Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.C([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(OC(C)(C)C)=O.CCN(CC)CC>CCO>[CH:9]1([C:4]2[CH:5]=[C:6]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:7]=[C:2]([NH2:1])[N:3]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Nc1nc(Cl)cc(C2CCCC2)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1nc(C2CCCC2)cc(N2CCNCC2)n1
Temperature: 25 °C
Yield: 18.1 %

Procedure:
A solution of crude 2-amino-4-chloro-6-cyclopentylpyrimidine (150 mg, 0.76 mmol), N-BOC piperazine (184 mg, 0.99 mmol) and Et3N (210 uL, 1.5 mmol) in EtOH (2 mL) was heated at 70° C. for 16 h. The reaction was cooled to rt and concentrated and the crude residue purified (2 M NH3 in MeOH/CH2Cl2) to yield a white solid (34 mg, 11%). MS (ESI): mass calcd. for C18H29N5O2, 347.2; m/z found, 348.3 [M+H]+. 1H NMR (MeOD): 6.01 (s, 1H), 3.66-3.58 (m, 4H), 3.53-3.43 (m, 4H), 3.33 (td, J=3.3, 1.6, 1H), 2.90-2.75 (m, 1H), 2.05-1.90 (m, 2H), 1.87-1.77 (m, 2H), 1.77-1.62 (m, 4H), 1.53-1.46 (m, 9H).
Reaction SMILES: NC1N=C(OCCCC)N=C2C=1N=C(OC)N2CCCC1CCCCN1C(OCC1C=CC=CC=1)=O.FC(F)(F)C(O)=O.[CH3:44][C@H:45]([O:49][C:50]1[N:58]=[C:57]2[C:53]([N:54]=[C:55]([O:59][CH3:60])[NH:56]2)=[C:52]([NH2:61])[N:51]=1)[CH2:46][CH2:47][CH3:48].Br[CH2:63][CH2:64][CH2:65][CH2:66][CH:67]1[CH2:72][CH2:71][CH2:70][N:69]([C:73]([O:75][CH2:76][C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)=[O:74])[CH2:68]1>>[NH2:61][C:52]1[N:51]=[C:50]([O:49][C@@H:45]([CH3:44])[CH2:46][CH2:47][CH3:48])[N:58]=[C:57]2[C:53]=1[N:54]=[C:55]([O:59][CH3:60])[N:56]2[CH2:63][CH2:64][CH2:65][CH2:66][CH:67]1[CH2:72][CH2:71][CH2:70][N:69]([C:73]([O:75][CH2:76][C:77]2[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=2)=[O:74])[CH2:68]1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)[nH]c2n1
Reactant: O=C(OCc1ccccc1)N1CCCC(CCCCBr)C1
Agent: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCC3CCCN(C(=O)OCc4ccccc4)C3)c2n1

Procedure:
Prepared similarly to Intermediate 31 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9H-purin-6-amine trifluoroacetate salt and phenylmethyl 3-(4-bromobutyl)-1-piperidinecarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:32]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.Cl.C([O-])(O)=O.[Na+]>>[CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH2:32])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)[C@@H](N)Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-{(S)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-propionic acid methyl ester was treated with HCl according to General Procedure C and followed by aqueous NaHCO3 wash to give (S)-2-amino-3-{(S)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-propionic acid methyl ester. This was subjected to alkylation with (1-bromo-propyl)-benzene according to General Procedure P. Resulting product was purified on silica gel to give (S)-3-{(S)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-((R)-1-phenyl-propylamino)-propionic acid methyl ester (slower moving diastereomer). LCMS (m/z): 606. 1H NMR (400 MHz, Acetone-d6) 7.72 (d, 1H), 7.62 (d, 1H), 7.48 (m, 1H) 7.44 (d, 2H), 7.3 (m, 4H), 7.22 (m, 1H) 7.10 (d, 1H) 6.8 (d, 1H) 6.74 (d, 1H) 6.68 (m, 1H) 5.2 (s, 2H) 5.1 (m, 1H) 4.35 (m, 1H) 4.0 (m, 1H) 3.56 (t, 1H) 3.45 (s, 3H) 3.40 (t, 1H) 3.15 (s, 3H) 2.9 (m, 2H) 1.74 (m, 1H) 1.56 (m, 1H) 0.75 (t, 3H).
Reaction SMILES: [H-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][OH:14].Cl[C:16]1[N:21]=[CH:20][C:19]([C:22](OC)=[O:23])=[CH:18][CH:17]=1.O>CN(C)C=O>[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][O:14][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][OH:23])=[CH:20][N:21]=1
Reactant: OCc1ccc2ccccc2n1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCc1ccc(OCc2ccc3ccccc3n2)nc1
Reaction time: 1 h
Yield: 50.5 %

Procedure:
Sodium hydride (60%, oily, 1.58 g) was added to a solution of 2-quinolylmethanol (6.29 g) and methyl 6-chloro-3-pyridinecarboxylate (6.78 g) in N,N-dimethylformamide (100 ml) at 0° C., and the mixture was stirred for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. Lithium aluminium hydride (1.50 g) was added to a solution of the residue in tetrahydrofuran (150 ml) at 0° C., which was stirred at room temperature for 10 minutes. Sodium sulfate decahydrate (12.7 g) was added to the reaction mixture, which was stirred at room temperature for 1 hour. The precipitate was removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 2-(2-quinolylmethoxy)-5-pyridylmethanol (5.31 g, yield 50%) as colorless crystals from the fraction eluted with ethyl acetate. This was recrystallized from ethyl acetate-hexane. Melting point: 124–125° C.
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([CH:16]1[O:21][CH2:20][CH2:19][N:18](CC2C=CC=CC=2)[CH2:17]1)([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[OH:9].CCN(C(C)C)C(C)C.[Cl:44]C(OC(Cl)C)=O>C(Cl)Cl.CO>[ClH:44].[C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([CH:16]1[O:21][CH2:20][CH2:19][NH:18][CH2:17]1)([CH:10]1[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1)[OH:9]
Reactant: CC(Cl)OC(=O)Cl
Reactant: OC(Cc1ccccc1-c1ccccc1)(C1CCOCC1)C1CN(Cc2ccccc2)CCO1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cl
Product: OC(Cc1ccccc1-c1ccccc1)(C1CCOCC1)C1CNCCO1

Procedure:
The free base of 56 is obtained from 55 (0.588 g, 1.28 mmol), solid supported Hünig's base (0.72 g) and α-chloroethyl chloroformate (0.53 mL) in anhydrous DCM (20 mL) following General Procedure 3. Purification by ion exchange chromatography gives the free base of 56 as viscous oil (0.483 g), contaminated with a small amount of the N-protected compound 55. The residue is treated with an excess of reagents (1 eq), solid supported Hünig's base (0.36 g) and α-chloroethyl chloroformate (0.26 mL) in anhydrous DCM (20 mL) and methanol (20 mL) and purified by ion exchange chromatography to give the free base of 56 (0.432 g). Purification by preparative LCMS followed by conversion to its hydrochloride salt following General Procedure 4 gives 56 (0.280 g, 54%). MW 403.95; C23H29NO3.HCl; 1H NMR (CD3OD): δ 7.45-7.59 (1H, m), 7.10-7.35 (8H, m), 3.85 (1H, dd, 13 Hz, 3.5 Hz), 3.75 (1H, dd, 11.5 Hz, 3.5 Hz), 3.51-3.59 (3H, m), 2.83-3.12 (7H, m), 2.64 (1H, t, 12 Hz), 1.36-1.52 (2H, m), 1.02-1.21 (2H, m), 0.90-0.94 (1H, m); LCMS: (12 min method) m/z 368 [M−HCl+H]+, RT 4.6 min.
Reaction SMILES: FC(F)(F)C(O[C:6](=[O:11])[C:7](F)(F)F)=O.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(Cl)Cl.C1C[O:26]CC1>>[C:15]([C:16]1[CH:7]=[C:6]([OH:11])[CH:19]=[CH:18][C:17]=1[OH:26])#[N:14]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: c1ccncc1
Reactant: C1CCOC1
Solvent: ClCCl
Product: N#Cc1cc(O)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
Trifluoroacetic anhydride (3.06 mL, 22 mmoles) was added dropwise to a stirred, ice-cooled solution of 34 (770 mg, 5.0 mmoles) in 10 mL of dry THF and anhydrous pyridine (3.23 mL, 40 mmoles) at such a rate that the temperature was kept below 5° C. The addition was over in 30 minutes. The reaction mixture was then allowed to warm to room temperature and stirred for another 16 hr. 650 mL of CH2Cl2 was added and the organic solution was washed with water (3×10 mL) and saturated brine (3×15 mL), dried on Na2SO4 and evaporated under reduced pressure. The crude product was applied to silica gel (230-400 mesh, ethyl acetate) to yield 462 milligrams (68%) of 20.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]([N:27]([CH:36]([CH3:38])[CH3:37])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)=[O:26]>CN(C)C=O>[F:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([NH:16][CH2:24][C:25]([N:27]([CH:36]([CH3:38])[CH3:37])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[O:26])=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=1
Reactant: Nc1cc(F)c(F)cc1Nc1ccccc1
Reactant: COc1ccc(N(C(=O)CBr)C(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CNc2cc(F)c(F)cc2Nc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.8 %

Procedure:
A mixture of 3.004 g of 4,5-difluoro-N-phenyl-benzene-1,2-diamine (J. Gen. Chem. USSR (Engl. Transl.), 1964, 34), 1.910 g of potassium carbonate (13.82 mmol, 1.0 equiv), and 3.956 g of 2-bromo-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (13.82 mmol, 1.0 equiv) in 20 mL of dimethylformamide is stirred under nitrogen at ambient temperature for 16 h. An additional 3.00 g of 2-bromo-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (10.5 mmol, 0.75 equiv) is added and the reaction is heated at 50° C. for 2 h. The mixture is cooled to ambient temperature and then partitioned between diethyl ether and 1:1 water/saturated aqueous brine. The layers were separated and the aqueous layer is back-extracted twice with diethyl ether. The ether layers were combined, washed with saturated aqueous brine, dried over anhydrous sodium sulfate and then evaporated in vacuo to a residue. The residue is purified on flash grade silica gel using 10-20% ethyl acetate in hexane. The appropriate fractions were combined, evaporated in vacuo and dried under vacuum to provide 5.62 g of 2-(4,5-Difluoro-2-phenylamino-phenylamino)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide as a solid: Low resolution MS (FAB)m/e 425 (M+); TLC Rf =0.43 (ethyl acetate/hexane 3:7).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][NH:11][CH3:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>C(#N)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][NH:11][CH2:12][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: BrCc1ccccc1
Reactant: CNCc1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1cccc(CNCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a solution of the compound (630 mg) obtained in Example 42 and triethylamine (768 mg) in acetonitrile (20 ml), benzyl bromide (778 mg) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 h and, after addition of water, extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=4:1) to give 925 mg of the titled compound (yield, 95%).
Reaction SMILES: C1(N2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=CC=CC=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.[CH2:49]([NH2:54])[C:50]([CH3:53])([CH3:52])[CH3:51]>C(O)(=O)C>[CH2:49]([N:54]1[C:12](=[O:13])[C:11]2[S:14][CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[N:9]=[CH:8]1)[C:50]([CH3:53])([CH3:52])[CH3:51]
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: CC(C)(C)CN
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: CC(C)(C)Cn1cnc2c(-c3ccccc3)csc2c1=O
Yield: 35.7 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), neopentylamine (0.117 ml, 0.99 mmol), and acetic acid (0.1 ml) were used to give 45.8 mg (0.15 mmol, 35.7% yield) of the title compound.
Reaction SMILES: [OH:1][N:2]=[C:3]([Cl:12])[C@:4]1([CH3:11])[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5]1.[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C>CCOCC>[CH3:10][C:6]1([CH3:9])[O:5][C@:4]([CH3:11])([C:3]([Cl:12])=[N:2][O:1][S:14]([CH3:13])(=[O:16])=[O:15])[CH2:8][O:7]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OC[C@@](C)(C(Cl)=NO)O1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC1(C)OC[C@@](C)(C(Cl)=NOS(C)(=O)=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
(S)-N-hydroxy-2,2,4-trimethyl-1,3-dioxolane-4-carbimidoyl chloride (5.5 g, 28.4 mmol) was dissolved in Et2O (150 mL) and methanesulfonyl chloride (2.21 ml, 28.4 mmol) was added. Triethylamine (3.96 ml, 28.4 mmol) was added dropwise and the reaction was stirred at ambient temperature for 1 hour. The resulting solids were filtered and the filtrate concentrated. The residue was purified over silica gel (100% CH2Cl2) to afford (S)-2,2,4-trimethyl-N-(methylsulfonyloxy)-1,3-dioxolane-4-carbimidoyl chloride (4.7 g, 17.3 mmol, 60.9% yield) as an amber oil.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].N1C=CC=CC=1.[CH3:17][C:18]([CH3:23])([CH3:22])[C:19](Cl)=[O:20].O>CC(C)=O>[CH3:17][C:18]([CH3:23])([CH3:22])[C:19]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])=[O:20]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(O)c1ccccc1O
Solvent: O
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 105 %

Procedure:
10 g (72.4 mmol) of salicylic acid and 6.1 ml (76 mmol) of pyridine are placed in 100 ml of acetone at −5° C. 9.3 ml (76 mmol) of 2,2-dimethylpropionyl chloride are added and, after stirring at ambient temperature for 2 hours, water is added and the mixture is extracted with dichloromethane. The organic phase is dried over magnesium sulphate, filtered and concentrated. The residue is precipitated from heptane at 0° C. and then filtered off. 16.9 g of 2-(2,2-dimethylpropionyloxy)benzoic acid are obtained in the form of a white powder with a yield of 95%.
Reaction SMILES: C(O[CH2:5][C:6]1[N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:8](=[O:15])[C:9]([C:13]#[N:14])=[C:10](Cl)[CH:11]=1)(=O)C.[OH2:23].[NH2:24][NH2:25]>C(O)C>[NH2:14][C:13]1[C:9]2[C:8](=[O:15])[N:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]([CH2:5][OH:23])=[CH:11][C:10]=2[NH:25][N:24]=1
Reactant: NN
Reactant: CC(=O)OCc1cc(Cl)c(C#N)c(=O)n1-c1ccccc1Cl
Reactant: O
Solvent: CCO
Product: Nc1n[nH]c2cc(CO)n(-c3ccccc3Cl)c(=O)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.6 %

Procedure:
To a solution of (4-chloro-1-(2-chlorophenyl)-5-cyano-6-oxo-1,6-dihydropyridin-2-yl)methyl acetate obtained in Step G (670 mg) in ethanol (3.97 mL) was added hydrazine monohydrate (398 mg) at room temperature. The reaction mixture was stirred at room temperature for 5 hr. The resulting solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (500 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([N:28]2[CH2:33][CH2:32][N:31]([CH2:34][C:35]([O:37]C)=[O:36])[CH2:30][CH2:29]2)[CH2:11][O:12][CH2:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=2)=[CH:6][CH:5]=1.[OH-].[K+]>CO>[OH2:2].[CH3:1][O:2][C:3](=[O:39])[C:4]1[CH:5]=[CH:6][C:7]([CH:10]([N:28]2[CH2:29][CH2:30][N:31]([CH2:34][C:35]([OH:37])=[O:36])[CH2:32][CH2:33]2)[CH2:11][O:12][CH2:13][C:14]2[CH:19]=[C:18]([C:20]([F:22])([F:23])[F:21])[CH:17]=[C:16]([C:24]([F:25])([F:26])[F:27])[CH:15]=2)=[CH:8][CH:9]=1.[F:23][C:20]([C:18]1[CH:19]=[C:14]([CH:15]=[C:16]([C:24]([F:25])([F:26])[F:27])[CH:17]=1)[CH2:13][O:12][CH2:11][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:39])=[CH:9][CH:8]=1)[N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([OH:37])=[O:36])[CH2:30][CH2:29]1)([F:22])[F:21]
Reactant: COC(=O)CN1CCN(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(C(=O)OC)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)N2CCN(CC(=O)O)CC2)cc1
Product: O
Temperature: 0 °C
Reaction time: 8 h
Yield: 104.6 %

Procedure:
In a round-bottomed flask was introduced 4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-(4-methoxycarbonylmethyl-piperazin-1-yl)-ethyl]-benzoic acid methyl ester (compound 316 prepared at example 2 above; 2.17 g, 3.86 mmoles) dissolved in MeOH (30 ml). To this solution cooled at 0° C. was added KOH (0.54 g, 9.62 mmoles) dissolved in MeOH (20 ml). The reaction mixture was allowed to stand at room temperature overnight. The reaction was cooled to 0° C., quenched by addition of HCl 0.1 N and extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated. The residu was purified by chromatography on silica gel (eluent: CH2Cl2/MeOH/H2O: 95/5/0.5) to yield 4-[2-(3,5-bis-trifluoromethyl-benzyloxy)-1-(4-carboxymethyl-piperazin-1-yl)-ethyl]-benzoic acid methyl ester hemihydrate (compound 318; 1.5 g, 71%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[C:5]#[N:6].[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.O>CS(C)=O>[C:5]([C:4]1[CH:3]=[C:2]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=1)#[N:6]
Reactant: N#Cc1cc(F)cc(C(F)(F)F)c1
Reactant: C1CNCCN1
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc(N2CCNCC2)cc(C(F)(F)F)c1
Yield: 89.2 %

Procedure:
2.42 g (13 mmol) 3-fluoro-5-trifluoromethyl-benzonitrile and 6.0 g (70 mmol) piperazine was dissolved in 50 ml dimethylsulfoxide and the solution was refluxed for one day. The mixture was poured into 200 ml of water and extracted with diethylether (3×100 ml). The organic layers were washed with saturated sodium chloride solution, then dried and evaporated to dryness in vacuo giving 2.96 g (yield 89.2%) of the title compound, melting at 85-7° C.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([F:32])=[C:6]2[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.C([Sn]([C:46]#[N:47])(CCCC)CCCC)CCC.[O:48]1CCOCC1>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>[F:32][C:5]1[CH:4]=[N:3][C:2]([C:46]([NH2:47])=[O:48])=[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:31])[C:12](=[O:13])[N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)[C:6]=12
Reactant: O=C(C(=O)N1CCN(c2nnnn2-c2ccccc2)CC1)c1c[nH]c2c(Br)ncc(F)c12
Reactant: C1COCCO1
Reactant: CCCC[Sn](C#N)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: NC(=O)c1ncc(F)c2c(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c[nH]c12
Temperature: 100 °C

Procedure:
To a sealable flask containing 1-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (1.0 g, 2.0 mmol) in 1,4-dioxane (20 mL) was added tributyltin cyanide (0.70 g, 2.2 mmol) followed by Pd(PPh3)4 (0.12 g, 0.1 mmol). The mixture was flushed with N2, and the tube was sealed and heated to 100° C. After 20 h of heating, the mixture was cooled to rt, and was diluted with MeOH (50 mL) and was filtered through a pad of celite to remove solids. To the solution was added H2O (20 mL), and the mixture was heated with a heat gun. Solids formed upon cooling, and were collected by filtration. The solids were dissolved in DMF and were purified by prep HPLC to give the title compound as an off-white solid (30 mg). LCMS: m/e 464.11 (M+H)+, ret time 1.095 min (method 3). 1H NMR (500 MHz, DMSO-D6) δ ppm 12.78 (s, 1 H) 8.34 (d, J=2.14 Hz, 1 H) 8.30 (s, 1 H) 8.25 (d, J=3.36 Hz, 1 H) 7.88 (s, 1 H) 7.56-7.71 (m, 5 H) 3.67-3.72 (m, 2 H) 3.43-3.47 (m, 2 H) 3.30-3.34 (m, 2 H) 3.13-3.17 (m, 2 H).
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[CH2:4][CH2:5][O:6][C:7]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:8]=1[C:9]1[C:10]([O:28][CH3:29])=[CH:11][C:12]([O:24][CH2:25][CH2:26][CH3:27])=[C:13]([N+:21]([O-])=O)[C:14]=1[C:15]2=[O:20])[CH3:2].O.C(=O)(O)[O-].[Na+]>C(O)C.C(OCC)C>[NH2:21][C:13]1[C:14]2[C:15](=[O:20])[C:16]3[C:8](=[C:7]([O:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:30][CH3:31])[CH:19]=[CH:18][CH:17]=3)[C:9]=2[C:10]([O:28][CH3:29])=[CH:11][C:12]=1[O:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCOc1cc(OC)c2c(c1[N+](=O)[O-])C(=O)c1cccc(OCCN(CC)CC)c1-2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: CCCOc1cc(OC)c2c(c1N)C(=O)c1cccc(OCCN(CC)CC)c1-2

Procedure:
Prepare a solution, under argon, of 5-(2-diethylamino-ethoxy)-4-methoxy-1-nitro-2-propoxy-fluoren-9-one (0.52 g, 1.2 mmole) and stannous chloride (SnCl2, 1.3 g, 6 mmole) in 60 mL ethanol. Reflux overnight. Reduce volume on a rotovap. Add 200 mL deionized water and make basic with sodium bicarbonate. Extract with methylene chloride. Dry the organic layer with magnesium sulfate. Filter and evaporate on a rotary evaporator to give a red oil. Take up in anhydrous diethyl ether and filter through celite. Precipitate the hydrochloride salt by adding ethereal HCl. Filter the resulting red solid and wash with diethyl ether. Place under a high vacuum overnight at 100° C. to give the purified hydrochloride salt of the title compound. m.p. 163-165° C. Yield 0.338 g, 70%. Rf =0.33; 5% methanol/CH2Cl2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:35])=[C:21]([NH:25][S:26]([N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[NH4+:36].[OH-]>>[NH2:36][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:35])=[C:21]([NH:25][S:26]([N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)N1CCCCC1
Agent: [OH-]
Product: Nc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)N3CCCCC3)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 21 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1-piperidinesulfonamide (190 mg, 0.352 mmol) and NH4OH (4 mL) in a microwave reactor for 75 min at 120° C., the title compound was obtained an off-white solid (75 mg, 41% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.69 (s, 1H) 7.83 (d, J=5.3 Hz, 1H) 7.51 (td, J=7.4, 2.2 Hz, 1H) 7.05-7.38 (m, 2H) 6.54 (s, 2H) 5.79 (d, J=5.3 Hz, 1H) 3.68 (t, J=4.7 Hz, 4H) 3.43 (t, J=4.6 Hz, 4H), 3.01 (t, J=5.0 Hz, 4H) 1.33-1.52 (m, 6H). MS (ESI): 520.0 [M+H]+.