Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1I.[CH3:9][N:10]([CH3:27])[C:11]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15][C:14]([C:18]#[C:19][CH3:20])([OH:17])[CH2:13][CH2:12]1.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.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>[CH3:27][N:10]([CH3:9])[C:11]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15][C:14]([C:18]2[NH:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[C:19]=2[CH3:20])([OH:17])[CH2:13][CH2:12]1
Reactant: Nc1ccncc1I
Reactant: CC#CC1(O)CCC(c2ccccc2)(N(C)C)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(C2(O)CCC(c3ccccc3)(N(C)C)CC2)[nH]c2ccncc12
Temperature: 100 °C
Yield: 21.6 %

Procedure:
4-Amino-3-iodopyridine (2,331 mg, 10.60 mmol), 4-(dimethylamino)-4-phenyl-1-(prop-1-ynyl)cyclohexanol (3,000 mg, 11.66 mmol, diastereomer mixture), lithium chloride (472 mg, 11.13 mmol) and sodium carbonate (3,369 mg, 31.79 mmol) were combined in dimethylformamide (absolute, 45 ml) in an argon atmosphere. The catalyst ([Pd(dppf)Cl2×CH2Cl2], 865 mg, 1.06 mmol) was then added. The red solution was heated at 100° C. (oil bath temperature) for 4 h. The black reaction mixture was cooled to room temperature and water (50 ml; stirring for 10 min), methylene chloride (50 ml) and saturated sodium chloride solution (100 ml for better phase separation) were added in succession. The phases were separated. The mixture was filtered over kieselguhr beforehand. The aqueous phase was extracted with methylene chloride (3×30 ml). The combined organic phases were washed with saturated sodium chloride solution (3×20 ml), dried with sodium sulfate and filtered and the volatile constituents were then removed completely in vacuo. The residue was absorbed on silica gel and separated by chromatography (silica gel [200 g]; chloroform/ethanol [9:1 1,000 ml, 5:1, 500 ml, 3:1, 500 ml, 1:1, 500 ml and 1:3, 500 ml]). 800 mg of 4-dimethylamino-1-(3-methyl-1H-pyrrolo[3,2-c]pyridin-2-yl)-4-phenylcyclohexanol (non-polar diastereoisomer) were isolated as a colourless solid and 765 mg of the polar diastereoisomer were isolated as a colourless solid.
Reaction SMILES: [CH3:1][C:2]([CH3:45])([CH3:44])[CH:3]([NH:16][C:17]1[C:22]([F:23])=[CH:21][N:20]=[C:19]([C:24]2[C:32]3[C:27](=[N:28][CH:29]=[C:30]([F:33])[CH:31]=3)[N:26]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:25]=2)[N:18]=1)[CH2:4][CH2:5][Se]C1C=CC=CC=1[N+]([O-])=O.C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)(Cl)Cl.ClCCl>[CH3:1][C:2]([CH3:45])([CH3:44])[CH:3]([NH:16][C:17]1[C:22]([F:23])=[CH:21][N:20]=[C:19]([C:24]2[C:32]3[C:27](=[N:28][CH:29]=[C:30]([F:33])[CH:31]=3)[N:26]([S:34]([C:37]3[CH:38]=[CH:39][C:40]([CH3:41])=[CH:42][CH:43]=3)(=[O:36])=[O:35])[CH:25]=2)[N:18]=1)[CH:4]=[CH2:5]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC(CC[Se]c4ccccc4[N+](=O)[O-])C(C)(C)C)n3)c3cc(F)cnc32)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: C=CC(Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of racemic N-(4,4-dimethyl-1-((2-nitrophenyl)selanyl)pentan-3-yl)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-amine, 88a, (1.01 g, 1.45 mmol) in chloroform (15 mL) was added mCPBA (0.40 g of 77%, 1.79 mmol). After stirring for 1 hour at room temperature, the mixture was diluted with dichloromethane (100 mL) and the resulting solution was washed with aqueous sodium bicarbonate solution. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0 to 100% EtOAc/Hexanes) to afford 623 mg of the desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, (M+H) 496.76.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][C:4](=[O:12])[CH2:3][C:2]1=[O:13].[C:14]1([CH3:26])[CH:19]=[CH:18][C:17]([S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])=[CH:16][CH:15]=1>C1C=CC=CC=1>[C:14]1([CH3:26])[CH:15]=[CH:16][C:17]([S:20]([NH:23][C:24]([CH:3]2[C:2](=[O:13])[CH2:1][C:6]3([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)[CH2:5][C:4]2=[O:12])=[O:25])(=[O:21])=[O:22])=[CH:18][CH:19]=1
Reactant: O=C1CC(=O)CC2(CCCCC2)C1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)NC(=O)C2C(=O)CC3(CCCCC3)CC2=O)cc1

Procedure:
Reaction of equimolar amounts of spiro[5.5]undecane-2,4-dione with p-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 3-[N-(p-TOLUENESULFONYL)CARBAMOYL]SPIRO[5.5]UNDECANE-2,4-DIONE, m.p. 150.5°-152° C. (corr.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([O:19]C(OC)=O)[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[O-]CC.[Na+].CC(O)=O>CCO>[CH2:1]([O:3][C:4](=[O:24])[C:5]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([OH:19])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cc(OC(=O)OC)cc2ccccc12
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1cc(O)cc2ccccc12
Temperature: 5 °C
Reaction time: 1 h

Procedure:
1.35 g (4.1 mmol) of 2-(3-methoxycarbonyloxy-naphthalen-1-yloxy)-2-methyl-propionic acid ethyl ester was dissolved in 30 ml of EtOH and cooled down to 5° C.; while stirring, 1.66 ml=1.45 g (4.5 mmol) of a solution of sodium ethoxide (21% in EtOH) was added and the reaction mixture then warmed up to ambient temperature. After 1 hour, it was poured into crashed ice/MeCl2, the pH was adjusted to 5-6 with AcOH (1N) and the reaction mixture was subsequently extracted twice with MeCl2; the organic phases were washed with water, dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (SiO2, gradient of MeCl2/MeOH) to finally give 0.95 g of the title compound as light brown oil.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][CH:37]([NH:1][CH2:2][C@H:3]([OH:13])[CH2:4][O:5][C:6]4[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=4)[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: NC[C@H](O)COc1ccc(O)cc1
Reactant: COc1ccc(NS(=O)(=O)c2ccc(N3CCC(=O)CC3)cc2)cc1OC
Product: COc1ccc(NS(=O)(=O)c2ccc(N3CCC(NC[C@H](O)COc4ccc(O)cc4)CC3)cc2)cc1OC

Procedure:
The title compound was prepared from 4-((2S)-3-Amino-2-hydroxy-propoxy)-phenol and Reference Example 73, N-(3,4-dimethoxy-phenyl)-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to the procedure of Example 1 as an off-white solid; mp 101-106° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.15-1.30 (m, 2H), 1.70-1.90 (m, 2H), 2.50-2.90 (m, 5H), 3.61 (s, 3H) 3.63 (s, 3H), 3.60-3.90 (m, 5H), 6.45 (dd, 1H), 6.60-6.80 (m, 8H), 6.90 (d, 1H), 7.45 (d, 1H); MS (ES) m/z: 557.9 (MH+); HRMS Calcd. for C28H36N3O7S (MH+): 558.2274. Found: 558.2293.
Reaction SMILES: [CH:1]1([C:5]([NH2:7])=[NH:6])[CH2:4][CH2:3][CH2:2]1.[C:8]([OH:16])(=[O:15])/[C:9](=[C:11](\[CH:13]=O)/[Br:12])/Br>>[Br:12][C:11]1[C:9]([C:8]([OH:16])=[O:15])=[N:6][C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[N:7][CH:13]=1
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Reactant: N=C(N)C1CCC1
Product: O=C(O)c1nc(C2CCC2)ncc1Br

Procedure:
The product was obtained starting from cyclobutanecarboxamidine (200 mg, 1.5 mmol) and mucobromic acid (180 mg, 0.7 mmol) according to the method described in intermediate A-4, step 1 as light brown solid (38 mg, 21%).
Reaction SMILES: [CH2:1]([S:3]([C:5]1[N:9]=[CH:8][NH:7][N:6]=1)=[O:4])[CH3:2].[CH2:10]([N:13]([CH2:17][CH3:18])[C:14](Cl)=[O:15])[CH:11]=[CH2:12].C(N(CC)CC)C>O1CCCC1>[CH2:10]([N:13]([CH2:17][CH3:18])[C:14]([N:7]1[CH:8]=[N:9][C:5]([S:3]([CH2:1][CH3:2])=[O:4])=[N:6]1)=[O:15])[CH:11]=[CH2:12]
Reactant: CCS(=O)c1nc[nH]n1
Reactant: C=CCN(CC)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN(CC)C(=O)n1cnc(S(=O)CC)n1

Procedure:
A mixture of 7.25 g. 3-ethylsulphinyl-1,2,4-triazole, 7.8 g. N-allyl-N-ethylcarbamoyl chloride, 7.5 ml. dry triethylamine and 100 ml. dry tetrahydrofuran was refluxed under anhydrous conditions for 4 hours. The cooled reaction mixture was filtered and the filtrate distilled under reduced pressure to give 1-(N-allyl-N-ethylcarbamoyl)-3-ethylsulphinyl-1,2,4-triazole as a residual oil, nD25 1.5328.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34]C(OC(C)(C)C)=O)=[CH:30][CH:29]=2)[C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[C:1]([O:5][C:6](=[O:42])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([NH2:34])=[CH:32][CH:33]=2)[C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:8])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2ccc(NC(=O)OC(C)(C)C)cc2)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2ccc(N)cc2)nc1
Reaction time: 2.5 h
Yield: 77.7 %

Procedure:
2-[(4-{2-[{4-[(tert-Butoxycarbonyl)amino]benzyl}(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (1.2 g) synthesized in Example 439-1 was dissolved in dichloromethane (20 mL), p-toluenesulfonic acid monohydrate (3.64 g) was added thereto by small portions at room temperature. After 2.5 hr, the mixture was diluted with dichloromethane, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:1 to 1:1) to give the title compound (0.78 g) as a colorless oil.
Reaction SMILES: [C:1]([C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH2:8][CH:9]=[CH2:10])[CH2:4][C:5]([OH:7])=O)#[N:2].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C=O)C>[C:1]([C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH2:8][CH:9]=[CH2:10])[CH2:4][C:5]([NH:23][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=1)=[O:7])#[N:2]
Reactant: C=CCC(C#N)(CC(=O)O)c1ccccc1
Reactant: NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: C=CCC(C#N)(CC(=O)NCc1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution f 3-cyano-3-phenylhex-5-enoic acid (5.66 g, 26.3 mmol) and 4-fluorobenzylamine (3.95 g, 31.6 mmol) in DMF was added 1-hydroxybenzotriazole hydrate (6.04 g, 39.4 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.56 g, 39.4 mmol), and triethylamine (3.19 g, 31.5 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under vacuum. The residue was partitioned between EtOAc and water. The organic extract was dried with Na2SO4, filtered, and concentrated under vacuum to provide the title compound as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.47 (d, J=7.9 Hz, 2H), 7.36 (t, J=7 Hz, 2H) 7.35 (t, J=7 Hz, 1H), 7.04 (t, J=8.9 Hz, 2H), 6.97 (t, J=8.6 Hz, 2H), 5.53 (m, 1H), 5.12 (m, 2H), 4.21 (m, 1H), 4.08 (m, 1H), 2.88 (m, 3H), 2.77 (m, 1H) ppm. ES MS M+1=323.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][N:4](C(OCC(Cl)(Cl)Cl)=O)[CH2:3]1>C(O)(=O)C.[Zn]>[OH:1][C@H:2]1[C@H:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][NH:4][CH2:3]1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1C[C@@H](O)[C@H](Oc2ccccc2)C1
Agent: [Zn]
Solvent: CC(=O)O
Product: O[C@@H]1CNC[C@H]1Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.77 g (0.005 mol) of the resulting trans-3-hydroxy-4-phenoxy-1-(β,β,β-trichloroethoxycarbonyl)-pyrrolidine are dissolved in 20 ml of 90% strength acetic acid and the solution is treated at 0° with 2 g of zinc dust in portions. The reaction mixture is then stirred at room temperature for one hour and filtered through a layer of diatomaceous earth and the filtrate is rendered alkaline with concentrated sodium hydroxide solution and extracted 3 times with ether. The organic phase is washed with water, dried over calcium chloride and evaporated under a water pump vacuum, and trans-3-hydroxy-4-phenoxy-pyrrolidine is obtained in the form of the crude base, which crystallises from methylene chloride/hexane; melting point 120°-122°. The neutral fumarate of this compound, which has a melting point of 144°-146°, is obtained by reaction with a solution of fumaric acid in methanol/ether.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([NH:9][C:10]([NH:12][C:13]1[S:14][C:15]2[C:21]([C:22]#[C:23][C:24]3[N:25]([CH3:29])[CH:26]=[N:27][CH:28]=3)=[CH:20][C:19]([C:30]3[CH:31]=[N:32][C:33]([N:36]4[CH2:41][CH2:40][C:39]([CH3:47])([C:42]([O:44]CC)=[O:43])[CH2:38][CH2:37]4)=[N:34][CH:35]=3)=[CH:18][C:16]=2[N:17]=1)=[O:11])[CH3:8]>CS(C)=O>[CH2:7]([NH:9][C:10]([NH:12][C:13]1[S:14][C:15]2[C:21]([C:22]#[C:23][C:24]3[N:25]([CH3:29])[CH:26]=[N:27][CH:28]=3)=[CH:20][C:19]([C:30]3[CH:35]=[N:34][C:33]([N:36]4[CH2:37][CH2:38][C:39]([CH3:47])([C:42]([OH:44])=[O:43])[CH2:40][CH2:41]4)=[N:32][CH:31]=3)=[CH:18][C:16]=2[N:17]=1)=[O:11])[CH3:8]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(C#Cc3cncn3C)c2s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)cc(C#Cc3cncn3C)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
Potassium tertiary butoxide (150 mg, 1.35 mmol) was added to a solution of ethyl 1-[5-[2-(ethylcarbamoylamino)-7-[2-(3-methylimidazol-4-yl)ethynyl]-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate in DMSO (1.5 mL). The mixture was stirred at rt for 2 h after which time LCMS indicated clean conversion to the acid. The mixture was filtered through cotton wool to remove solid particulates and purified by preparative-HPLC to give Compound 144 as a white solid, 43 mg, 29% yield for 2 steps. 1H NMR δ (ppm) (DMSO-d6): 8.81 (2H, s), 7.95 (1H, d, J=1.55 Hz), 7.89 (1H, s), 7.73 (1H, d, J=1.56 Hz), 7.45 (1H, s), 7.27 (1H, t, J=5.58 Hz), 4.32 (2H, dt, J=13.70, 4.46 Hz), 3.83 (3H, s), 3.37 (2H, ddd, J=14.10, 10.43, 4.06 Hz), 3.23 (2H, p, J=6.90 Hz), 2.06 (2H, dt, J=13.39, 3.62 Hz), 1.41 (2H, ddd, J=13.36, 10.05, 3.86 Hz), 1.21 (3H, s), 1.13 (3H, t, J=7.15 Hz). MS: 545 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Cl-].[Cl:12][C:13]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:14]=1[CH:15]=[N+:16]([CH3:18])[CH3:17].ClC1C=C(Cl)C=CC=1C=O.CNC>>[Cl:12][C:13]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:14]=1[CH:15]([N:16]([CH3:18])[CH3:17])[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1
Reactant: Cn1ccc2ccccc21
Reactant: C[N+](C)=Cc1ccc(Cl)cc1Cl
Agent: CNC
Agent: O=Cc1ccc(Cl)cc1Cl
Agent: [Cl-]
Product: CN(C)C(c1ccc(Cl)cc1Cl)c1cn(C)c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-methylindole and (2,4-dichloro-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 2,4-dichloro-benzaldehyde and dimethylamine.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:31]=[C:30]([NH:32][CH3:33])[C:29]([NH2:34])=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C.[CH3:44][O:45][C:46]([CH:48]1[CH2:50][CH:49]1[C:51](O)=O)=[O:47]>CN(C=O)C>[Br:25][C:26]1[CH:27]=[CH:28][C:29]2[N:34]=[C:51]([CH:49]3[CH2:50][CH:48]3[C:46]([O:45][CH3:44])=[O:47])[N:32]([CH3:33])[C:30]=2[CH:31]=1
Reactant: COC(=O)C1CC1C(=O)O
Reactant: CNc1cc(Br)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1CC1c1nc2ccc(Br)cc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.6 %

Procedure:
HATU (554 mg) was added to a solution of 5-bromo-N1-methylbenzene-1,2-diamine (279 mg), N,N-diisopropylethylamine (0.727 ml) and (1RS,2SR)-2-(methoxycarbonyl)cyclopropanecarboxylic acid (200 mg) in DMF (5 ml) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in AcOH (5 ml), and the mixture was stirred at 80° C. for 1 h. After concentration of the mixture, the residue was neutralized with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/EtOAc) to give the title compound (80 mg) as an off-white solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:28])[NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:14]=1)[C:7](=[O:29])[N:6]([CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:5]2=[O:36].C(=O)([O-])[O-].[K+].[K+].[CH2:43]=[CH:44][CH2:45][CH2:46][CH3:47]>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:43]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:28])[NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:14]=1)[C:7](=[O:29])[N:6]([CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:5]2=[O:36])=[CH:44][CH2:45][CH2:46][CH3:47]
Reactant: COC(=O)CCn1c(=O)c2cc(I)ccc2n(Cc2cn(C(=O)NC(C)(C)C)c3ccccc23)c1=O
Reactant: C=CCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: CCCC=Cc1ccc2c(c1)c(=O)n(CCC(=O)OC)c(=O)n2Cc1cn(C(=O)NC(C)(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.4 %

Procedure:
1.09 g (1.8 mmol) of 6-iodo-3-(2-methoxycarbonylethyl)-1-(N-t-butylcarbamoyl-3-indolylmethyl)quinazoline-2,4-dione and 0.75 g (5.4 mmol) of potassium carbonate were introduced in 15 ml of DMF, and 0.63 g (9.0 mmol) of 1-pentene, 0.58 g (1.8 mmol) of tetrabutylammonium bromide and 10 mg of palladium acetate were added. The mixture was stirred at room temperature for 48 h and then concentrated under reduced pressure. The crude product was chromatographed on silica gel, eluent dichloromethane (2% methanol). 0.69 g (70%) of product, RF 0.12 (dichloromethane+2% methanol) was obtained.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH2:8][CH2:9][N:10]([CH2:14][CH2:15][O:16][CH3:17])[CH2:11][C:12]#[CH:13].[C:18](=[O:20])=[O:19].O>CCCCCC.O1CCCC1.CO>[CH3:6][O:7][CH2:8][CH2:9][N:10]([CH2:14][CH2:15][O:16][CH3:17])[CH2:11][C:12]#[C:13][C:18]([OH:20])=[O:19]
Reactant: O=C=O
Reactant: C#CCN(CCOC)CCOC
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COCCN(CC#CC(=O)O)CCOC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyl lithium in hexane (42 mL, 2.5M in n-hexane) was slowly added to bis-(2-methoxy-ethyl)-prop-2-ynyl-amine (18 g, 105 mmol) in 80 mL of tetrahydrofuran under nitrogen. The mixture was stirred for 1 h at −78° C., then dry carbon dioxide was passed through overnight. The resulting solution was poured into water and washed with ethyl acetate. The aqueous layer was evaporated under reduced pressure to give the crude acid. The dry acid was dissolved in methanol, and the insoluble salt was removed via filtration. The filtrate was collected and dried in vacuo to give 18 g of 4-[bis-(2-methoxy-ethyl)-amino]-but-2-ynoic acid: mass spectrum (m/e):M−H 214.
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][C:4]1[CH:24]=[CH:23][C:7]2[NH:8][C:9]([S:11][CH2:12][C:13]3[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][N:14]=3)=[N:10][C:6]=2[CH:5]=1.[OH-].[Na+].[O-:28]S([O-])(=S)=O.[Na+].[Na+].C(O)(=O)C>CO.O.OO>[CH3:22][O:21][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:12][S+:11]([O-:28])[C:9]2[NH:8][C:7]3[CH:23]=[CH:24][C:4]([O:3][CH:2]([F:1])[F:25])=[CH:5][C:6]=3[N:10]=2)[C:18]=1[O:19][CH3:20]
Reactant: COc1ccnc(CSc2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Reactant: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
2 g of 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-1H-benzimidazole was suspended in 36 ml of methanol at room temperature, to which 1.69 g of 45% NaOH in 14 ml water was added while stirring. 0.09 g of Na2WO4·2H2O oxidation catalyst was dissolved in 0.7 g H2O2 (50% aqueous solution), and further diluted with 10 ml of water. The oxidant/catalyst solution was added to the reactant/base solution dropwise so that the addition was completed in about 30 minutes while stirring at room temperature. The reaction was continued for additional 10 minutes while stirring. 10 ml of 10% Na2S2O3 aqueous solution was then added, and the resulting mixture was subjected to a reduced pressure to remove methanol therefrom. Finally, a precipitate was formed after adding a diluted acetic acid aqueous solution to a pH value of about 8, which was filtered, water washed, and dried in vacuo to obtain Pantoprazole with a yield of about 90.2% (LC purity>95%).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[CH:7]([C:12]([O:14]CC3C=CC([N+]([O-])=O)=CC=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[SH:27][C@@H:28]1[CH2:32][N:31]([CH3:33])[C@H:30]([C:34]([N:36]2[CH2:41][CH2:40][N:39]([C:42](=[N:44]C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[CH3:43])[CH2:38][CH2:37]2)=[O:35])[CH2:29]1>>[C:42]([N:39]1[CH2:40][CH2:41][N:36]([C:34]([C@@H:30]2[CH2:29][C@H:28]([S:27][C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]4[C:7]=3[C:12]([OH:14])=[O:13])[CH2:32][N:31]2[CH3:33])=[O:35])[CH2:37][CH2:38]1)(=[NH:44])[CH3:43]
Reactant: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCN(C(=O)[C@@H]2C[C@H](S)CN2C)CC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: CC(=N)N1CCN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2C)CC1
Yield: 8.5 %

Procedure:
Following a procedure similar to that described in Example 1, but using 181 mg of 4-nitrobenzyl (1R, 5R, 6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 220 mg of (2S, 4S)-4-mercapto-2-[4-(N-4-nitrobenzyloxycarbonylacetimidoyl)piperazin-1-ylcarbonyl]-1-methylpyrrolidine (prepared as described in Preparation 44), 20 mg of the title compound were obtained, as a powder.