
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(F)cc(Cl)cc1C#N
Temperature: 110 °C
Yield: 22.3 %

Procedure:
Methyl 4-chloro-2-fluoro-6-iodobenzoate (1.99 g, 10.6 mmol) was dissolved in DMF (12 mL). CuCN (2.84 g, 31.7 mmol) was added and the suspension was heated under microwave at 110° C. for 18 min. EtOAc was added and the suspension was filtered through a piece of filter paper. The filtrate was washed three times with water. The aqueous layers were combined and extracted once with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified on a silica gel column (heptane:EtOAc 1:0 to 9:1) to give the product as a colorless solid (505 mg). 1H NMR (400 MHz, CDCl3) δ ppm 7.56 (s, 1H), 7.40 (d, 1H, J=8 Hz), 4.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ ppm 161.78 (d, J=58 Hz), 159.44, 139.16 (d, J=11 Hz), 129.96, 121.99, 121.74, 115.48, 114.72, 53.04.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[S:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N+:9]([O-])[C:8]=2[CH:7]=[C:6]([C:19]([F:22])([F:21])[F:20])[CH:5]=1)([O-:3])=[O:2].P(OCC)(OCC)OCC>C(O)C>[N+:1]([C:4]1[C:12]2[S:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:9][C:8]=2[CH:7]=[C:6]([C:19]([F:22])([F:21])[F:20])[CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)c1sc2c([N+](=O)[O-])cc(C(F)(F)F)cc2[n+]1[O-]
Agent: CCOP(OCC)OCC
Solvent: CCO
Product: CCOC(=O)c1nc2cc(C(F)(F)F)cc([N+](=O)[O-])c2s1

Procedure:
A suspension of 20 g (59.48 mmol) of ethyl 7-nitro-5-(trifluoromethyl)-1,3-benzothiazole-2-carboxylate-3-oxide, the synthesis of which is carried out according to a process already described in the literature (K. Wagner et al.; Chem. Ber. 106, 640-654, 1973), in 300 ml of ethanol is stirred at AT. After the addition, dropwise, of 11.22 ml (65.43 mmol) of triethyl phosphite, the reaction mixture is stirred at 70° C. for 2 hours, during which time it becomes homogeneous and yellow. Silica is then added thereto and the solvent is evaporated off under reduced pressure. The powder obtained is loaded onto a silica column. The purification is carried out using a cyclohexane/ethyl acetate mixture. The fractions of pure product are evaporated and the residue is taken up with petroleum ether, filtered, and then rinsed with a minimum amount of ethyl ether. After drying at 40° C., under reduced pressure, 16.98 g of expected compound are obtained.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([CH:18]=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:21][CH2:20]1)([OH:17])=[O:16].N1CCCCC1>>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14][C:19]2([CH2:18][C:15]([OH:17])=[O:16])[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH2:21][CH2:20]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Sc1ccc(Oc2ccccc2)cc1
Solvent: C1CCNCC1
Product: O=C(O)CC1(Sc2ccc(Oc3ccccc3)cc2)CCN(C(=O)OCc2ccccc2)CC1

Procedure:
4-Phenoxythiophenol (7.4 g, 36.3 mmol), 4-carboxymethylene-N-CBZ-piperidine (10 g, 36.3 mmol) and piperidine (1.8 ml, 36.3 mmol) were stirred overnight at 100-110° C. in a sealed flask. After cooling, the crude reaction mixture was partitioned between ethyl acetate and 1N hydrochloric acid, the organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give a yellow solid. The solid was triturated in 1:1 (v/v) ethyl ether/hexane (500 ml) to give 2-[4-(4-phenoxyphenylthio)-N-CBZ-piperidin-4-yl]-acetic acid as a white solid.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[NH2:11][CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1>C(O)C>[CH2:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][CH:12]1[NH:11][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: NC1Cc2ccccc2C1
Solvent: CCO
Product: c1ccc2c(c1)CC(Nc1ncnc3nc[nH]c13)C2
Yield: 40 %

Procedure:
Using 6-chloropurine (150 mg, 1.0 mmol), 2-aminoindan (200 mg, 1.5 mmol), and ethanol (6 ml), a similar procedure to Example 1 was carried out. The precipitate obtained was crystallized from ethanol to obtain the title compound (100 mg, 0.40 mmol) having the following physical properties:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](O)=O)[C:5]([O:11]C)=[CH:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[C:15]=1[NH2:21].C([O-])([O-])=O.[Na+].[Na+]>>[Br:1][C:2]1[N:7]=[C:6]([C:8]2[NH:20][C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[C:15]=3[N:21]=2)[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: Nc1cccc(F)c1N
Reactant: COc1ccc(Br)nc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Oc1ccc(Br)nc1-c1nc2c(F)cccc2[nH]1
Temperature: 120 °C
Reaction time: 14 h
Yield: 36.8 %

Procedure:
A mixture of 6-bromo-3-methoxypicolinic acid (1.84 g, 7.93 mmol) and 3-fluorobenzene-1,2-diamine (1.0 g, 7.93 mmol) was stirred in PPA (3 mL) on a pre-heated oil-bath at 120° C. for 14 h. The mixture was poured to ice-water and basified to pH=8 with Na2CO3. Then the mixture was filtrated to collect the brown solid as 6-bromo-2-(4-fluoro-1H-benzo[d]imidazol-2-yl)pyridin-3-ol (900 mg, yield: 37%). The filtrated was extracted with ethyl acetate, and the organic layer was washed with brine and dried over Na2SO4. After concentrated, the residue was purified by column chromatography to give the product of 2-(6-bromo-3-methoxypyridin-2-yl)-4-fluoro-1H-benzo[d]imidazole (350 mg, yield: 14%). 1H-NMR (CDCl3, 400 MHz) δ 10.43˜10.56 (m, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H), 7.21˜7.30 (m, 2H), 6.90˜6.98 (m, 1H), 4.05 (s, 3H). MS (M+H)+: 322/324.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].Cl[CH:12]([O:14]C)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:5]([OH:9])=[CH:4][C:3]=1[CH3:10])[CH:12]=[O:14]
Reactant: Cc1cc(O)cc(C)c1Cl
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(O)c(C=O)c(C)c1Cl
Temperature: 2 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-chloro-3,5-dimethylphenol (16 g, 0.1 mole) in dichloromethane (100 ml) was stirred and cooled to 2° C. in an ice bath. Titanium tetrachloride (35 g, 0.18 mole) was added dropwise over a period of 10 minutes and dichloromethylmethyl ether (11.5 g, 0.1 mole) was added slowly to the dark red solution, the temperature being kept below 10° C. throughout. After the solution had been stirred at 5° C. for 30 minutes the temperature was allowed to rise and to remain at 20° C. for 30 minutes. Finally the solution was warmed at 35° C. for 15 minutes and then poured into ice water (200 ml). The mixture was shaken vigorously until almost colourless and then the dichloromethane layer was separated and the aqueous phase was extracted with more dichloromethane (2×50 ml). The combined organic layers were washed with water thoroughly (4×200 ml) and then dried over anhydrous magnesium sulphate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure using a rotary evaporator. The product, 3-chloro-6-hydroxy-2,4-dimethylbenzaldehyde was isolated as a white solid (13 g, 70%), mp 89°-90° C. Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 2.40 (3H, s); 2.64 (3H, s); 6.71 (1H, s); 10.23 (1H, s); 11.91 (1H, s).
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Cl.[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl>CN(C)C(=O)C>[CH2:6]([NH:13][CH2:3][CH:2]([F:5])[F:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: FC(F)CCl
Reactant: NCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: FC(F)CNCc1ccccc1
Yield: 90.2 %

Procedure:
An amount of 10 g (92 mmol) of 2,2-difluoro-1-chloroethane, 5 g (46 mmol) of benzylamine and 5.2 g (51 mmol) of triethylamine are heated in 18.7 g of N,N-dimethylacetamide in an autoclave at an internal temperature of 120° C. for 6 hours. Subsequently, 100 g of 1N hydrochloric acid are added and the solvent is removed under vacuum. The residue is taken up in 30 ml of dichloromethane and adjusted to pH 8 with solid sodium hydrogencarbonate. The phases are subsequently separated and the aqueous phase is again extracted with 20 ml of dichloromethane. The organic phase is distilled. An amount of 7.1 g of N-benzyl-2,2-difluoroethanamine is obtained, which corresponds to a yield of 90%, based on benzylamine
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46](=[O:53])[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:55](C(C)(C)C)=[C:56]=[O:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46]([N:47]1[CH2:52][CH2:51][N:50]([C:56]([NH2:55])=[O:57])[CH2:49][CH2:48]1)=[O:53]
Reactant: CC(C)(C)N=C=O
Reactant: O=C(COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)N1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)N1CCN(C(=O)COc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 60 %

Procedure:
The desired compound was prepared according to the procedures of Example D41, using 6-chloro-12-(2-oxo-2-piperazin-1-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 2-isocyanato-2-methylpropane as the starting materials, and Example D87 in 60% yield (2 steps). LCMS for C24H26ClN8O3 (M+H)+: m/z=509.0.