Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH:10]=[CH:11][C:5]=2[CH:4]=1.[I-:21].[Na+]>CC(C)=O>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][I:21])[CH:10]=[CH:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)C=C2
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc2c(cc1OC)CC(=O)N(CCCI)C=C2
Yield: 96.8 %

Procedure:
A suspension of 12 g of 7,8-dimethoxy-3-[3-chloropropyl]-1,3-dihydro-2H-3-benzazepin-2-one obtained in accordance with the method described in the literature (Reiffer M. et al., J. Med. Chem. 1990; vol 33 (5): 1496-1504) and 6.2 g of sodium iodide in 50 cm3 of acetone are refluxed for 24 hours. After filtration and evaporation to dryness of the solvent, the residue is taken up in water and extracted with dichloromethane. The extract is separated off, dried over anhydrous magnesium sulphate and then concentrated in vacuo to yield 15.2 g of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=2)[C:5]2[N:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1.C(N(CC)CC)C.[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([Cl:37])[CH:36]=1)[C:31](Cl)=[O:32]>O1CCOCC1>[CH3:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:31](=[O:32])[C:30]3[CH:29]=[C:28]([Cl:27])[CH:36]=[C:35]([Cl:37])[CH:34]=3)[CH:10]=2)[C:5]2[N:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: Cc1nc2cccnc2n(-c2cccc(N)c2)c1=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1nc2cccnc2n(-c2cccc(NC(=O)c3cc(Cl)cc(Cl)c3)c2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.3 %

Procedure:
To a solution of 2-methyl-4-(3-aminophenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (7.4 g) and triethylamine (5.72 ml) in dioxane was added 3,5-dichlorobenzoyl chloride (6.14 g) in dropwise. The mixture was stirred for 3 hours at room temperature. The reaction mixture was quenched by water and extracted with ethyl acetate (100 ml). The crude product was purified by chromatography to obtain 2-methyl-4-[3-(3,5-dichlorobenzoylamino)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (4.4 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:9]=[C:10]([C:15]2[O:19][C:18]([CH2:20][CH2:21][NH:22][C:23]([C:25]3[NH:29][N:28]=[C:27]([C:30](O)=[O:31])[CH:26]=3)=[O:24])=[CH:17][CH:16]=2)[CH:11]=[CH:12][C:13]=1[Cl:14]>>[Cl:7][C:8]1[CH:9]=[C:10]([C:15]2[O:19][C:18]([CH2:20][CH2:21][NH:22][C:23]([C:25]3[NH:29][N:28]=[C:27]([C:30]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:31])[CH:26]=3)=[O:24])=[CH:17][CH:16]=2)[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: C1COCCN1
Reactant: O=C(O)c1cc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)[nH]n1
Product: O=C(NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1)c1cc(C(=O)N2CCOCC2)n[nH]1
Yield: 17 %

Procedure:
The title compound was prepared as in Example 1 starting from morpholine and 5-{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylcarbamoyl}-1H-pyrazole-3-carboxylic acid. Crude product was purified by chromatography (CombiFlash, 1st column silica, eluent: 0-10% MeOH/DCM: 2nd column C-18 RP, eluent: 0-100% MeCN/water) to give 505 mg (17%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 2.95 (t, 1H), 3.56 (q, 1H), 3.62 (br s, 6H), 3.90 (br s, 2H), 6.34 (d, 1H), 7.02 (d, 1H), 7.08 (s, 1H), 7.62 (m, 2H), 7.85 (d, 1H), 8.61 (s, 1H), 13.94 (s, 1H).
Reaction SMILES: [CH2:1](O)[CH:2](O)[CH:3](O)[CH:4](O)[CH:5]=O.[NH2:11][C@H:12]([C:18]([OH:20])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17].[NH2:21][C@H:22]([C:30]([OH:32])=[O:31])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:29])[NH2:28].O=C[C@@H]([C@@H]([C@@H](CO)O)O)O>>[CH:2]1[CH:3]=[C:4]2[C:5](=[N:29][C:27]([NH:26][CH2:25][CH2:24][CH2:23][C@H:22]([NH2:21])[C:30]([OH:32])=[O:31])=[N:28]2)[N:17]([CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]([NH2:11])[C:18]([OH:20])=[O:19])[CH:1]=1
Reactant: O=CC(O)C(O)C(O)CO
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: NCCCC[C@H](N)C(=O)O
Agent: O=C[C@H](O)[C@H](O)[C@H](O)CO
Product: N[C@@H](CCCCn1cccc2nc(NCCC[C@H](N)C(=O)O)nc1-2)C(=O)O
Temperature: 80 °C

Procedure:
In order to confirm the pentose-derived nature of the native fluorophore 100 mM each of L-lysine, L-arginine and D-ribose were heated for 1 hour at 80° C. Injection of a small amount of this synthetic material on HPLC revealed a major fluorescent peak coeluting with the native fluorophore. (see FIG. 5) In order to substantiate the proposed structure, the synthetic fluorophore was prepared preparatively and purified. Total yield was 21 mg; i.e., 0.02% of the reactants.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[C:13]3=[C:14]([F:22])[CH:15]=[N:16][C:17]4[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=43)[CH2:10]2)[CH2:4][C@H:3]1[F:23].[O:24]=[C:25]1[CH2:30][O:29][C:28]2[CH:31]=[CH:32][C:33]([CH:35]=O)=[N:34][C:27]=2[NH:26]1.[Cl:37]CCl.CO>>[ClH:37].[F:22][C:14]1[CH:15]=[N:16][C:17]2[CH:18]=[CH:19][C:20](=[O:21])[N:11]3[CH2:10][CH:9]([CH2:8][N:5]4[CH2:6][CH2:7][C@H:2]([NH:1][CH2:35][C:33]5[CH:32]=[CH:31][C:28]6[O:29][CH2:30][C:25](=[O:24])[NH:26][C:27]=6[N:34]=5)[C@H:3]([F:23])[CH2:4]4)[C:13]=1[C:12]=23
Reactant: ClCCl
Reactant: N[C@H]1CCN(CC2Cn3c(=O)ccc4ncc(F)c2c43)C[C@H]1F
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Solvent: CO
Product: Cl
Product: O=C1COc2ccc(CN[C@H]3CCN(CC4Cn5c(=O)ccc6ncc(F)c4c65)C[C@H]3F)nc2N1
Yield: 88 %

Procedure:
The free base of the title compound was synthesised from 4-{[cis-4-amino-3-fluoro-1-piperidinyl]methyl}-3-fluoro-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde (for a synthesis see WO2003087098, Example 31(e)), according to the general method of Example 2(h), chromatographing with dichloromethane/methanol/0.88 ammonia 95:5:0.5, in 88% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:46]=[CH:47][CH:48]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([N:26]5[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][C:34]#[N:35])[CH2:28][CH2:27]5)[CH:23]=[CH:24][CH:25]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:46]=[CH:47][CH:48]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([N:26]5[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][C:34]#[N:35])[CH2:30][CH2:31]5)[CH:23]=[CH:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cccc(N5CCN(CCC#N)CC5)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: N#CCCN1CCN(c2cccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)c2)CC1
Yield: 7.6 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 3-(4-(3-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl) propanenitrile (86 mg, 0.13 mmol) was hydrolyzed by lithium hydroxide (27 mg, 6.525 mmol), THF/Methanol/water (15/4/4 ml) to yield 5 mg (5.6% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.481 (s, 1H), 8.407-8.402 (d, 1H), 8.198 (s, 1H), 7.955 (s, 1H), 7.674 (s, 1H), 7.48-7.292 (m, 4H), 7.123-6.98 (m, 4H), 5.439 (s, 2H), 3.8-3.4 (m, 4H), 3.2-3.0 (t, 2H). MS: m/z=506.4 (M+1); HPLC: 98.91% in method A.
Reaction SMILES: [S:1]1[C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([N:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=2)=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:13]([CH3:14])[C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C:5]2[S:1][C:2]3[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=3[CH:4]=2)=[CH:12][CH:11]=1
Reactant: CN(C)c1ccc(C(O)c2cc3ccccc3s2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1ccc(Cc2cc3ccccc3s2)cc1

Procedure:
2-(4-dimethyaminobenzyl)benzo[b]thiophene was prepared by the method of Example 47B with a-(2-benzo[b]thienyl)-4-dimethylaminobenzyl alcohol (7.5 mmoles, 2.1 g), triethylsilane (2.8 mmoles, 1.3 ml), CH2Cl2 (50 ml) and TFA (11.2 mmoles, 0.9 ml). Flash chromatography (10% ethyl acetate/hexanes) provided 1.5 g (73%—for two steps) of a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH:17]=[CH:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:28]#[N:29].[Na+]>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][C@H:16]4[C:28]#[N:29])[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1C=CC2=O
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1[C@H](C#N)CC2=O
Temperature: 75 °C
Yield: 50.2 %

Procedure:
This procedure is based on the literature method.22,23 A solution of 1.03 g (2.88 mmol) of 44, 2.03 g (41.5 mmol) of NaCN in THF (30 mL) with 21 drops of H2O was stirred and heated at 75° C. under reflux for 2 h. The reaction mixture was poured into ice water (300 mL) and extracted with CH2Cl2 (3×, 100 mL). Combined organic extracts were washed with H2O (100 mL), dried over Na2SO4 and concentrated in vacuo giving a brown oil. Purification by flash chromatography on a 3×17 cm column of silica gel using 2:1 hexanes/EtOAc as eluent gave 557 mg (50%) of 45 as a white solid. Data for 45: TLC, T-1, Rf 0.3; 1H NMR (400 MHz, CDCl3) δ 1.24 (s, 3H, H-18), 5.06 (s, 2H, benzylic-H), 6.76 (d, 1H, J=2.7 Hz, H-4), 6.81 (dd, 1H, J=8.6, 2.7 Hz, H-2), 7.20 (d, 1H, J=8.6 Hz, H-1), 7.33–7.45 (m, 5H, Ar—H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[NH2:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][CH:26]=[N:27]2)=[CH:22][CH:21]=1>CCOC(C)=O.[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:19][C:20]2[CH:29]=[C:28]3[C:23]([CH:24]=[CH:25][CH:26]=[N:27]3)=[CH:22][CH:21]=2)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)nnc2Cl)cc1
Reactant: Nc1ccc2cccnc2c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(-c2cc(Nc3ccc4cccnc4c3)nnc2Cl)cc1
Temperature: 220 °C
Reaction time: 0.33 h

Procedure:
(Analogous to the procedure of WO 178270). A mixture of 3,6-dichloro-4-(4-trifluoromethylphenyl)pyridazine, Example 81(d), (2.0 g, 6.8 mmol), 7-amino-quinoline (984 mg, 6.8 mmol) and ZnCl2 (980 mg, 3.4 mmol) was heated in a microwave with stirring at 220° C. for 20 min. The reaction mixture was cooled to room temperature, a second portion of 3,6-dichloro-4-(4-trifluoromethylphenyl)-pyridazine (2.0 g, 6.8 mmol), was added and the mixture was heated again in microwave at 220° C. for 40 min. The reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL) and washed with H2O (3×). The organic layer was dried over Na2SO4, filtered and the solvent evaporated in vacuo. The residue was purified by preparative thin layer chromatography, eluting with MeOH:CH2Cl2 (1:39), to give the title compound as a light-yellow powder. MS (ESI, pos. ion) m/z: 401 (M+1).
Reaction SMILES: [N:1]1([C:10]2[N:15]=[C:14]([NH:16][C@H:17]3[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19][CH2:18]3)[C:13]([N+:24]([O-])=O)=[CH:12][N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.O.CCOC(C)=O>[NH2:24][C:13]1[C:14]([NH:16][C@H:17]2[CH2:18][CH2:19][C@H:20]([OH:23])[CH2:21][CH2:22]2)=[N:15][C:10]([N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)=[N:11][CH:12]=1
Reactant: O=[N+]([O-])c1cnc(-n2cnc3ccccc32)nc1N[C@H]1CC[C@H](O)CC1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cnc(-n2cnc3ccccc32)nc1N[C@H]1CC[C@H](O)CC1
Reaction time: 0.42 h

Procedure:
A solution of trans-4-(2-(1H-benzo[d]imidazol-1-yl)-5-nitropyrimidin-4-ylamino)cyclohexanol (162 mg) in THF (20 ml) was treated with a solution of sodium hydrosulfite (500 mg) and NaHCO3 (500 mg) in 20 mL of water and stirred for 25 minutes. The mixture was diluted with 200 mL EtOAc and washed twice with saturated sodium chloride. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to provide 150 mg of the title compound.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[C:7]([O:11][C:12]([N:14]([C:22]1[C:27]([C:28]#[C:29][Si:30]([CH3:33])([CH3:32])[CH3:31])=[N:26][C:25]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:24][N:23]=1)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:13])([CH3:10])([CH3:9])[CH3:8].CCN(C(C)C)C(C)C>CN(C=O)C>[C:7]([O:11][C:12]([N:14]([C:22]1[C:27]([C:28]#[C:29][Si:30]([CH3:31])([CH3:33])[CH3:32])=[N:26][C:25]([N:34]2[CH2:35][CH2:36][N:37]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:38][CH2:39]2)=[CH:24][N:23]=1)[C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:13])([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(N2CCNCC2)nc1C#C[Si](C)(C)C
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N1CCN(c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C#C[Si](C)(C)C)n2)CC1
Reaction time: 0.08 h
Yield: 109.3 %

Procedure:
Ethanesulfonyl chloride (147.0 mg, 108.3 μL, 1.143 mmol) was added slowly to a stirred solution of tert-butyl N-tert-butoxycarbonyl-5-(piperazin-1-yl)-3-((trimethylsilyl)ethynyl)pyrazin-2-ylcarbamate (494 mg, 1.039 mmol) and DIPEA (161.2 mg, 217.3 μL, 1.247 mmol) in DMF (5 mL) at ambient temperature. The reaction was allowed to stir for 5 minutes and then partitioned between EtOAc/water. The aqueous layer was extracted with EtOAc (3×) and the combined organics washed with brine, dried (MgSO4), filtered and concentrated to give the product as a terracotta oil (645 mg, quantitative yield). MS (ES+) 590.05
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH2:18](O)[CH3:19]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([O:6][CH2:18][CH3:19])=[O:5]
Reactant: CCO
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc([N+](=O)[O-])ccc1C
Temperature: 0 °C

Procedure:
A mixture of 2-methyl-5-nitrobenzoic acid (10.0 g, 55.2 mmol) in ethanol (200 ml) was cooled to 0° C. with an ice bath and thionyl chloride (16.0 mL, 220 mmol) was added dropwise over 10 min. After this time, the mixture was warmed to room temperature for 1 h, then transferred to an oil bath and heated to reflux overnight. The mixture was then cooled to room temperature and concentrated under reduced pressure. Purification by flash chromatography (silica, 9:1 hexanes/ethyl acetate) afforded ethyl 2-methyl-5-nitrobenzoate (12.4 g, quant.) as a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ 8.76 (d, J=2.5 Hz, 1H), 8.24 (dd, J=8.5, 2.5 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 2.72 (s, 3H), 1.44 (t, J=7.1 Hz, 3H).
Reaction SMILES: CCN(CC)CC.[NH2:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12]([O:14]CC)=[O:13].N1P(Cl)(Cl)=NP(Cl)(Cl)=NP=1(Cl)Cl.[Br:32][C:33]1[C:34]([CH3:49])=[N:35][O:36][C:37]=1[NH:38][S:39]([CH:42]1[CH:46]=[CH:45][S:44][C:43]1=[C:47]=[O:48])(=[O:41])=[O:40]>C1COCC1.O>[Br:32][C:33]1[C:34]([CH3:49])=[N:35][O:36][C:37]=1[NH:38][S:39]([C:42]1[CH:46]=[CH:45][S:44][C:43]=1[C:47]([NH:8][C:9]1[CH:19]=[CH:18][CH:17]=[C:11]([C:12]([OH:14])=[O:13])[CH:10]=1)=[O:48])(=[O:40])=[O:41]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: Cc1noc(NS(=O)(=O)C2C=CSC2=C=O)c1Br
Agent: ClP1(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=N1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1noc(NS(=O)(=O)c2ccsc2C(=O)Nc2cccc(C(=O)O)c2)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.9 %

Procedure:
Et3N (2.27 ml. 16. mmol), ethyl 3-aminobenzoate (0.836 ml, 5.44 mmol) and phosphonitrilic chloride trimer (1.89 g, 5.44 mmol) were sequentially added to a solution of N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carbonyl)thiophene-3-sulfonamide (Example 17) (1 g, 2.27 mmol) in dry THF (20 ml). The reaction was stirred at room temperature for 1 hour and cooled. Water (5 ml) was added to quench the reaction. The resulting solution was concentrated on a rotavap. The residue was diluted with EtOAc and washed with 2N HCl (2×150 ml). The organic layer was dried (MgSO4). The solid was filtered off and the filtrate was concentrated. The residue was treated with 1 N NaOH (200 ml) and stirred at 0° C. for 15 minutes. The mixture was then acidified with conc. HCl to pH˜1. The resulting yellow precipitate was filtered off and recrystallized from CH3CN/H2O to give N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(3-carboxyphenyl)aminocarbonyl]thiophene-3-sulfonamide (153 mg., 11.6%) as a yellowish powder, m.p. 183-185° C.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][C@H:4]([CH2:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])[C:5]([OH:7])=O.[NH2:19][CH:20]([CH2:32][CH2:33][CH3:34])[C@@H:21]([C:23]1[O:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1)[OH:22]>>[O:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[C:21]([C@@H:20]([NH:19][C:5](=[O:7])[C@@H:4]([CH2:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])[CH2:3][C:2]([CH3:1])([CH3:18])[CH3:17])[CH2:32][CH2:33][CH3:34])=[O:22]
Reactant: CCCC(N)[C@H](O)c1nc2ccccc2o1
Reactant: CC(C)(C)C[C@H](CC(=O)N1CCOCC1)C(=O)O
Product: CCC[C@H](NC(=O)[C@@H](CC(=O)N1CCOCC1)CC(C)(C)C)C(=O)c1nc2ccccc2o1

Procedure:
It is similarly prepared according to general procedure given for example 10 above but using (R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid and (S)-2-Amino-1-benzoxazol-2-yl-pentan-1-ol.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:13])[CH2:8]2
Reactant: C1CCNC1
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Product: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1N1CCCC1

Procedure:
Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 88 mg; 0.30 mmol) and pyrrolidine (0.25 mL; 3.0 mmol) under microwave irradiation according to the procedure described for Example 14 provided after purification by reverse phase HPLC, 1-methyl-5-pyrrolidin-1-yl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (60 mg, 61%) as an off-white powder. ES-HRMS m/e calcd for C19H29N4O (M+H+) 329.2336, found 329.2334.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH2:30])[CH2:4]1)[CH3:2].CCN(C(C)C)C(C)C.[CH3:40][C:41]([S:44](Cl)=[O:45])([CH3:43])[CH3:42].ClC1C=CC=C(C(OO)=[O:55])C=1>C(Cl)Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH:30][S:44]([C:41]([CH3:43])([CH3:42])[CH3:40])(=[O:45])=[O:55])[CH2:4]1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC[C@@H]1C[C@H](N)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Reactant: CC(C)(C)S(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C(C)(C)C)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Yield: 64.4 %

Procedure:
To a solution of (1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine (115 mg, 0.271 mmol, Preparation #BB.1*) in DCM (1.5 mL) was added DIEA (0.071 mL, 0.406 mmol) followed by 2-methylpropane-2-sulfinic chloride (0.037 mL, 0.298 mmol). After about 4 h the reaction mixture was diluted with EtOAc (10 mL) and aqueous saturated NaHCO3 (10 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concd in vacuo. The crude residue was dissolved in DCM (1.5 mL) and a freshly prepared solution of m-chloroperbenzoic acid (0.271 mL, 0.271 mmol, 1M in DCM) was added. After about 2 h the reaction mixture was diluted with EtOAc (10 mL) and saturated aqueous NaHCO3 (10 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concd in vacuo. The crude residue was purified by chromatography on silica gel eluting with EtOAc to provide N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-2-methylpropane-2-sulfonamide (95 mg, 64% yield) as an oil. LC/MS (Table 1, Method a) Rt=2.40 min; MS m/z: 545 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH2:19][OH:20])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[F:21][CH:22]([F:39])[O:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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:21][CH:22]([F:39])[O:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[N:4][C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([CH:15]([CH2:19][OH:20])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=3)=[N:6][CH:7]=2)=[CH:26][CH:25]=1
Reactant: CC1(C)OB(c2ccc(OC(F)F)cc2)OC1(C)C
Reactant: O=C(O)C(CO)c1ccc(Nc2ncc(Br)cn2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)C(CO)c1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1
Temperature: 150 °C

Procedure:
To a solution of 2-(4-(5-bromopyrimidin-2-ylamino)phenyl)-3-hydroxypropanoic acid 25 (0.5 mmol) in 1,4-dioxane (2 mL) is added 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 7 (0.5 mmol), Na2CO3 (1.5 mmol of a 3.0 M aq. solution) and Pd(PPh3)4 (0.025 mmol). The reaction is evacuated and backfilled with nitrogen twice then heated at 150° C. for 10 min. The reaction mixture is diluted with water (10 mL). The aqueous layer is washed with DCM (2×50 mL) and acidified to pH 5 using aqueous HCl (1 N). The resulting mixture is extracted with DCM (2×50 mL). The organic layer is separated, dried over Na2SO4 and concentrated to yield a crude 2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxypropanoic acid 26 which is used without further purification. 1H NMR (400 MHz, d6-DMSO) δ 9.65 (s, 1H), 8.79 (s, 2H), 7.76 (d, J=8.8 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.30 (s, 1H), 7.27 (d, J=8.8 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 3.60-3.70 (m, 2H), 3.50-3.58 (m, 2H), 3.20-3.26 (m, 2H). MS (m/z) (M+1)+: 402.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].[C:13]([CH:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:16](=[O:22])[C:17](OCC)=[O:18])#[N:14]>C(COC)OC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17](=[O:18])[C:16](=[O:22])[CH:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:13]#[N:14])[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)C(C#N)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: N#CC(C(=O)C(=O)C(C#N)c1ccc(Cl)cc1)c1ccccc1
Reaction time: 12 h

Procedure:
To a solution of 6.6 g. (0.044 mol.) of p-chlorophenylacetonitrile and 20 ml. of dry glyme was added 6.2 g. (0.13 mol.) of sodium hydride (50% in oil). Ethyl 3-cyano-3-phenylpyruvate (9.55 g., 0.044 mol.) was added in portions at -10° and the reaction mixture was stirred at 25° for 12 hours. The mixture was diluted with 150 ml. of water, extracted with ether, acidified with 15 ml. of acetic acid and the solid was collected by filtration to yield 2-(p-chloro-phenyl)-5-phenyl-3,4-dioxoadiponitrile, m.p. 210° (dec.).