Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].[Na+].[CH3:3][OH:4].[F:5][C:6]1([C:20]([F:23])([F:22])[F:21])[O:11][C:10]([F:13])([F:12])[C:9](F)([C:14]([F:17])([F:16])[F:15])[O:8][C:7]1=[O:19].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[F:5][C:6]([C:20]([F:23])([F:22])[F:21])([O:11][C:10]([F:13])([F:12])[C:9](=[O:8])[C:14]([F:15])([F:17])[F:16])[C:7]([O:4][CH3:3])=[O:19]
Reactant: O=C1OC(F)(C(F)(F)F)C(F)(F)OC1(F)C(F)(F)F
Reactant: CO
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [F-]
Agent: [Na+]
Product: COC(=O)C(F)(OC(F)(F)C(=O)C(F)(F)F)C(F)(F)F
Reaction time: 65 h
Yield: 84.6 %

Procedure:
A suspension of 50.4 g (1.2 mol) of NaF in 128 g (4.0 mol) of methanol was stirred and cooled with an ice bath while 310 g (1.0 mol) of perfluoro(3,6-dimethyl-2-oxo-1,4-dioxane) was added at a rate sufficient to maintain a temperature of 25°-30° C. The ice bath was removed after completion of the addition and the reaction mixture was stirred overnight. The NaF.HF was filtered off, the filter cake was rinsed well with ether, and the filtrates were added to 213 g (1.5 mol) of P2O5. The resultant mixture was allowed to stand for about 65 h and then distilled to give 272.6 g (85%) of methyl perfluoro(2-methyl-5-oxo-3-oxahexanoate), bp 48°-51° (50 mm), identified by IR and NMR.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N+:14]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH3:16])[CH3:15].[C:24]([OH:32])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH2:33]>CC(C)=O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N+:14]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH3:16])[CH3:15].[C:24]([O-:32])(=[O:31])[C:25]1[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=1)[OH:33]
Reactant: O
Reactant: O=C(O)c1ccccc1
Agent: CCCCCCCCCCCCC[N+](C)(C)Cc1ccccc1
Solvent: CC(C)=O
Product: O=C([O-])c1ccccc1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Benzalkonium saccharinate (0.01 mol) and benzoic acid (0.01 mol) were dissolved in 25 mL of hot acetone. The mixture was stirred at room temperature for 5 h. Distilled water was added. The organic phase was separated and washed with distilled water. Organic phase was evaporated and the product, benzalkonium salicylate, was dried under vacuum. 1H and 13C NMR (DMSO) were obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:22]2[CH:23]=[C:24]([C:27]3[CH2:28][CH2:29][N:30]([C:33]([C@H:35]4[CH2:40][CH2:39][CH2:38][CH2:37][N:36]4C(OC(C)(C)C)=O)=[O:34])[CH2:31][CH:32]=3)[CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1)[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:22]2[CH:23]=[C:24]([C:27]3[CH2:28][CH2:29][N:30]([C:33]([C@H:35]4[CH2:40][CH2:39][CH2:38][CH2:37][NH:36]4)=[O:34])[CH2:31][CH:32]=3)[CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1)[CH3:17]
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1cnc2ccc(C3=CCN(C(=O)[C@H]4CCCCN4C(=O)OC(C)(C)C)CC3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](c1ccc(Cl)cc1Cl)n1cnc2ccc(C3=CCN(C(=O)[C@H]4CCCCN4)CC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of (R)-t-butyl 2-(4-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d]imidazol-6-yl)-1,2,3,6-tetrahydropyridine-1-carbonyl)piperidine-1-carboxylate (1.5 g, 2.6 mmol) in dichloromethane (8 mL) at 0° C. under nitrogen. The reaction mixture was stirred at room temperature for 1 h. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane (30 mL). The organic layer was neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was further extracted with dichloromethane (2×30 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 3-10% methanol in dichloromethane) to give the title compound as a white solid (1.1 g, 2.3 mmol, 83%). 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1 H), 7.74 (d, J=8.4 Hz, 1 H), 7.47 (d, J=1.9 Hz, 1 H), 7.25-7.21 (m, 1 H), 7.16-7.13 (m, 1H), 7.04 (s, 1 H), 6.86 (d, J=8.4 Hz, 1 H), 6.00-5.93 (m, 2 H), 4.29-4.07 (m, 2 H), 3.86-3.66 (m, 2 H), 3.30-3.26 (m, 1 H), 2.82-2.50 (m, 3 H), 1.99 (d, J=7.0 Hz, 3 H), 1.97-1.52 (m, 8 H); MS: (ES) m/z calculated for C26H29Cl2N4O [M+H]+483.2, found 483.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][C@H:8]([CH3:11])[CH:9]=O)([CH3:4])([CH3:3])[CH3:2].[C:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:15])[CH3:14].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[C:1]([O:5][C:6](=[O:12])[NH:7][C@H:8]([CH3:11])[CH2:9][N:19]1[CH2:20][CH2:21][N:16]([C:13](=[O:15])[CH3:14])[CH2:17][CH2:18]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](C=O)NC(=O)OC(C)(C)C
Reactant: CC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(=O)N1CCN(C[C@@H](C)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.1 %

Procedure:
(R)-(1-methyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (1.85 g, 10.7 mmole) and acetyl piperazine (1.53 g, 12 mmole) were combined in dichloroethane (125 mL). NaBH(OAc)3 (4.53 g. 21 mmole) was added. The resultant reaction solution was stirred at room temperature for 20 h. An equal volume of saturated NaHCO3 was added. The aqueous phase was extracted 3 times with CH2Cl2. The combined organic extracts were washed with saturated NaCl, dried over Na2SO4 and concentrated under vacuum. Purification by silica chromatography (5% methanol in CH2Cl2 provided (R)-[2-(4-acetylpiperazin-1-yl)-1-methyl-ethyl]-carbamic acid tert-butyl ester (Intermediate XXIXa, 2.6 g)
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:30])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16](=[O:29])[CH2:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[C:20]([O:26]C)[C:19]=1[CH3:28])(=[O:10])=[O:9].B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[C:3]([CH3:30])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16](=[O:29])[CH2:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[C:20]([OH:26])[C:19]=1[CH3:28])(=[O:10])=[O:9]
Reactant: COc1c(C)cc(C)c(CC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)c1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(C)c(CC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)c(C)c1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To a solution of N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-methoxy-2,4,6-trimethylphenyl)acetyl)-3-thiophenesulfonamide (Example 49) (50 mg, 0.107 mmol) in dichloromethane (20 mL) at 0° C. was added BBr3 (1 M in dichloromethane, 3 mL, 3.0 mmol). The resulting mixture was stirred at 0° C. for 1 h and at room temperature for 8 h before it was poured into crushed ice (˜100 g). The aqueous mixture was stirred until all ice melted and extracted with dichloromethane (2×100 mL). The organic layers were combined and concentrated, and the residue was purified by HPLC to give N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-hydroxy-2,4,6-trimethylphenyl)acetyl)-3-thiophenesulfonamide (47 mg, 85%).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:16]=[C:15]([N:17]4[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][CH2:26][O:27]C(=O)C)[CH2:19][CH2:18]4)[CH:14]=[CH:13][CH:12]=3)[CH:9]=2)[CH2:4][CH2:3]1.Cl>>[CH3:1][C:2]1([CH3:31])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:16]=[C:15]([N:17]4[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[CH2:21][CH2:22]4)[CH:14]=[CH:13][CH:12]=3)[CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OCCCCN1CCN(c2cccc(-c3ccc4c(c3)C(C)(C)CC4)n2)CC1
Agent: Cl
Product: CC1(C)CCc2ccc(-c3cccc(N4CCN(CCCCO)CC4)n3)cc21

Procedure:
The preparation is carried out analogously to FS402 starting from 104 mg (0.23 mmol) of acetic acid 4-{4-[6-(3,3-dimethylindan-5-yl)pyridin-2-yl]piperazin-1-yl}butyl ester. The product is the hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:16][NH2:17].O>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:16][NH2:17])[CH:5]=[CH:4][N:3]=1
Reactant: NN
Reactant: Clc1ccnc(Cl)n1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: NNc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.8 %

Procedure:
To a solution of 2,4-dichloropyrimidine (1.49 g, 10.0 mmol) in ethanol (25 mL) was added triethylamine (2.02 g, 2.78 mL, 20.0 mmol) and hydrazine (321 mg, 0.321 mL, 10.0 mmol). The mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with dichloromethane. The organic layer was dried over MgSO4, concentrated. The residue was purified by silica gel column chromatograghy eluted with methanol:dichloromethane (2 to 5% methanol) to give (2-chloro-pyrimidin-4-yl)-hydrazine (330 mg, 23%) as a white solid. MS (ES+): m/z=144.9.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([Cl:14])[N:6]=[CH:5]2.[CH3:15][O:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1.C(=O)([O-])[O-].[Ce+3].C(=O)([O-])[O-].C(=O)([O-])[O-].[Ce+3]>C1COCC1.O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:14][C:7]1[N:6]=[CH:5][C:4]2[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:2]([C:19]3[CH:18]=[C:17]([O:16][CH3:15])[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=3)[CH:3]=2)[N:8]=1
Reactant: COc1cc2nc(Cl)ncc2cc1Br
Reactant: COc1cc(OC)cc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ce+3]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(OC)cc(-c2cc3cnc(Cl)nc3cc2OC)c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 37.7 %

Procedure:
A mixture of 6-bromo-2-chloro-7-methoxyquinazoline (2.4 g, 8.82 mmol), 3,5-dimethoxyphenylboronic acid (1.6 g, 8.82 mmol), cerium carbonate (8.6 g, 26.46 mmol) and Pd(PPh3)2Cl2 (1.4 g, 2.1 mmol) in THF (10 mL), dioxane (10 mL) and water (2 mL) was degassed with nitrogen three times and stirred at 85° C. for 3 h. LCMS monitored the reaction was completed. The mixture was cooled to RT and extracted with dichloromethane (3×50 mL). The organic layers were separated, combined, washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate=1:4) to give the title compound (1.1 g, 38%) as a white solid. MS (ES+) C17H15ClN2O3 requires: 330, 332. found: 331, 333 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([O:32][CH3:33])=[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][N:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.CC1(C)C(C)(C)OB([C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:50][CH2:49]3)=[CH:44][CH:43]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O.O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:33][O:32][C:5]1[CH:4]=[N:3][C:2]([C:42]2[CH:43]=[CH:44][C:45]([N:48]3[CH2:49][CH2:50][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:52][CH2:53]3)=[CH:46][CH:47]=2)=[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:31])[C:12](=[O:13])[N:14]3[CH2:15][CH2:16][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[N:23]=[N:22][N:21]=4)[CH2:18][CH2:19]3)[C:6]=12
Reactant: COc1cnc(Br)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccn4)CC3)c12
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COc1cnc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccn4)CC3)c12
Temperature: 80 °C
Yield: 61.5 %

Procedure:
A mixture of 1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (300 mg, 0.586 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (250 mg, 0.644 mmol), Na2CO3 (310 mg, 2.93 mmol) and PdCl2(dppf)2-CH2Cl2 adduct (47.8 mg, 0.059 mmol) in water (1.000 mL) and 1,4-dioxane (1 mL) was heated up at 80° C. for 2 h. The reaction mixture was cooled to room temperature, filtered through a silica gel pad and concentrated under reduced pressure. The resulting crude was purified by prep HPLC to give tert-butyl 4-(4-(4-methoxy-3-(2-oxo-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)phenyl)piperazine-1-carboxylate (250 mg, 62%) as white solid. LCMS: m/e 694.36 (M+H)+, ret time 1.68 min (method 8). 1H NMR (500 MHz, MeOD) δ ppm 1.52 (s, 9H) 3.41-3.46 (m, 4H) 3.47-3.51 (m, 2H) 3.52-3.56 (m, 2H) 3.64 (m, 4H) 3.69-3.75 (m, 2H) 3.86-3.95 (m, 2H) 4.17 (s, 3H) 7.28 (d, J=8.54 Hz, 2H) 7.63 (dd, J=7.63, 4.88 Hz, 1H) 7.77 (d, J=8.55 Hz, 2H) 7.90 (d, J=8.24 Hz, 1H) 8.00 (s, 1H) 8.17 (t, J=7.78 Hz, 1H) 8.68 (s, 2H)
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].N1C(N)=[C:17]2[C:13](N=CN2)=NC=1.N1C=CC(=O)NC1=O.N1C(=O)C2NC=NC=2N=C1N.N1C=CC(N)=NC1=O.NC1N=C2C(NC=N2)=C(N)N=1>>[C:8]([C:7]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][CH:9]=1)#[C:13][CH3:17]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: Nc1ncnc2nc[nH]c12
Agent: Nc1cc[nH]c(=O)n1
Agent: Nc1nc(N)c2[nH]cnc2n1
Agent: Nc1nc2nc[nH]c2c(=O)[nH]1
Product: CC#Cc1c[nH]c(=O)[nH]c1=O

Procedure:
wherein T7 and T8 are each independently O or S and T9 is H, amino, hydroxy, Cl, or Br. 8) B is thymine, adenine, uracil, a 5-halouracil, a 5-alkyluracil, guanine, cytosine, a 5-halocytosine, a 5-alkylcytosine, or 2,6-diaminopurine. 9) B is guanine, cytosine, uracil, or thymine. 10) B is adenine.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[F:13].[H-].[Na+].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>CC(N(C)C)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([CH2:22][C:21]3[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[C:9]2=[O:12])=[CH:4][C:3]=1[F:13]
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1[nH]ccc2cc(F)c(Br)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(Cn2ccc3cc(F)c(Br)cc3c2=O)cc1
Temperature: 25 °C
Yield: 116.3 %

Procedure:
9.66 g (39.9 mmol) of 7-Bbromo-6-fluoro-2H-isoquinolin-1-one (95) were dissolved in 180 ml of dimethyl acetamide and 1.92 g (48.0 mmol) of sodium hydride (60%) were added. After 1 h at room temperature a solution of 7.50 g (48.0 mmol) of 4-methoxy benzylchloride in 25 ml of dimethyl acetamide was added. The mixture was stirred at room temperature until complete conversion was achieved. The solvent was removed under reduced pressure, the residue was taken up in saturated sodium bicarbonate solution and extracted three times with dichloromethane. The organic layers were dried with magnesium sulfate and evaporated to yield 16.8 g of a dark oil as crude product, which was stirred in methanol. Filtration of the precipitate gave 6.56 g of the title compound as a yellow solid. The mother liquor was evaporated and the residue purified by preparative HPLC to yield additional 2.62 g of the desired product. Rt=1.71 min (Method C). Detected mass: 362.3/364.3 (M+H+).
Reaction SMILES: [OH-].[Na+:2].C([O:5][C:6](=[O:22])[CH2:7][C:8]1[NH:9][C:10](=[O:21])[C:11]([Cl:20])=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:13]=1)C>C1COCC1>[Cl:20][C:11]1[C:10](=[O:21])[NH:9][C:8]([CH2:7][C:6]([O-:22])=[O:5])=[N:13][C:12]=1[N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1.[Na+:2]
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)c(Cl)c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C([O-])Cc1nc(N2CCOCC2)c(Cl)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.8 ml of 2N sodium hydroxide are added to a solution of 800 mg of (5-chloro-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetic acid ethyl ester in 7.2 ml of THF. The reaction medium is stirred at ambient temperature for 24 hours. The reaction medium is concentrated under reduced pressure. The residue obtained is oven-dried under vacuum in the presence of P2O5, so as to give 750 mg of sodium (5-chloro-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate, the characteristics of which are the following:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[NH:10][N:9]=[CH:8][C:5]2=[N:6][CH:7]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C]=O.[C:66]([O:69][CH2:70]C)(=[O:68])C>CO.C(#N)C.[Pd](Cl)Cl.CCCCCC>[NH:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:66]([O:69][CH3:70])=[O:68])[CH:3]=2)[CH:8]=[N:9]1
Reactant: Brc1cnc2cn[nH]c2c1
Reactant: CCOC(C)=O
Agent: Cl[Pd]Cl
Agent: [C]=O
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCCCCC
Solvent: CC#N
Solvent: CO
Product: COC(=O)c1cnc2cn[nH]c2c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
To a solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (5.5 g, 27.9 mmol) in methanol (125 mL) and acetonitrile (75 mL) was added triethylamine (22 mL, 156 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.98 g, 3.07 mmol), palladium dichloride (1.23 g, 6.98 mmol). The mixture was placed under 20 bar of carbon monoxide, heated to 100° C., and stirred vigorously for 18 hours. The reaction mixture was cooled to ambient temperature and filtered through Celite® before the solvent was removed in vacuo to yield a brown oil. This crude oil was then punt led by flash column chromatography (1:1, ethyl acetate:hexane) to give methyl 1H-pyrazolo[4,3-b]pyridine-6-carboxylate as a pale yellow solid (4.52 g, 92% yield). 1HNMR (400, CDCl3) δ ppm 10.56 (s, 1H), 9.23 (s, 1H), 8.35 (s, 1H), 8.40 (s, 1H), 4.01 (s, 3H).
Reaction SMILES: [C:1]([N:4]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[S:21][C:20]([C:22]([O:24]C)=[O:23])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:26])[CH2:6]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:1]([N:4]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[S:21][C:20]([C:22]([OH:24])=[O:23])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:26])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(C(=O)O)s2)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.3 %

Procedure:
Methyl 5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}thiophene-2-carboxylate (80 mg, 0.17 mmol, 1 eq.) was dissolved in methanol (6 ml). A solution of potassium carbonate (200 mg, 1.4 mmol, 8 eq.) in water (2 ml) was added and reaction mixture was stirred at room temperature for 20 h. The mixture was concentrated and the residue was acidified with a 1N HCl aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydro-quinolin-1(2H)-yl]carbonyl}thiophene-2-carboxylic acid (76 mg, 99%).
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-])=O)[CH:3]=1.Cl>C(O)C.[Fe]>[F:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([NH2:11])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(F)c2c(c1)CCO2
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: Nc1cc(F)c2c(c1)CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
Compound 7 (1.4 g, 7.64 mmol) was suspended in ethanol (51 mL). Iron (2.57 g, 45.85 mmol) and conc. HCl (4 mL) was added at 0° C. The resulting suspension was stirred overnight at room temperature. The reaction was quenched by addition of NaHCO3. The crude was extracted with ethyl acetate. It was purified by column chromatography, eluted at 25% ethyl acetate/hexane, to yield the desired compound 8 (1.09 g, yield 93.1%).
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:28][C@H:29]1[CH2:34][C:33]2[C:35]([N:39]3[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]3)=[CH:36][CH:37]=[CH:38][C:32]=2[O:31][CH2:30]1>CN(C)C=O>[CH3:45][N:42]1[CH2:43][CH2:44][N:39]([C:35]2[C:33]3[CH2:34][C@H:29]([NH:28][C:11](=[O:13])[C:10]4[CH:9]=[CH:8][C:7]([N:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)=[CH:15][CH:14]=4)[CH2:30][O:31][C:32]=3[CH:38]=[CH:37][CH:36]=2)[CH2:40][CH2:41]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Reactant: O=C(O)c1ccc(N2CCCCC2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCCCC4)cc2)CO3)CC1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 36.3 %

Procedure:
A suspension of 4-piperidinobenzoic acid (276 mg, 1.35 mmol; described in: Weringa, W. D.; Janssen, M. J. Recl. Trav. Chim. Pays-Bas 1968, 87(12), 1372–1380) and 1,1′-carbonyldiimidazole (229 mg, 1.41 mmol) in anhydrous N,N-dimethylformamide (11 mL) was placed in an oil bath at 75° C. After 45 min of stirring, the mixture was allowed to cool. A solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (317 mg, 1.28 mmol) in N,N-dimethylformamide (5 mL) was added, and the mixture was stirred at room temperature for 40 h. Another portion of 1,1′-carbonyldiimidazole (83 mg, 0.51 mmol) was added, and the reaction was stirred for 3 days. At this time, the reaction was not complete and a final amount of 1,1′-carbonyldiimidazole (42 mg, 0.25 mmol) was added. The reaction mixture was heated for 3 h at 50° C. after which the solvent was removed in vacuo. The residue was purified by column chromatography on silica (eluent: chloroform/ethanol; 92:8+0.5% NH3) affording 202 mg (36% yield) of the title compound as a white solid: mp 178–180° C.; [α]22D−159° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 434 (35, M+).
Reaction SMILES: CN(C)C=O.[C:6]([N:10]1[C:15](=[O:16])[C:14]([Br:17])=[C:13]([SH:18])[CH:12]=[N:11]1)([CH3:9])([CH3:8])[CH3:7].[C:19]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>O>[C:6]([N:10]1[C:15](=[O:16])[C:14]([Br:17])=[C:13]([S:18][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:24][CH:25]=2)[CH:12]=[N:11]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: CC(C)(C)n1ncc(S)c(Br)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Br)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 64 %

Procedure:
To a dimethylformamide solution of 4.4 g of 2-tert.-butyl-4-bromo-5-mercapto-3(2H)-pyridazinone and 4.7 g of 4-tert.-butylbenzyl bromide was added 3.5 g of sodium carbonate. The resulting reaction liquid was stirred at 80° C. for 4 hours, allowed to cool to room temperature, incorporated with water and extracted with benzene. The benzene layer was washed with 3% aqueous solution of sodium hydroxide and then with water, dried and then freed of benzene by distillation to give yellowish brown solid. The solid was recrystallized from a mixed solvent of benzene and n-hexane to obtain white crystals (yield: 64%).