Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.[CH2:30]([C:32]1[N:37]=[CH:36][C:35]([CH2:38]O)=[CH:34][CH:33]=1)[CH3:31].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.C(OCC)(=O)C>[CH2:30]([C:32]1[N:37]=[CH:36][C:35]([CH2:38][N:6]2[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]3[N:3]=[C:2]([CH3:1])[N:29]=[C:5]23)=[CH:34][CH:33]=1)[CH3:31]
Reactant: CCc1ccc(CO)cn1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(Cc2ccc(CC)nc2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.5 %

Procedure:
To a solution of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (1.5 g), (6-ethylpyridin-3-yl)methanol (0.46 g) and tributylphosphine (1.1 mL) in THF (50 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.88 g) at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.43 g, 49%).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH:3]([CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH2:10]1)[CH2:4][C:5]([OH:7])=[O:6].CCN(C(C)C)C(C)C.CN(C=O)C.Br[CH2:42][C:43]([C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=1)=[O:44]>C(OCC)(=O)C>[F:26][C:2]([F:1])([F:25])[CH:3]([CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=2)[CH2:10]1)[CH2:4][C:5]([O:7][CH2:42][C:43]([C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=1)=[O:44])=[O:6]
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: O=C(O)CC(CN1CCCC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CC(CN1CCCC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F)OCC(=O)c1ccc(Cl)cc1
Yield: 77.5 %

Procedure:
In a 10 mL pear-shaped flask, 4,4,4-trifluoro-3-((3-(3-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)butanoic acid (50 mg, 130 μmol) and DIEA (50.6 mg, 68.3 μl, 391 μmol) were combined with DMF (2 ml) to give a colorless solution. 2-Bromo-1-(4-chlorophenyl)ethanone (60.9 mg, 261 μmol) was added and the resultant mixture was stirred at room temperature overnight. The reaction was diluted with ethyl acetate, washed with brine and H2O, dried with MgSO4, filtered and concentrated. The crude residue was purified on a silica column (100% hexane to 30% ethyl acetate/hexane eluent) to afford 54 mg (77%) of 2-(4-chlorophenyl)-2-oxoethyl 4,4,4-trifluoro-3-((3-(3-(trifluoromethyl)-phenyl)piperidin-1-yl)methyl)butanoate as an oil. MH+=536.
Reaction SMILES: NN.[CH2:3]([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([O:13][C@H:14]2[CH2:19][CH2:18][C@@H:17]([N:20]3[C:28](=[O:29])C4C(=CC=CC=4)C3=O)[CH2:16][CH2:15]2)=[CH:9][CH:8]=1)[CH3:4].[F:32][C:33]([F:45])([F:44])[O:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]=C=O)=[CH:37][CH:36]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C.O.CO>[CH2:3]([O:5][C:6](=[O:31])[C:7]1[CH:8]=[CH:9][C:10]([O:13][C@H:14]2[CH2:15][CH2:16][C@@H:17]([NH:20][C:28]([NH:41][C:38]3[CH:39]=[CH:40][C:35]([O:34][C:33]([F:32])([F:44])[F:45])=[CH:36][CH:37]=3)=[O:29])[CH2:18][CH2:19]2)=[CH:11][CH:12]=1)[CH3:4]
Reactant: CCOC(=O)c1ccc(O[C@H]2CC[C@@H](N3C(=O)c4ccccc4C3=O)CC2)cc1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Agent: NN
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccc(O[C@H]2CC[C@@H](NC(=O)Nc3ccc(OC(F)(F)F)cc3)CC2)cc1
Reaction time: 24 h

Procedure:
Anhydrous hydrazine (0.17 mL, 5.3 mmol) was added to a solution of compound 14f (1 g, 2.6 mmol) in 20 mL of CH2Cl2 followed by MeOH (20 mL) at room temperature. The reaction mixture was allowed to stir for 1 d. The resulting white precipitates were filtered off and the solvent was removed in vacuo. The resulting white solids were dissolved in aqueous 1N HCl solution and washed with CH2Cl2. The aqueous layer was basified with excess 1N NaOH solution and then extracted with CH2Cl2. After drying with MgSO4, the solvent was evaporated affording crude amine, which was used in the next step without further purification. To a solution of crude amine in DMF (50 mL) was added 4-(trifluoromethoxy)phenyl isocyanate (1.1 g, 4.3 mmol) followed by triethylamine (0.74 mL, 5.3 mmol) at 0° C. The reaction mixture was stirred overnight. The reaction mixture was poured into water, and the resulting precipitates were collected and washed with water. The crude product was purified by column chromatography to give the titled compound (1.7 g, 85%) as a white solid. 1H NMR (CDCl3): δ 7.98 (d, J=9 Hz, 2H), 7.35 (d, J=9 Hz, 2H), 7.13 (d, J=9 Hz, 2H), 6.87 (d, J=9 Hz, 2H), 6.85 (s, 1H), 5.01 (d, J=8 Hz, 1H), 4.57-4.51 (m, 1H), 4.36 (q, J=7 Hz, 2H), 3.89-3.72 (m, 1H), 2.07-1.52 (m, 8H), 1.39 (t, J=7 Hz, 3H). MS (ESI) m/z: 467.2 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH2:21]([NH2:26])[CH2:22][CH2:23][CH2:24][CH3:25].[BH4-].[Na+]>CO>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:26][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=1
Reactant: CCCCCN
Reactant: COc1cc(C=O)ccc1Oc1cnc(C(N)=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCNCc1ccc(Oc2cnc(C(N)=O)cn2)c(OC)c1
Reaction time: 8 h
Yield: 71.4 %

Procedure:
Place 5-(4-formyl-2-methoxyphenoxy)pyrazine-2-carboxamide (Example 719, Part A) (0.200 g, 0.732 mmol), amylamine (0.0670 g, 0.769 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (3.6 mL), cap and stir overnight. Add NaBH4 (ca. 3-5 eq in two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 60% to 90% (5% (2.0 M NH3 in methanol) in ethyl acetate) in hexanes. Concentrate the fractions containing the product. Take the solid up in ethyl acetate (50 mL) and wash with 1.0 N NaOH to give the title compound (0.180 g, 71.7%): TOF MS ES+ 345.2 (M+H)+, HRMS calcd for C18H25N4O3 345.1927 (M+H)+, found 345.1926, time 0.52 min; HPLC [Waters XTerra™ C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 23 min], tR=10.4 min, 100% purity.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:9][CH2:8][N:7]([C:10]([CH3:21])([CH3:20])[C:11](=[O:19])[CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6](=[O:22])[C:5]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH3:29]COCC>CN(C)C=O>[CH3:3][C:4]1[O:9][CH2:8][N:7]([C:10]([CH3:20])([CH3:21])[C:11](=[O:19])[C:12]([CH3:29])([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6](=[O:22])[C:5]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOCC
Reactant: CCOC(=O)C(C)C(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)C(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Reaction time: 16 h

Procedure:
Sodium hydride (67 mg of 60%) was added to a stirred solution of ethyl 4-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2,4-dimethyl-3-oxo-pentanoate (0.4 g) in N,N-dimethylformamide at 0° C. lodomethane (0.1 ml) was added and stirring continued for 16 hours. Ether was added and the organic phase washed (brine), dried (magnesium sulphate), evaporated and the residue purified by column chromatography eluting with ethyl acetate/hexane (1:2) to give ethyl 4-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2,2,4-trimethyl-3-oxo-pentanoate (Compound 197, 0.3 g), NMR 1.21(3H, t), 1.47(6H, s), 1.52(6H, s), 1.92(3H, s), 4.13(2H, q), 5.16(2H, s), 7.2-7.4(5H, m).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].N1([O:16][C:17]2[C:18]3[O:25][CH:24]=[C:23]([CH:26]4[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]4)[C:19]=3[N:20]=[CH:21][N:22]=2)C2C=CC=CC=2N=N1.[N:39]1([C:44]2[CH:49]=[CH:48][C:47](O)=[CH:46][CH:45]=2)[CH:43]=[N:42][N:41]=[N:40]1.O>CN(C=O)C>[N:39]1([C:44]2[CH:49]=[CH:48][C:47]([O:16][C:17]3[C:18]4[O:25][CH:24]=[C:23]([CH:26]5[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:28][CH2:27]5)[C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:46][CH:45]=2)[CH:43]=[N:42][N:41]=[N:40]1
Reactant: Oc1ccc(-n2cnnn2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2coc3c(On4nnc5ccccc54)ncnc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2coc3c(Oc4ccc(-n5cnnn5)cc4)ncnc23)CC1
Temperature: 70 °C
Reaction time: 5 h
Yield: 69.4 %

Procedure:
Potassium carbonate (5.0 mg, 0.035 mmol) was added to a solution of the tert-butyl 4-{4-[(1H-benzo[d][1,2,3]triazol-1-yl)oxy]furo[3,2-d]pyrimidin-7-yl}piperidine-1-carboxylate obtained in Step 7 of Example 1 (10.0 mg, 0.023 mmol) and 4-(1H-tetrazol-1-yl)phenol (4.0 mg, 0.025 mmol) in DMF (0.2 mL), followed by stirring at 70° C. for 5 hours. Water was added to the reaction liquid, and the reaction liquid was extracted with chloroform:methanol=5:1 and concentrated under a reduced pressure. The obtained residue was purified by using silica gel chromatography (chloroform:methanol=50:1) to give the titled compound (7.4 mg, 70%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].C[O-].[Na+:27].CO>CC(C)=O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[N-:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[Na+:27]
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: 28 °C

Procedure:
A solution of esomeprazole (19.5 g, 56.5 mmol; 1.3% sulfone, 1.05% R-enantiomer) in acetone (120 mL) was cooled to 15° C. 30% sodium methoxide in methanol (10.7 mL, 57.6 mmol) was added in 15 min. Subsequently, the solution was stirred at 28° C. A solid started to crystallize. The resulting slurry was stirred overnight at room temperature. The solid was collected by filtration, rinsed with acetone (2×20 mL) and dried under reduced pressure at 50° C. to yield esomeprazole sodium. Yield: 10.6 g (51%). Sulfone content: 0.06%. R-enantiomer content: 0.02%
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:12]4[C:17]([C:18](=[O:21])[C:19]=3[OH:20])=[CH:16][C:15]([NH:22]C(=O)C)=[CH:14][CH:13]=4)=[CH:9][C:4]=2[O:3][CH2:2]1.S(=O)(=O)(O)O.O.N>C(O)C>[NH2:22][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[O:11][C:10]([C:8]1[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=1)=[C:19]([OH:20])[C:18]2=[O:21]
Reactant: CC(=O)Nc1ccc2oc(-c3ccc4c(c3)OCO4)c(O)c(=O)c2c1
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: Nc1ccc2oc(-c3ccc4c(c3)OCO4)c(O)c(=O)c2c1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
3 g (8.85 mmol) of the compound obtained in Example 23 was stirred in 30 ml of aqueous 80% ethanol solution and 10 ml of aqueous 30% sulfuric acid solution at 120° C. for 18 hours. After the reaction was completed, the mixture was cooled to room temperature, and neutralized with conc. ammonia water. Then the obtained solid was filtered, washed with water, and dried to give 1.8 g of the title compound in a yield of 68%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[C:11]([N:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:21]2[CH2:22][CH2:23][CH2:24][N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:19][CH2:20]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)cn2)CC1

Procedure:
Intermediate B-21 was prepared by the general procedure for intermediate B-2, by using 2-chloro-5-nitropyridine and 1-BOC-homopiperazine as starting materials. MS (M+1): 293.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH2:35][CH3:36])[CH2:23]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:17][CH:16]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F-:37].[K+].C1N2CCOCCOCCN(CCOCCOCC2)CCOCCOC1>C(#N)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH2:35][CH3:36])[CH2:23][F:37])=[CH:17][CH:16]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [F-]
Reactant: CCC(COS(=O)(=O)c1ccc(C)cc1)Oc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Agent: C1COCCN2CCOCCOCCN(CCO1)CCOCCOCC2
Agent: [K+]
Solvent: CC#N
Product: CCC(CF)Oc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Reaction time: 1.5 h
Yield: 64.8 %

Procedure:
The product of Example 3F (28 mg, 52.4 μmol) was dissolved in 0.5 mL acetonitrile in a 5 mL flask and to this was added a solution of potassium fluoride (4.5 mg, 78.6 μmol) and Kryptofix 222 (29.6 mg, 78.6 μmol) in 0.5 mL acetonitrile. The above solution was then immersed in a oil bath preheated to 90° C. The reaction was allowed to stir for 90 minutes after which all the volatiles were removed under reduced pressure and the crude mixture purified by preparative thin layer chromatography to obtain 13 mg (65%) of pure desired compound. 1H (CDCl3) δ (ppm): 7.72 (s, 1H), 7.3 (d, 2H), 6.9 (d, 2H), 5.23 (s, 2H), 4.57-4.59 (m, 2H), 4.4 (m, 4H), 1.74 (m, 2H), 1.6 (s, 9H), 1.0 (t, 3H). 13C (CDCl3) δ (ppm): 159, 158.7, 153.7, 129, 127.5, 125.2, 118.3, 116.4, 83.85 (d, 1JCF=172.2), 78, 71.1, 66.3, 27.8, 23.2, 9.48. 19F (CDCl3, CFCl3 as internal standard) δ (ppm): −228 (d of t, J=−19, −60 Hz).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[I:43][C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][C:50]=1[CH3:51])[NH2:47].CCN(C(C)C)C(C)C>CN(C=O)C>[I:43][C:44]1[CH:45]=[C:46]([NH:47][C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[O:8])[CH:48]=[CH:49][C:50]=1[CH3:51]
Reactant: O=C(O)c1ccsc1
Reactant: Cc1ccc(N)cc1I
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccsc2)cc1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Thiophene-3-carboxylic acid (2.75 g, 21.45 mmol) and HATU (8.15 g, 21.45 mmol) in DMF (25 ml) were stirred at room temperature for 15 mins. HOBT (2.9 g, 21.45 mmol), 3-iodo-4-methylaniline (5.0 g, 21.45 mmol) and DIPEA (11.2 ml, 64.35 mmol) were added and the reaction stirred at room temperature for 16 hrs. The solvent was evaporated under vacuum and the residue partitioned between ethyl acetate (100 ml) and aqueous sodium carbonate (10%, 100 ml). The aqueous layer was extracted with ethyl acetate (50 ml) and the combined organic phases washed with hydrochloric acid (2N, 75 ml), water (75 ml) and brine (75 ml). The organic phase was dried (magnesium sulphate) and absorbed onto silica. The silica was applied to a flash silica column and eluted with cyclohexane/ethyl acetate (4:1). The solvent was evaporated from the product fractions under vacuum to give N-(3-iodo-4-methylphenyl)thiophene-3-amide. LCMS: retention time 3.69 min, MH+ 344. NMR: δH [2H6]-DMSO 10.06,(1H, b), 8.34,(1H, m), 8.29,(1H, d), 7.70,(1H, dd) 7.66,(1H, dd), 7.62,(1H, dd), 7.30,(1H, d), 2.34,(3H, s).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8]([OH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][Si:15]([CH3:25])([CH3:24])[C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8]([O:13][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([Si:15]([CH3:14])([CH3:25])[CH3:24])=[CH:17][CH:18]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)c1ccc(CBr)cc1
Reactant: Cc1c(O)cnn(C(C)(C)C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(OCc2ccc([Si](C)(C)C)cc2)cnn(C(C)(C)C)c1=O
Yield: 69.7 %

Procedure:
To a solution of 0.9 g (0.005 mol) of 2-t-butyl-5-hydroxy-4-methyl-3(2H)-pyridazinone and 1.2 g (0.005 mol) of p-trimethylsilyl benzylbromide dissolved in 20 ml of N,N-dimethylformamide was added 1.0 g (0.007 mol) of potassium carbonate at room temperature under stirring. After addition, the resulting mixture was stirred at 120° C. for three hours. After allowed to cool, the reaction mixture was poured into 200 ml of water and extracted with 100 ml of benzene. The resulting benzene layer was washed with 100 ml of water, dried over anhydrous sodium sulfate, and freed of solvent by distillation to give 1.8 g of crude product. The crude product was recrystallized from 20 ml of hexane to obtain 1.2 g of 2-t-butyl-4-methyl-5-(p-trimethylsilyl benzyloxy)-3(2H)-pyridazinone.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31]C(=O)OC(C)(C)C)[CH2:26]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])=[CH:13][CH:12]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:31][C@@H:27]1[CH2:28][CH2:29][CH2:30][N:25]([C:7]2[CH:6]=[CH:5][C:4]([C:1]([NH2:2])=[O:3])=[C:9]([NH:10][C:11]3[CH:12]=[CH:13][C:14]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])=[CH:15][CH:16]=3)[N:8]=2)[CH2:26]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(C(N)=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccc(N2CCC[C@@H](N)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
A solution of (R)-tert-butyl 1-(5-carbamoyl-6-(4-(morpholine-4-carbonyl)phenylamino)pyridin-2-yl)piperidin-3-ylcarbamate (1.7 g) in CH2Cl2 (3 ml) was treated with 3 ml of TFA and stirred at rt for 2 h. The reaction mixture was concentrated, basified with 1N NaOH, and extracted three times with CH2Cl2. The resulting organic layer was concentrated to obtained 1.367 g of (R)-6-(3-aminopiperidin-1-yl)-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide as a pale yellow solid. LCMS: (M+H)+=425.08. 1H NMR (400 MHz, CDCl3) δ ppm 11.21 (1H, s), 7.71 (2H, d, J=8.56 Hz), 7.52 (1H, d, J=8.81 Hz), 7.38 (2H, d, J=8.56 Hz), 6.06 (1H, d, J=8.80 Hz), 5.62 (2H, s), 4.19 (1H, d, J=9.57 Hz), 4.06-4.14 (1H, m, J=13.35 Hz), 3.59-3.79 (8H, m), 3.03-3.13 (1H, m), 2.78-2.92 (2H, m), 1.95-2.06 (1H, m), 1.73-1.86 (1H, m), 1.51-1.64 (1H, m), 1.30-1.46 (1H, m).
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]([F:12])=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1.[C-:13]#[N:14].[Na+].O>CS(C)=O>[F:12][C:11]1[C:3]([CH2:2][C:13]#[N:14])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: [C-]#N
Reactant: Fc1cc2c(cc1CCl)OCO2
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1cc2c(cc1F)OCO2
Temperature: 30 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A mixture of 5-chloromethyl-6-fluoro-benzo[1,3]dioxole (640 mg, 3.4 mmol) and NaCN (340 mg, 6.8 mmol) in DMSO (20 mL) was stirred at 30° C. for 1 h and then poured into water. The mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, and evaporated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (5-10% ethyl acetate/petroleum ether) to afford (6-fluoro-benzo[1,3]dioxol-5-yl)-acetonitrile (530 mg, 70%). 1H-NMR (300 MHz, CDCl3) δ 6.82 (d, J=4.8, 1H), 6.62 (d, J=5.4, 1H), 5.99 (s, 2H), 3.65 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:31])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[C:21]=2[CH2:29]Br)=[O:19])=[CH:4][CH:3]=1.Cl.[CH3:33][NH:34][CH3:35]>C(Cl)Cl.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:31])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[C:21]=2[CH2:29][N:34]([CH3:35])[CH3:33])=[O:19])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1sc2ccccc2c1CBr
Agent: Cl
Solvent: CC#N
Solvent: ClCCl
Product: CN(C)Cc1c(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cc2)sc2ccccc12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 43 %

Procedure:
To a suspension of N-(4-chlorophenyl)-2-[((3-(bromomethyl)benzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide (0.075 g, 0.14 mmol) in methylene chloride (1.5 mL) in a pressure vessel was added dimethylamine hydrochloride (0.035 g, 0.43 mmol), followed by BioRad AG1-X8 anion exchange resin (0.55 g, 0.7 mmol equivalents, OH− form). The vessel was sealed and the mixture was stirred at ambient temperature for 3.5 hours. The vessel was opened and the reaction mixture diluted with methylene chloride (25 mL) and acetonitrile (25 mL), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel, followed by crystallization from acetonitrile afforded 0.030 g (43% yield) of N-(4-chlorophenyl)-2-[((3-(dimethylamino)methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide, as a crystalline solid; NMR (DMSO-d6/TFA) 13.2 (s, 1),10.7 (s, 1), 7.3-8.1 (m, 11), 3.9 (s, 2), 2.1 (s, 6) ppm.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]([CH:12]([C:38]([O:40][CH3:41])=[O:39])[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([N+:23]([O-:25])=[O:24])=[CH:15][C:14]=1[C:26]([O:28]CC1C=CC(OC)=CC=1)=[O:27])=[O:11].C1(OC)C=CC=CC=1>O>[CH3:8][O:9][C:10]([CH:12]([C:38]([O:40][CH3:41])=[O:39])[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([N+:23]([O-:25])=[O:24])=[CH:15][C:14]=1[C:26]([OH:28])=[O:27])=[O:11]
Reactant: COC(=O)C(C(=O)OC)c1c(C(=O)OCc2ccc(OC)cc2)cc([N+](=O)[O-])c2ccccc12
Solvent: COc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(C(=O)OC)c1c(C(=O)O)cc([N+](=O)[O-])c2ccccc12
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 93.1 %

Procedure:
Trifluoroacetic acid (36 mL) was added in one portion to a mixture of 5 (9.20 g, 19.7 mmol) and anisole (12.16 g, 20 mmol), and the resulting solution was stirred at 20° C. for 10 min and then diluted with cold water (800 mL). The precipitated semi-solid was collected, dissolved in EtOAc and the solution was washed with water, dried (Na2SO4) and then concentrated under reduced pressure below 30° C. The residue was triturated with iPr2O to provide a crude product, which was recrystallised from EtOAc/iPr2O/petroleum ether/AcOH (1drop) to give 1-[di(methoxycarbonyl)-methyl]-4-nitronaphthalene-2-carboxylic acid (6) (6.37 g, 93%), mp 153-154° C. (dec.). 1H NMR [(CD3)2SO] δ 14.1 (br s, 1H, CO2H), 8.62 (s, 1H, H-3), 8.36 (d, J=8.2 Hz, 1H, H-5), 8.30 (d, J=8.7 Hz, 1H, H-8), 7.92 (br t, J=7.6 Hz, 1H, H-6), 7.84 (br t, J=7.7 Hz, 1H, H-7), 6.65 (s, 1H, ArCH), 3.63 (s, 6H, 2×CO2CH3). Anal. Calculated for C16H13NO8 : C, 55.3; H, 3.8; N, 4.0. Found: C, 55.4; H, 3.8; N, 3.7%.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][NH:4]1.[S:13](=O)(=[O:16])([OH:15])[OH:14]>O>[OH:16][S:13]([O:1][CH2:2][C@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][NH:4]1)(=[O:15])=[O:14]
Reactant: OC[C@H]1Cc2ccccc2CN1
Reactant: O=S(=O)(O)O
Solvent: O
Product: O=S(=O)(O)OC[C@H]1Cc2ccccc2CN1
Reaction time: 1 h

Procedure:
A solution of (R)-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (22.8 g.) in a mixture of sulphuric acid (d = 1.83; 7.9 cc.) and water (50 cc.) is concentrated for 1 hour at 100° C., under reduced pressure (20 mm.Hg) and then for 1 hour at 160° C. The residue crystallises on cooling. (R)-3-Hydroxysulphonyloxymethyl-1,2,3,4-tetrahydroisoquinoline (33.9 g.) is thus obtained in the form of a white crystalline mass melting at 318° C.