Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([C:18]2[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=2)[CH2:13]1.[H-].[Na+].Br[CH2:28][C:29]([O:31]CC)=[O:30].CC(C)([O-])C.[K+]>CN(C=O)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([C:18]2[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=2)[O:24][CH2:28][C:29]([OH:31])=[O:30])[CH2:13]1
Reactant: Oc1cccc([C@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)COc1cccc([C@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 71.5 %

Procedure:
To a solution of (R*)-3-{1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenol (201 mg, 0.62 mmol) in dry DMF (2 ml) was added NaH (60% in oil, 30 mg, 0.75 mmol) under nitrogen atmosphere and the mixture was stirred at 0° C. for 5 min, then allowed to warm to RT and stirred for further 2.5 h. The reaction mixture was cooled to 0° C., ethyl bromoacetate (106 mg, 0.62 mmol) was added and the mixture was stirred at RT overnight. Potassium tert-butoxide (69 mg, 0.61 mmol) was added and the mixture was stirred for 3 h at RT and filtered. The precipitate was dissolved in dry MeOH, the solution filtered and evaporated to dryness to give 170 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:12])=[N:5][C:6]([N+:9]([O-])=O)=[CH:7][CH:8]=1>[Pd].CO>[NH2:9][C:6]1[N:5]=[C:4]([CH3:12])[C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: COc1ccc([N+](=O)[O-])nc1C
Agent: [Pd]
Solvent: CO
Product: COc1ccc(N)nc1C

Procedure:
3-Methoxy-2-methyl-6-nitropyridine (0.317 g.) in 20 ml. of methanol, was hydrogenated over 0.1 g. of 5% palladium-on-carbon catalyst. The catalyst was removed by filtration and the filtrate was concentrated to dryness to give 6-amino-3-methoxy-2-methylpyridine, which was used directly in the next step.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[C:17]2[C:19]3=[C:20]4[C:10]([CH:11]=[CH:12][CH:13]=[C:14]4[CH:15]=[CH:16]2)=[CH:9][CH:8]=[C:7]3[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:21]N1C(=O)CCC1=O>O1CCCC1>[Br:21][C:13]1[C:14]2[C:20]3=[C:19]4[C:17](=[CH:16][CH:15]=2)[CH:18]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=[C:7]4[CH:8]=[CH:9][C:10]3=[CH:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1cc2ccc3cccc4ccc(c1)c2c34
Solvent: C1CCOC1
Product: CC(C)(C)c1cc2ccc3ccc(Br)c4ccc(c1)c2c34
Temperature: 30 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a mixed solution of 120 g (content 79.2%) of 2-t-butylpyrene, and 3000 ml of tetrahydrofuran was added 69.66 g of N-bromosuccinimide under a nitrogen stream. This mixed solution was stirred at 30° C. for about 3 hours, and concentrated, 500 ml of methanol was added, and the mixture was stirred for about 1 hour, and filtered. To the resulting solid was added 500 ml of hexane, and the mixture was heated and stirred for about 1 hour, and filtered. After the resultant was vacuum dried, 106.9 g of 1-bromo-7-t-butylpyrene was obtained.
Reaction SMILES: O.[NH2:2][NH2:3].[CH:4]([CH:7]([C:10]#[N:11])[C:8]#[N:9])([CH3:6])[CH3:5]>CCO>[CH:4]([C:7]1[C:10]([NH2:11])=[N:2][NH:3][C:8]=1[NH2:9])([CH3:6])[CH3:5]
Reactant: NN
Reactant: CC(C)C(C#N)C#N
Solvent: O
Solvent: CCO
Product: CC(C)c1c(N)n[nH]c1N
Temperature: 80 °C

Procedure:
Hydrazine monohydrate (2.05 mL, 42 mmol) was added to a solution of the product from Example 112A (1.16 g, 10.7 mmol) in EtOH (15 mL). The reaction flask was evacuated and purged with nitrogen (3 cycles), then heated at 80° C. for 22 hours. The yellow solution was cooled to room temperature and concentrated under vacuum. Toluene (8 mL) was added to the residue, and the mixture was concentrated under vacuum to remove excess hydrazine (repeated twice more) to provide the title compound. MS (ESI) m/z 141 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[CH:17]([OH:20])([CH3:19])[CH3:18].C1CCN2C(=NCCC2)CC1>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10]([O:20][CH:17]([CH3:19])[CH3:18])[N:9]=[C:8]([NH2:16])[N:7]=1
Reactant: CC(C)O
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)Oc1nc(N)nc(-c2ccco2)c1I

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine, isopropanol and DBU in THF. ES-MS m/e (%): 346 (M+H+, 100).
Reaction SMILES: [I:1]Cl.[N+:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)([O-:5])=[O:4].O>C(O)(=O)C>[I:1][C:11]1[CH:12]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=[CH:8][C:9]=1[NH2:10]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: ClI
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc([N+](=O)[O-])cc1I
Yield: 107.6 %

Procedure:
A solution of iodine monochloride (23.54 g) in acetic acid (50 ml) is added dropwise over an hour to a stirred solution of p-nitroaniline (20 g). After stirring for another hour, the dark mixture is poured into water (1 liter), the precipitated yellow solid is collected and dried to afford 41.15 g title product, m.p. 90°-95° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:6]1[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH2:11][CH:10]([CH2:18][O:19][Si](C(C)(C)C)(C)C)[CH2:9][N:8]3[CH:7]=1)=O.[F:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([CH2:38][C:39]([NH2:41])=[O:40])=[CH:34][NH:35]2)=[CH:31][CH:30]=1>>[F:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([CH:38]3[CH:4]([C:6]4[C:16]5=[C:17]6[C:12](=[CH:13][CH:14]=[CH:15]5)[CH2:11][CH:10]([CH2:18][OH:19])[CH2:9][N:8]6[CH:7]=4)[C:3](=[O:2])[NH:41][C:39]3=[O:40])=[CH:34][NH:35]2)=[CH:31][CH:30]=1
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CC(CO[Si](C)(C)C(C)(C)C)C2
Reactant: NC(=O)Cc1c[nH]c2cc(F)ccc12
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CC(CO)C3)C1c1c[nH]c2cc(F)ccc12

Procedure:
Beginning with (5-(tert-butyldimethylsilyloxymethyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester and (6-fluoro-1H-indol-3-yl)acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [C:1]([CH2:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:20].C(N(CC)CC)C>C(OCC)C>[CH2:22]([O:21][C:19]([O:17][C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCOC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCOC(=O)OC(=CC(=O)c1ccccc1)c1ccccc1

Procedure:
The preparation is carried out as described in Example 1, using 44.8 g (0.2 mole) of dibenzoyl methane, 61.0 g (0.2 mole) of n-hexadecyl chloroformate and 200 ml of diethyl ether as well as 22 g (0.22 mole) of triethylamine. The resultant yellow viscous liquid crystallises out. The crystals melt at 39°-40° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][NH2:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[C:14]1[C:15]([NH2:21])=[N:16][CH:17]=[C:18]([Br:20])[N:19]=1.C(N(CC)CC)C>C(Cl)Cl.O>[Br:20][C:18]1[N:19]=[C:14]([NH:12][CH2:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)[C:15]([NH2:21])=[N:16][CH:17]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: NCc1ccc2ncccc2c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Nc1ncc(Br)nc1NCc1ccc2ncccc2c1
Temperature: 130 °C
Yield: 92.2 %

Procedure:
A mixture of quinolin-6-ylmethanamine (3.6 g, 22.76 mmol), 3,5-dibromopyrazin-2-amine (5.75 g, 22.76 mmol) and triethyl amine (4.61 g, 45.5 mmol) was heated with microwave irradiation at 130° C. for 5 h. The reaction mixture was diluted with CH2Cl2 and water and the organic layer was separated, washed with aqueous NH4Cl, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography with EtOAc:hexanes to provide 6.93 g (92%) of the title compound. LCMS (method A): [MH]+=330, tR=4.89 min.
Reaction SMILES: OO.[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[CH3:14])[NH:10]C(=O)[C:8]2=[O:16].S(=O)(=O)(O)[OH:18]>[OH-].[Na+]>[NH2:10][C:11]1[CH:12]=[C:13]([CH3:14])[C:5]([O:4][CH3:3])=[CH:6][C:7]=1[C:8]([OH:16])=[O:18]
Reactant: COc1cc2c(cc1C)NC(=O)C2=O
Reactant: O=S(=O)(O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(C(=O)O)c(N)cc1C
Yield: 61 %

Procedure:
10% Hydrogen peroxide (H2O2) (80 mL) was added dropwise to a stirring solution of 5-methoxy-6-methyl-1H-indole-2,3-dione (4.7 g, 24.6 mmol) in 3N NaOH (aq.) (100 mL). The H2O2 solution was added over a period of 1.5 h in order to keep the temperature below 35° C. The solution was then acidified to pH 4 with 2.5M sulfuric acid. A precipitate formed and was collected by filtration. The solid was washed with water and dried to give 2-amino-5-methoxy-4-methylbenzoic acid (2.7 g, 14.9 mmol, 61%).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[C:23]([O:26][CH2:27][C@@:28]1([CH3:50])[O:32][C@@H:31]([N:33]2[CH:41]=[C:39]([CH3:40])[C:37](=O)[NH:36][C:34]2=[O:35])[C@H:30]([O:42][C:43](=[O:45])[CH3:44])[C@@H:29]1[O:46][C:47](=[O:49])[CH3:48])(=[O:25])[CH3:24]>ClCCCl>[C:23]([O:26][CH2:27][C@@:28]1([CH3:50])[O:32][C@@H:31]([N:33]2[CH:41]=[C:39]([CH3:40])[C:37](=[S:10])[NH:36][C:34]2=[O:35])[C@H:30]([O:42][C:43](=[O:45])[CH3:44])[C@@H:29]1[O:46][C:47](=[O:49])[CH3:48])(=[O:25])[CH3:24]
Reactant: CC(=O)OC[C@@]1(C)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: ClCCCl
Product: CC(=O)OC[C@@]1(C)O[C@@H](n2cc(C)c(=S)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 8 h
Yield: 137.3 %

Procedure:
Lawesson's reagent (119 mg, 0.29 mmol) was added under argon to a solution of 15 (0.167 g, 4.19 mmol) in anhydrous 1,2-dichloroethane (11 mL) and the reaction mixture was stirred overnight under reflux. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography [eluent: stepwise gradient of methanol (1–2%) in chloroform] to give pure 16 (0.165 g, 95%) as a yellow foam. 1H-NMR (DMSO-d6): δ 12.81 (s, 1H, NH), 7.64 (s, 1H, H-6), 5.84 (d, 1H, H-1′, J1′-2′=4.66 Hz), 5.5–5.4 (m, 2H, H-2′ and H-3′), 4.11 (dd, 2H, H-5′ and H-5″, J=11.7 Hz, J=31.3 Hz), 2.0–1.8 (m, 12H, 3 CH3CO2 and CH3), 1.33 (s, 3H, CH3); MS (matrix GT): FAB>0 m/z 829 (2M+H)+, 415 (M+H)+, 273 (S)+, 143 (BH2)+, 43 (CH3CO)+ FAB<0 m/z 827 (2M−H)−, 413 (M−H)−, 141 (B)31 , 59 (CH3CO2)−.
Reaction SMILES: [CH:1]1[C:13]2[C:12]3([C:25]4[CH:24]=[C:23]([C:26]([OH:28])=[O:27])[CH:22]=[CH:21][C:20]=4[C:19]4[C:14]3=[CH:15][C:16](C(O)=O)=[CH:17][CH:18]=4)[C:11]3[C:6](=[CH:7][CH:8]=[C:9](C(O)=O)[CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:35]([OH:37])=[O:36].BrC1C=CC2C3C(=CC(Br)=CC=3)C3(C4C=C(Br)C=CC=4C4C3=CC(Br)=CC=4)C=2C=1.C1C2C3(C4C=C(C(O)=O)C=CC=4C4C3=CC=CC=4)C3C(=CC=C(C(O)=O)C=3)C=2C=CC=1C(O)=O.BrC1C=CC2C3C(=CC(Br)=CC=3)C3(C4C=C(Br)C=CC=4C4C3=CC=CC=4)C=2C=1.C1C2C3(C4C=C(C(O)=O)C=C(C(O)=O)C=4C4C3=CC(C(O)=O)=CC=4)C3C(=CC=C(C(O)=O)C=3)C=2C(C(O)=O)=CC=1C(O)=O.BrC1C=C(Br)C2C3C(=CC(Br)=CC=3)C3(C4C=C(Br)C=C(Br)C=4C4C3=CC(Br)=CC=4)C=2C=1>>[CH:1]1[C:13]2[C:12]3([C:25]4[CH:24]=[C:23]([C:26]([OH:28])=[O:27])[CH:22]=[CH:21][C:20]=4[C:19]4[C:14]3=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:35]([OH:37])=[O:36]
Reactant: O=C(O)c1ccc2c(c1)C1(c3cc(C(=O)O)ccc3-2)c2cc(C(=O)O)ccc2-c2ccc(C(=O)O)cc21
Agent: Brc1ccc2c(c1)C1(c3cc(Br)ccc3-2)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: Brc1ccc2c(c1)C1(c3cc(Br)ccc3-c3c(Br)cc(Br)cc31)c1cc(Br)cc(Br)c1-2
Agent: Brc1ccc2c(c1)C1(c3ccccc3-2)c2cc(Br)ccc2-c2ccc(Br)cc21
Product: O=C(O)c1ccc2c(c1)C1(c3ccccc3-2)c2ccccc2-c2ccc(C(=O)O)cc21

Procedure:
i-k) 9,9′-Spirobifluorene-2,2′,7,7′-tetracarboxylic acid can be prepared in an analogous way from 2,2′,7,7′-tetrabromo-9,9′-spirobifluorene; likewise, 9,9′-spirobifluorene-2,2′,7-tricarboxylic acid can be prepared from 2,2′,7-tribromo-9,9′-spirobifluorene and 9,9′-spirobifluorene-2,2′,4,4′,7,7′-hexacarboxylic acid can be prepared from 2,2′,4,4′,7,7′-hexabromo-9,9′-spirobifluorene by analogous methods.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C@H:4]([NH:10][C@H:11]([C:13]([N:15]1[C@@H:23]([C:24]([O:26]CC2C=CC=CC=2)=[O:25])[CH2:22][C@H:21]2[C@@H:16]1[CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:14])[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6].O>C1CCCCC1.[Pd]>[CH3:1][CH2:2][CH2:3][C@H:4]([NH:10][C@H:11]([C:13]([N:15]1[C@H:23]([C:24]([OH:26])=[O:25])[CH2:22][C@H:21]2[C@@H:16]1[CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:14])[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCC[C@H](N[C@@H](C)C(=O)N1[C@@H](C(=O)OCc2ccccc2)C[C@@H]2CCCC[C@@H]21)C(=O)OCC
Agent: [Pd]
Solvent: O
Solvent: C1CCCCC1
Product: CCC[C@H](N[C@@H](C)C(=O)N1[C@H](C(=O)O)C[C@@H]2CCCC[C@@H]21)C(=O)OCC
Reaction time: 3 h

Procedure:
The Perindopril benzyl ester (20 g, 0.0436 moles) was dissolved in cyclohexane (80 ml) in a round bottom flask and the resulting solution was transferred into a hydrogenation bottle. To this was added 10% Palladium on carbon (10% loading), followed by water (70 ml). The reaction mixture was hydrogenated at 27° C. for 3 hrs, under 60 psi pressure when the reaction was complete. The reaction mixture was filtered off and the residue was washed with cyclohexane (20 ml). The filtrate was allowed to settle for 15 min. The aqueous phase was separated. It was washed with cyclohexane (20 ml, twice). Perindopril was isolated in an amount of 11.5 g (71.5%) from the aqueous layer by freeze drying.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:10]=2)=[CH:5][C:4]=1[OH:26].C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([CH:46]2[NH:55][C:54](=[O:56])[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[NH:47]2)=[CH:42][C:41]=1[O:57][CH3:58]>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[CH3:58][O:57][C:41]1[CH:42]=[C:43]([CH:46]2[NH:55][C:54](=[O:56])[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[NH:47]2)[CH:44]=[CH:45][C:40]=1[O:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][O:26][C:4]1[CH:5]=[C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:10]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCBr
Reactant: COc1ccc(-c2cc(-c3cc(OC)c(OC)c(OC)c3)no2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCOc1cc(-c2cc(-c3cc(OC)c(OC)c(OC)c3)no2)ccc1OC
Temperature: 30 °C
Reaction time: 30 h
Yield: 78.5 %

Procedure:
2-methoxy-5-(3-(3,4,5-trimethoxyphenyl)isoxazol-5-yl)phenol (29a) (357.36 mg 1.0 mmol) in DMF (20 mL) was added anhydrous potassium carbonate (690 mg, 5.0 mmol) and 2-[4-(5-Bromo-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one (2d) (419.29 mg, 1.0 mmol). The reaction mixture was stirred at a temperature of 30° C. for 30 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. Then to this ice is added and extracted with ethyl acetate. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (30d) (546 mg, 80% yield).
Reaction SMILES: C[O-].[Na+:3].CO.[CH3:6][C:7]1[CH:8]=[N:9][C:10]([CH2:16][S+:17]([O-:29])[C:18]2[NH:19][C:20]3[CH:21]=[CH:22][C:23]([O:27][CH3:28])=[CH:24][C:25]=3[N:26]=2)=[C:11]([CH3:15])[C:12]=1[O:13][CH3:14].CC(C)=O>C(C(C)=O)C(C)C>[CH3:6][C:7]1[CH:8]=[N:9][C:10]([CH2:16][S+:17]([O-:29])[C:18]2[N-:19][C:20]3[CH:21]=[CH:22][C:23]([O:27][CH3:28])=[CH:24][C:25]=3[N:26]=2)=[C:11]([CH3:15])[C:12]=1[O:13][CH3:14].[Na+:3]
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Solvent: CC(=O)CC(C)C
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Reaction time: 0.25 h

Procedure:
30% sodium methoxide in methanol (4.7 mL, 25.3 mmol) was added dropwise to a solution of esomeprazole (8.5 g, 24.6 mmol; 2.2% sulfone, 4.7% R-enantiomer) in methyl isobutyl ketone (60 mL). The mixture was stirred for 15 min. Acetone (60 mL) was added in 30 min. The resulting slurry was stirred overnight at room temperature. The solid was collected by filtration, rinsed with acetone (2×10 mL) and dried under reduced pressure at 50° C. to yield esomeprazole sodium. Yield: 5.5 g (61%). Sulfone content: 0.17%. R-enantiomer content: 0.00%.
Reaction SMILES: N.C[Si](C)(C)Cl.[N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][CH:8]=1.[CH:16]1([S:22]Cl)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C1(C)C=CC=CC=1.CCCCC>[CH:16]1([S:22][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[CH:8]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: ClSC1CCCCC1
Agent: C[Si](C)(C)Cl
Agent: N
Solvent: CCCCC
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)ncn2SC1CCCCC1
Reaction time: 10 h
Yield: 85.2 %

Procedure:
NH3 gas was passed into 80.4 g of trimethylchlorosilane in 500 ml of dry toluene at 50° to 60° C. to saturation. 59.1 g of benzimidazole were then added and the mixture was boiled for 10 hours under reflux. To remove excess ammonia, 250 ml of toluene were distilled off in vacuo, and 0.5 mol of cyclohexylsulphenyl chloride in 500 ml of pentane was then added dropwise. The mixture was subsequently stirred for 4 hours and filtered, and the solvent was removed in vacuo. 99 g of 1-cyclohexylthiobenzimidazole were obtained as a red-brown oil.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4F)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][N:28]([CH3:38])[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][NH:30]1>>[CH3:27][N:28]([CH3:38])[C:29]1[CH:34]=[CH:33][C:32]([O:25][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[CH2:17][CH2:16][C@H:15]3[O:14][C:12]2[CH:11]=[CH:10][C:9]3[C@H:5]([CH2:4][C:3]([OH:26])=[O:2])[CH2:6][O:7][C:8]=3[CH:13]=2)=[CH:31][N:30]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: CN(C)C1(B(O)O)C=CC=CN1
Product: CN(C)c1ccc(Oc2cccc3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)O)cn1

Procedure:
The methyl ester of the title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-dimethylamino-pyridineboronic acid following a procedure analogous to that described for Intermediate 6. The title compound is obtained after saponification of the methyl ester as described for Example 1. LC (method 2): tR=0.91 min; Mass spectrum (ESI+): m/z=465 [M+H]+.
Reaction SMILES: [C:1]1([C:11]2O[C:15](=O)[C:14]([C:18]#[N:19])=[C:13]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+]>C1COCC1>[C:1]1([C:11]2[C:12]3[CH2:11][C:1]4[C:2](=[CH:3][CH:4]=[CH:5][CH:10]=4)[C:15]=3[C:14]([C:18]#[N:19])=[C:13]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2cccc3ccccc23)oc1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1c(N2CCCCC2)cc(-c2cccc3ccccc23)c2c1-c1ccccc1C2

Procedure:
A mixture of 6-(naphthalen-1-yl)-2-oxo-4-(piperidin-1-yl)-2H-pyran-3-carbonitrile (330 mg), indanone-1 (132 mg) and NaH (39 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 188-190° C.; ESIMS 401 (M++1); IR (KBr) 2214 cm−1 (CN); 13C NMR (75.53 MHz, CDCl3): δ 22.86, 25.03, 34.33, 52.76, 97.13, 116.68, 117.50, 121.36, 123.53, 124.14, 124.34, 124.87, 124.91, 125.22, 125.94, 127.00, 127.19, 127.25, 129.68, 132.40, 135.37, 136.53, 138.21, 141.05, 143.26, 143.37, 156.43.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:15]([C:16](OC)=[O:17])=[CH:14][C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[OH:17][CH2:16][C:15]1[N:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[N:12]=[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=1
Reactant: COC(=O)c1cc(-c2ccccc2)nn1CCNC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCn1nc(-c2ccccc2)cc1CO
Temperature: 25 °C
Yield: 44.4 %

Procedure:
The compound prepared in Example 121 (0.620 g) was suspended in methanol (30 mL) and sodium borohydride (0.088 g) was added portion-wise to the stirred reaction mixture at room temperature. Excess sodium borohydride was added portion-wise to the reaction mixture and the system heated at reflux overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The solids were partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organics were washed with brine, dried, magnesium sulfate and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (pre-absorbed to silica) (eluant: 50-75% ethyl acetate/hexane 0.5% triethylamine) to furnish the title compound (0.253 g) having the following physical data.
Reaction SMILES: Cl[C:2]1[CH:23]=[C:22]([I:24])[CH:21]=[CH:20][C:3]=1[C:4]([C:6](=[CH:12][NH:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].CC([O-])(C)C.[K+]>CS(C)=O>[CH:14]1([N:13]2[C:20]3[C:3](=[CH:2][CH:23]=[C:22]([I:24])[CH:21]=3)[C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)C(=CNC1CCCCC1)C(=O)c1ccc(I)cc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(C2CCCCC2)c2cc(I)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
mg) A suspension of 17.8 g of ethyl 2-(2-chloro-4-iodo-benzoyl)-3-cyclohexylamino-acrylate in 150 ml of dimethyl sulphoxide is treated portionwise at room temperature while stirring with 4.75 g of potassium tert-butylate and the mixture is subsequently heated at 50° for 1 hr. The mixture is left to cool to room temperature, poured into 500 ml of ice-water and stirred for a further 30 min. The suspension is suction filtered, the filter residue is washed three times with 100 ml of water each time and three times with 100 ml of hexane each time and dried. Recrystallization of the crude product from ethyl acetate/hexane yields 14.8 g (90%) of ethyl 1-cyclohexyl-7-iodo-4-oxo-1,4-dihydro-quinoline-3-carboxylate as a colourless solid. M.p. 169°-171° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][NH:11][C@H:10]1[CH2:13][CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:16]1[S:17][C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:19]([CH3:21])[N:20]=1.C(N(C(C)C)CC)(C)C>>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][N:11]([C:16]2[S:17][C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:19]([CH3:21])[N:20]=2)[C@H:10]1[CH2:13][CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@@H]1NC[C@H]1NC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1sc(Br)nc1C
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(N2C[C@@H](NC(=O)OC(C)(C)C)[C@@H]2CC)nc1C
Yield: 76.8 %

Procedure:
The same operation as in Example (232c) was performed using trans(±)-3-(tert-butoxycarbonyl)amino-2-ethylazetidine obtained in Example (234e) (110 mg, 0.55 mmol), ethyl 2-bromo-4-methylthiazole-5-carboxylate (137 mg, 0.55 mmol) and diisopropylethylamine (0.19 mL, 1.10 mmol), to obtain 156 mg of the title compound as a pale yellow oily substance (77%).