Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:16]=[C:15]([C:17]2[O:18][CH:19]=[CH:20][N:21]=2)[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[OH-].[Li+]>C1COCC1>[CH3:13][N:9]([CH2:10][CH2:11][CH3:12])[C:7](=[O:8])[C:6]1[CH:5]=[C:4]([CH:16]=[C:15]([C:17]2[O:18][CH:19]=[CH:20][N:21]=2)[CH:14]=1)[C:3]([OH:22])=[O:2]
Reactant: CCCN(C)C(=O)c1cc(C(=O)OC)cc(-c2ncco2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Yield: 99.8 %

Procedure:
Stir a solution of N-methyl-5-oxazol-2-yl-N-propyl-isophthalamic acid methyl ester (225 mg, 0.74 mmol) in 1 N lithium hydroxide (3.0 mL, 3.0 mmol) and THF (3.0 mL) at room temperature for 3 h. Add water (40 mL) and extract with ethyl acetate (40 mL). Acidify the aqueous with 5 N HCl, extract with ethyl acetate (2×40 mL), dry (magnesium sulfate) and concentrate to give the title compound (213 mg, 100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][C:9]#[N:10])[CH:2]=1.C([O-])([O-])=[O:12].[K+].[K+].CS(C)=O.OO>O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][C:9]([NH2:10])=[O:12])[CH:2]=1
Reactant: N#CCOc1cccnc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)COc1cccnc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.5 %

Procedure:
To a mixture of 2-(pyridin-3-yloxy)acetonitrile (100 mg, 0.75 mmol), K2CO3 (103 mg, 0.75 mmol) and DMSO (0.1 mL) in H2O (2 mL) was added H2O2 (0.1 mL, 30%) dropwise in an ice bath and the mixture was stirred at rt for 5 min. It was then concentrated in vacuo and the residue was purified by a silica gel column chromatography (EtOAc) to give the title compound as a white solid (62.2 mg, 55%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH2:13][CH2:14][O:15][C:16](=[O:37])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:36])[CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:38][C:39]1[C:40]([CH2:51][S:52]([C:54]2[NH:58][C:57]3[CH:59]=[CH:60][CH:61]=[CH:62][C:56]=3[N:55]=2)=[O:53])=[N:41][CH:42]=[CH:43][C:44]=1[O:45][CH2:46][C:47]([F:50])([F:49])[F:48].[H-].[Na+].O>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH2:13][CH2:14][O:15][C:16](=[O:37])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:36])[CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([N:55]3[C:56]4[CH:62]=[CH:61][CH:60]=[CH:59][C:57]=4[N:58]=[C:54]3[S:52]([CH2:51][C:40]3[C:39]([CH3:38])=[C:44]([O:45][CH2:46][C:47]([F:48])([F:49])[F:50])[CH:43]=[CH:42][N:41]=3)=[O:53])(=[O:34])=[O:33])=[CH:28][CH:27]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(COc1ccc(S(=O)(=O)Cl)cc1)NCCCCCC(=O)OCCS(=O)(=O)c1cccc([N+](=O)[O-])c1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2n1S(=O)(=O)c1ccc(OCC(=O)NCCCCCC(=O)OCCS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc1
Reaction time: 2 h
Yield: 92.9 %

Procedure:
6-[2-(4-chlorosulfonyl-phenoxy)-acetylamino]-n-hexanoic acid 2-(3-nitro-benzenesulfonyl)ethyl ester (Intermediate 19, 1.0 g, 1.73 mmol, 1.27 eq) in CH2Cl2 (5 mL) was added to a heterogeneous mixture of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-ylmethanesulfinyl]-1H-benzimidazole (500 mg, 1.36 mmol) in CH2Cl2 (10 mL) and NaH (40 mg, 1.65 mmol) at room temperature, and the mixture was stirred for 2 h. Thereafter water was added, the mixture was extracted with CH2Cl2, and the organic layers were dried and concentrated under reduced pressure. The residual oil was purified by column chromatography (CH2Cl2 to 3% MeOH in CH2Cl2) to yield 6-[2-(4-{2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-benzimidazole-1-sulfonyl}-phenoxy)acetylamino]hexanoic acid 2-(3-nitrobenzenesulfonyl)ethyl ester (Intermediate 20, 1.15 g, 94%) as an off-white foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:43][CH2:44][CH:45]([OH:57])[CH2:46][N:47]1[CH2:56][CH2:55][C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH2:48]1>CN(C=O)C.O>[CH2:48]1[C:49]2[C:54](=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:55][CH2:56][N:47]1[CH2:46][CH:45]([OH:57])[CH2:44][NH:43][C:16]([C:15]1[CH:14]=[C:13]([CH:10]2[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)[CH:21]=[CH:20][CH:19]=1)=[O:18]
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(C(=O)O)c2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(C(=O)NCC(O)CN3CCc4ccccc4C3)c2)C1
Temperature: 31 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
To a solution of 3-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)benzoic acid (200 mg, 0.69 mmol) in DMF (4 ml) was added TEA (208 mg, 2.06 mmol), HOBt (139 mg, 1.03 mmol), EDCI (197 mg, 1.03 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (170 mg, 0.82 mmol) at 33° C. The reaction mixture was stirred for 16 h at 31° C. The mixture was treated with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give the title compound which was used in next step without further purification (300 mg, Yield 92%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH:19]([CH3:21])[CH3:20])[CH:17]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:51][C:52]1[N:56]([CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=2)[N:55]=[C:54]([NH2:64])[CH:53]=1>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH:19]([CH3:21])[CH3:20])[CH:17]=1)[C:12]([NH:64][C:54]1[CH:53]=[C:52]([CH3:51])[N:56]([CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=2)[N:55]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(N)nn1Cc1ccccn1
Reactant: CC(C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cc(NC(=O)c2cc(OCc3ccccc3)cc(OC(C)C)c2)nn1Cc1ccccn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 31 %

Procedure:
3-Benzyloxy-5-isopropoxy-benzoic acid (0.35 mmol) is dissolved in acetonitrile, di-isopropyl ethyl amine (3 eq.), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium (1.2 eq.) and 5-methyl-1-pyridine-2-ylmethyl-1H-pyrazole-3-ylamine (1.0 eq., prepared similar to 1-pyridine-2-ylmethyl-1H-pyrazole-3-ylamine) is added and stirred at RT for 14 hours. The solvent is removed in vacuo. 3-Benzyloxy-5-isopropoxy-N-(5-methyl-1-pyridine-2-ylmethyl-1H-pyrazole-3-yl)-benzamide is obtained after column chromatography (chloroform (methanol) as a colourless powder in a yield of 31%; HPLC (Method B): 3.25 min; LC-MS: 2.350 min, 457.15 (M÷H+);
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[C:10]([CH2:19]O)=[N:9]2)[CH:5]=[N:6][CH:7]=1.S(Cl)([Cl:23])=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:23][CH2:19][C:10]1[C:11]([NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])=[CH:12][N:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=2)[N:9]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)C(=O)Nc1cn(-c2cncc(F)c2)nc1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C(=O)Nc1cn(-c2cncc(F)c2)nc1CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a solution of N-(1-(5-fluoropyridin-3-yl)-3-(hydroxymethyl)-1H-pyrazol-4-yl)isobutyramide (0.100 g, 0.359 mmol) in dichloromethane (3.59 ml) was added thionyl chloride (0.157 ml, 2.151 mmol). The reaction was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate was added, and the mixture was extracted with dichloromethane. The combined organic phases were washed with brine and concentrated to give N-(3-(chloromethyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-yl)isobutyramide (100 mg, 0.337 mmol, 94% yield) as a white solid: mp 172.0-177.0° C.; 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 8.67 (s, 1H), 8.40 (s, 1H), 7.80 (dt, J=9.4, 2.3 Hz, 1H), 7.42 (s, 1H), 4.77 (s, 2H), 2.63 (hept, J=6.9 Hz, 1H), 1.30 (d, J=6.9 Hz, 6H); ESIMS m/z 298 ([M+H]+).
Reaction SMILES: B(Cl)([C@H]1[C@H](C)[C@H]2C(C)(C)[C@@H](C2)C1)[C@H:2]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.[OH:23][C:24]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][C:34]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([CH3:48])([CH3:47])[C:43]([O:45][CH3:46])=[O:44])=[CH:38][CH:37]=2)=[O:35])[CH2:27][CH2:26]1.O.OO>O1CCCC1>[OH:23][C:24]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][C@@H:34]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([CH3:48])([CH3:47])[C:43]([O:45][CH2:46][CH3:2])=[O:44])=[CH:38][CH:37]=2)[OH:35])[CH2:27][CH2:26]1
Reactant: COC(=O)C(C)(C)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1B(Cl)[C@@H]1C[C@@H]3C[C@@H]([C@H]1C)C3(C)C)C2(C)C
Agent: OO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)c1ccc([C@@H](O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Dissolve (−)-B-chlorodiisopinocamphenylborane (2.5 g, 7.8 mmol) in anhydrous tetrahydrofuran (5 mL). Add a solution of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetic acid, methyl ester (3.54 mmol) in anhydrous tetrahydrofuran (5 mL). Stir at room temperature for 3 days and cool to 0° C. Add water (1 mL) and 30% hydrogen peroxide (2 mL) and stir for 20 minutes. Add methylene chloride (30 mL) and wash with brine (30 mL), then aqueous sodium hydrogen carbonate (30 mL), then brine (30 mL). Dry (MgSO4), evaporate the solvent in vacuo and purify by chromatography to give the title compound.
Reaction SMILES: C(OC([N:8]1[CH:12]=[CH:11][C:10]([N:13]([C:16]([C:18]2[C:23]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([C:35]([F:38])([F:37])[F:36])[CH:29]=3)(=[O:27])=[O:26])=[CH:22][C:21]([Cl:39])=[CH:20][N:19]=2)=[O:17])[CH2:14][CH3:15])=[N:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:14]([N:13]([C:10]1[CH:11]=[CH:12][NH:8][N:9]=1)[C:16]([C:18]1[C:23]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([C:35]([F:38])([F:36])[F:37])[CH:29]=2)(=[O:27])=[O:26])=[CH:22][C:21]([Cl:39])=[CH:20][N:19]=1)=[O:17])[CH3:15]
Reactant: CCN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ccn(C(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1cc[nH]n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-{[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine -2-carbonyl]-ethyl-amino}-pyrazole-1-carboxylic acid tert-butyl ester from step 2 was dissolved in a mixture of DCM and TFA (1:1) (5 mL). It was stirred at RT for 1 hour, concentrated, purified with HPLC to give 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid ethyl-(1H-pyrazol-3-yl)-amide: 1H NMR (400 MHz, CDCl3) δ 8.11 (d, 1 H), 8.0 (d, 1 H), 7.94 (m, 1 H), 7.88 (br, 1 H), 7.6 (d, 1 H), 7.37 (br, 1 H), 5.8 (s, 1 H), 3.8 (m, 2H), 1.1 (m, 3H); MS m/z: 508 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:36])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[CH2:28][N:29]3[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:37][C:38]([CH3:40])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:1]1([NH:4][C:5](=[O:36])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:26][CH2:27]3)[CH:17]=[C:16]4[CH2:28][N:29]3[CH2:35][CH2:34][CH2:33][N:32]([CH:38]([CH3:40])[CH3:37])[CH2:31][CH2:30]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCCNCC3)c2c1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCCN(C(C)C)CC3)c2c1
Reaction time: 0.03 h

Procedure:
The product of Example 70 (50 mg) was dissolved in dichloromethane (10 mL) and acetone (0.15 mL) added. The mixture was stirred for 2 minutes then sodium triacetoxyborohydride (109 mg) added. The mixture was stirred at room temperature for 12 hours. The volatiles were removed under reduced pressure and the residue purified by HPLC to give the title compound as a solid (33 mg).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:29]([Cu])#[N:30]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:29]#[N:30])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: N#C[Cu]
Reactant: CCCCOC(=O)c1nc(Br)c2ccc(Oc3ccc(OC)cc3)cc2c1O
Product: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccc(OC)cc3)cc2c1O

Procedure:
The title compound was synthesized from 1-Bromo-4-hydroxy-6-(4-methoxy-phenoxy)-isoquinoline-3-carboxylic acid butyl ester and CuCN in analogy to example 3a; MS-(+)-ion: M+1=392.9.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:8]([CH3:16])=[N:9][N:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[N:11]2)=O.[CH:18]1([NH:21][C:22]([NH2:24])=[NH:23])[CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:18]1([NH:21][C:22]2[N:24]=[C:5]([C:7]3[C:8]([CH3:16])=[N:9][N:10]4[C:15]=3[CH:14]=[CH:13][CH:12]=[N:11]4)[CH:4]=[CH:3][N:23]=2)[CH2:20][CH2:19]1
Reactant: N=C(N)NC1CC1
Reactant: Cc1nn2ncccc2c1C(=O)/C=C/N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn2ncccc2c1-c1ccnc(NC2CC2)n1
Temperature: 135 °C
Yield: 38 %

Procedure:
To a solution (2E)-3-(dimethylamino)-1-(2-methylpyrazolo[1,5-b]pyridazin-3-yl)-2-propen-1-one (50 mg, 0.22 mmol) in DMF (2.5 mL) was added N-cyclopropylguanidine.0.5H2SO4 (130 mg, 0.66 mmol) and potassium carbonate (152 mg, 1.10 mmol). The reaction was heated at an oil bath temperature of 135° C. for about 18 hours. The mixture was cooled to RT and the solvent was removed in vacuo. The residue was dissolved in chloroform and filtered. The filtrate was concentrated in vacuo then disolved in CH2Cl2 and triturated with diethylether to give the title compound as a yellow solid (22 mg, 38%). 1H-NMR (300 MHz, CDCl3) δ 9.02 (d, 1H, J=8.8 Hz), 8.39 (d, 1H, J=5.2 Hz), 8.35 (dd, 1H, J=4.4, 2.0 Hz), 7.15 (dd, 1H, J=8.8, 4.4 Hz), 6.94 (d, 1H, J=5.3 Hz), 5.45 (s, 1H), 2.89 (m, 1H), 2.83 (s, 3H), 0.91 (m, 2H), 0.68 (m, 2H); MS (ESI) (M+H)+ 267.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:30]=[C:29]4[C:25]([N:26]=[C:27]([CH:33]5[CH2:35][CH2:34]5)[N:28]4[CH2:31][CH3:32])=[C:24]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][C@@H:37]4[CH3:42])[N:23]=3)=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.CCOC(C)=O.[OH-].[OH-].[Pd+2]>[CH:33]1([C:27]2[N:28]([CH2:31][CH3:32])[C:29]3[C:25]([N:26]=2)=[C:24]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][C@@H:37]2[CH3:42])[N:23]=[C:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:13]4[NH:14][C:9](=[O:8])[CH:10]=[CH:11][CH:12]=4)=[CH:21][CH:20]=2)[N:30]=3)[CH2:34][CH2:35]1
Reactant: CCn1c(C2CC2)nc2c(N3CCOC[C@@H]3C)nc(-c3ccc(Nc4cccc(OCc5ccccc5)n4)cc3)nc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCn1c(C2CC2)nc2c(N3CCOC[C@@H]3C)nc(-c3ccc(Nc4cccc(=O)[nH]4)cc3)nc21
Reaction time: 2 h
Yield: 1 %

Procedure:
To a solution of (S)-6-(benzyloxy)-N-(4-(8-cyclopropyl-9-ethyl-6-(3-methylmorpholino)-9H-purin-2-yl)phenyl)pyridin-2-amine (100 mg, 1.78 mmol) in anhydrous MeOH (4 mL) and EtOAc (4 mL) was added 20 wt % Pd(OH)2 on carbon (10.0 mg). The reaction mixture was evacuated with vacuum and purged with H2 (3×), then stirred under an atmosphere of H2 for 2 hours. The reaction mixture was then filtered through a pad of Celite®. The filtrate was concentrated in vacuo and the crude was purified by column chromotagraphy (Si-PPC, gradient 0 to 30% methanol in dichloromethane). Crystallization from ether-heptane afforded the title compound (x-1) (8.6 mg, 10.2%) as a solid. 1H NMR (DMSO-d6, 500 MHz) δ ppm 10.16 (broad s, 1H), 9.05 (broad s, 1H), 8.27 (d, J=8.7 Hz, 2H), 7.76 (broad s, 2H), 7.41 (t, J=7.9 Hz, 1H), 6.29 (broad s, 1H), 5.98 (d, J=6.3 Hz, 1H), 5.36 (broad s, 1H), 5.06 (broad s, 1H), 4.36 (q, J=7.2 Hz, 2H), 3.98 (d, J=8.5 Hz, 1H), 3.78 (d, J=11.2 Hz, 1H), 3.69 (d, J=8.7 Hz, 1H), 3.54 (t, J=10.6 Hz, 1H), 3.44 to 3.33 (m, 1H), 2.30 to 2.19 (m, 1H), 1.40 (t, J=7.1 Hz, 3H), 1.29 (d, J=6.7 Hz, 3H), 1.12 to 0.93 (m, 4H); LC-MS m/z (method C)=472.2 [M+H]+, RT=4.93 min.
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[N:9]([CH2:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:35][NH:34][CH2:33][CH2:32][NH:31]2)=[CH:26][CH:25]=1>N1C=CC=CC=1>[CH2:19]([N:9]1[C:8]2[N:7]=[C:6]3[CH:21]=[C:2]([N:34]4[CH2:33][CH2:32][NH:31][CH:30]([C:27]5[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=5)[CH2:35]4)[C:3]([F:22])=[CH:4][C:5]3=[CH:14][C:13]=2[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]1)[CH3:20]
Reactant: Fc1ccc(C2CNCCN2)cc1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(c5ccc(F)cc5)C4)cc3nc21
Yield: 42.3 %

Procedure:
The reaction is performed under the conditions of Example 4, but starting with 8-chloro-1-ethyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8 ]-naphthyridine-3-carboxylic acid (1.5 g) and (RS)-2-(4-fluorophenyl)piperazine (3.4 g) in pyridine (15 cc). (RS)-1-Ethyl-7-fluoro-4-oxo-8-[3-(4-fluorophenyl)-1-piperazinyl]-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (0.92 g) is obtained in the form of a yellow solid, m.p. 298° C.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][C:3]=1OC.C(N(CC)CC)C.[C:33](Cl)(=[O:38])[CH2:34][CH:35]([CH3:37])[CH3:36]>C(Cl)Cl>[CH3:36][CH:35]([CH3:37])[CH2:34][C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:22][CH:23]=1)=[O:38]
Reactant: CC(C)CC(=O)Cl
Reactant: COc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 3 h
Yield: 129.1 %

Procedure:
To a stirred solution of 0.10 g of 10,11-dihydro-10-(4-amino-3-methoxybenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 1 ml of methylene chloride is added 0.06 g of triethylamine followed by 0.05 g of iso-valeryl chloride. The reaction mixture is stirred for 3 hours and then quenched with 1N NaOH. The organic layer is evaporated in vacuo to a residue which is stirred in 5 ml of tetrahydrofuran for 1 hour, then evaporated in vacuo to a residue. The residue is extracted with ethyl acetate-methylene chloride, washed with brine, dried (Na2SO4), filtered through hydrous magnesium silicate and evaporated in vacuo to give 0.15 g of residue which is stirred with ether-hexane to give 0.13 g of light yellow solid. MS(CI): 418(M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([OH:20])[C:13]3[CH:14]=[CH:15][N:16]([CH3:19])[C:17]=3[CH:18]=2)=[CH:4][N:3]=1.[CH3:21][CH:22]([CH3:28])[CH2:23][S:24](Cl)(=[O:26])=[O:25]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[CH:15][N:16]3[CH3:19])=[C:12]([O:20][S:24]([CH2:23][CH:22]([CH3:28])[CH3:21])(=[O:26])=[O:25])[CH:11]=2)=[CH:4][N:3]=1
Reactant: CC(C)CS(=O)(=O)Cl
Reactant: Cn1ccc2c(O)cc(Cc3cnc(N)nc3N)cc21
Product: CC(C)CS(=O)(=O)Oc1cc(Cc2cnc(N)nc2N)cc2c1ccn2C

Procedure:
This compound was produced by reaction of 6-(2,4-diamino-pyrimidin-5-ylmethyl)-1-methyl-1H-indol-4-ol (Example 4,269 mg, 1.00 mmol) with 2-methylpropane-1-sulfonyl chloride (188 mg, 1.20 mmol), following the procedure detailed in Example 5c. Yield: 58 mg (15%). White solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[Li+].[OH-].Cl>C1COCC1.O>[NH2:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: COC(=O)c1nc(Br)cnc1N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncc(Br)nc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.5 %

Procedure:
(Step 6-ii) To a solution of methyl 3-amino-6-bromopyrazine-2-carboxylate (1 g, 4.33 mmol) in 10 mL THF was added a solution of LiOH (540 mg, 12.86 mmol) in 20 mL of water. The mixture was stirred at room temperature for 4 hours and acidified with 6M HCl to a pH of 2. The yellow precipitate was collected by filtration and washed with water. After drying in vacuo, the product, 3-amino-6-bromopyrazine-2-carboxylic acid (600 mg, 2.75 mmol, 64% yield), can be used directly in the next reaction without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].[N+:9]([O-])([OH:11])=[O:10]>C(OC(=O)C)(=O)C.C(O)(=O)C>[N+:9]([C:5]1[S:1][C:2]([C:6]([OH:8])=[O:7])=[CH:3][CH:4]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cccs1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(O)c1ccc([N+](=O)[O-])s1

Procedure:
2-Thiophenecarboxylic acid (6.4 g, 50 mM) was suspended in acetic anhydride (15 ml) and fuming nitric acid (16 ml) in glacial acetic acid (25 ml) added slowly over 1 hour with stirring, while keeping the temperature of the reaction mixture below 30° C. The reaction mixture was stirred at ambient temperature for 2 hours. The product was purified by subjecting to chromatography (470 ml) on HP20SS resin using methanol/(water +1% acetic acid): as eluant. The pure title compound was obtained together with a mixture of 4- and 5-nitrothiophene-2-carboxylic acid.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:33])[CH:12]([C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:19]=[C:20]([OH:22])[CH:21]=1)[CH2:13][CH2:14][CH3:15])[CH3:9].[F:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>CC([O-])=O.CC([O-])=O.[Cu+2].C(Cl)Cl>[CH2:8]([O:10][C:11](=[O:33])[CH:12]([C:16]1[CH:17]=[C:18]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:27][CH:28]=2)[CH:19]=[C:20]([O:22][C:38]2[CH:39]=[CH:40][C:35]([F:34])=[CH:36][CH:37]=2)[CH:21]=1)[CH2:13][CH2:14][CH3:15])[CH3:9]
Reactant: CCCC(C(=O)OCC)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(C(=O)OCC)c1cc(Oc2ccc(F)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Reaction time: 24 h
Yield: 58.2 %

Procedure:
Triethylamine (100 μL, 0.72 mmol) was added to a stirred mixture of 2-(5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (90 mg, 0.25 mmol), Cu(OAc)2 (68 mg, 0.38 mmol), 4-fluorophenylboronic acid (70 mg, 0.57 mmol), 4 {acute over (Å)} molecular sieves (25 mg, powdered) and DCM (2 mL) at room temperature open to the air. After 24 h, the reaction mixture was loaded onto silica and purified (0-10% ethyl acetate in petrol) to give 2-(5-(4-fluorophenoxy)-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (67 mg) as a colourless oil.