Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[CH3:18][CH2:19][CH2:20][CH2:21][CH3:22].C[O:24][CH2:25][CH2:26]OC>>[C:25]([C:12]1[CH:11]=[CH:10][O:9][C:8]=1[C:6]([NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])(=[O:24])[C:26]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COCCOC
Reactant: CC(C)(C)NC(=O)c1ccco1
Reactant: CCCCC
Agent: [Li]C(C)(C)C
Product: CC(C)(C)NC(=O)c1occc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirring solution of N-tert-butylfuran-2-carboxamide (1.8 ml, 12 mmol) in 100 mL DME under argon at −78° C. was added tert-butyllithium, 1.7 M solution in pentane (14 ml, 24 mmol) slowly dropwise over 5 min. The heterogeneous reaction mixture was allowed to stir 1 h, at which point a solution of N-tert-butylfuran-2-carboxamide (1.8 ml, 12 mmol) in 10 mL DME was added over 5 min, dropwise. After 15 min, the bath was removed and the reaction was allowed to warm to ambient temperature. The reaction was quenched by addition of saturated aqueous ammonium chloride, water, and EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting material was purified by silica gel chromatography, ISCO, 80 g, 0-40% EtOAc/hexanes over 33 min to give a semi-solid. This material was triturated 3× hexanes to give 3-benzoyl-N-tert-butylfuran-2-carboxamide as white crystals. MS m/z=272 [M+H]+. Calc'd for C16H17NO3: 271.3.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=O)[CH:2]=1.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1.Cl>O.N1C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[CH:14][C:15]([OH:17])=[O:16])[CH:2]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cnc2ccccc2c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cnc2ccccc2c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
80 g of 3-quinoline carboxaldehyde, 85 g of malonic acid and 6.50 g of piperidine were added to 350 ml of pyridine, and stirred at 100° C. for 3 hours. After mixing with 1000 ml of distilled water, concentrated HCl was added thereto until pH of the solution became 4.8, and stirred for 1 hour. The resulting solid was filtrated under a reduced pressure, washed with 1500 ml of distilled water, and dried for 15 to 40 hours to obtain 96 g of the title compound as a white solid (yield 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([C:13](O)=O)[C:9]2=[O:16])=[CH:4][CH:3]=1.C=O.COC1CCNCC1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C:10](=[CH2:13])[C:9]2=[O:16])=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCN(c2ccc(Cl)cc2)C1=O
Agent: C=O
Agent: COC1CCNCC1
Solvent: CO
Product: C=C1CCN(c2ccc(Cl)cc2)C1=O
Yield: 62.9 %

Procedure:
1.56 g of 1-(4-chlorophenyl)-3-carboxy-2-pyrrolidinone was mixed with 7 ml of methanol. Thereto were added 0.26 g of 75% paraformaldehyde and 0.75 g of 4-methoxypiperidine. The mixture was refluxed for 2 hours. The reaction mixture was concentrated to dryness. The residue was purified by silica gel column chromatography using chloroform (a solvent) to obtain 0.85 g of 1-(4-chlorophenyl)-3-methylene-2-pyrrolidinone.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4](=[C:13]1[CH2:16][N:15]([CH:17]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:14]1)[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=1.[BH4-].[Na+].CCOCC>CO.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:32])[CH:4]([CH:13]1[CH2:16][N:15]([CH:17]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[CH2:14]1)[C:5]1[CH:6]=[C:7]([F:12])[CH:8]=[C:9]([F:11])[CH:10]=1
Reactant: COC(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of 5.0 g (10.54 mmol) of methyl{1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(3,5-difluorophenyl)acetate in 60 mL of MeOH and 15 mL of CH2Cl2 was slowly added 798 mg (21.08 mmol) of NaBH4. The solution was stirred for 5 h at 0° C., then poured into 250 mL of ether and washed with 50 mL of aq NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate to afford the title compound; 1NMR(CDCl3) δ 2.68 (m, 1H), 2.92 (m, 1H), 3.10-3.15 (m, 2H), 3.44 (m, 1H)3.69 (s, 3H), 3.86 (d, J=11 Hz, 1H), 4.30 (s, 1H), 6.74 (m, 1H), 6.85 (m, 2H), 7.24-7.34 (m, 8H); Mass Spectrum: m/e=476 (M+1 35Cl, 35Cl) and 478 (M+1 35Cl, 37Cl).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[F:28][C:29]1([F:35])[CH2:31][CH:30]1[C:32](O)=[O:33]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32]([CH:30]5[CH2:31][C:29]5([F:35])[F:28])=[O:33])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)C1CC1(F)F
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)C1CC1(F)F

Procedure:
The title compound, white solid (5 mg, 15%), MS (ISP) m/z=436.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and 2,2-difluorocyclopropanecarboxylic acid
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[O:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1.C([N-]C(C)C)(C)C.[Li+:24].[CH2:25]=[O:26]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH:1]([N-:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Li+:24].[OH:26][CH2:25][C:11]1([C:14]([OH:16])=[O:15])[CH2:12][CH2:13][O:8][CH2:9][CH2:10]1
Reactant: CC(C)NC(C)C
Reactant: C=O
Reactant: O=C(O)C1CCOCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(O)C1(CO)CCOCC1
Reaction time: 0.33 h
Yield: 58 %

Procedure:
Lithium diisopropylamide was prepared by the addition of 2.45M N-butyl lithium (16.5 mL) in hexanes to a solution diisopropylamine (5.80 mL, 41.4 mmmol) in tetrahydrofuran (40 mL) at 0° C. with stirring for 20 minutes. Then a solution of tetrahydropyran-4-carboxylic acid (2.5 g, 19.2 mmol) in tetrahydrofuran (10 mL) was added to the solution of lithium diisopropylamide over 15 minutes to form a slurry, followed by hexamethylphosphoramide (2 mL). The resulting solution was stirred for 25 minutes, then immediately warmed to room temperature after a stream of gaseous formaldehyde (prepared by heating 4 g of paraformaldehyde at 175-200° C. over 5-10 minutes) was passed through the solution. The slurry was carefully concentrated at ambient temperature, acidified to pH 3 with 8M hydrochloric acid, saturated with solid sodium chloride, and extracted with ethyl acetate (8×100 mL). The combined organic layers were dried over magnesium sulfate, concentrated in vacuo. Chromatography over silica gel (80 g), and eluting with 10% methanol/methylene chloride, yielded 4-(hydroxymethyl)tetrahydropyran-4-carboxylic acid as a white solid (1.80 g, 58%). mp 113.7-115° C.; IR (KBr) 3420 (br), 1724 cm-1, 1HNMR (DMSO-d6) δ 1.43 (ddd, J=13.5, 11.0, 4.4 Hz, 2H), 1.85 (dm, J=13.4 Hz, 2H), 3.37 (td, J=11.3, 3.0 Hz, 2H), 3.43 (s, 2H), 3.71 (dt, J=11.6, 3.9 Hz, 2H), 4.81 (br, s, 1H); 12.24 (s, 1H); 13CNMR (DMSO-d6) δ 30.42 (t), 46.38 (s), 64.35 (t), 68.15 (t), 69.02 (t), 176.08 (s); HRMS Calcd. for C7H12O4 : 160.0735. Found: 160.0731. Anal. Calcd. for C7H12O3 : C, 52.49; H, 7.55. Found: C, 52.50; H, 7.62.
Reaction SMILES: [C:1](OC(=O)CC)(=O)CC.[O:10]=[S:11]1(=[O:36])[CH:16]=[CH:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:34])[CH:31](F)F)[O:25][C:24]3=[O:35])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1>N1C=CC=CC=1.ClCCl>[O:10]=[S:11]1(=[O:36])[CH:16]=[CH:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:34])[CH2:31][CH3:1])[O:25][C:24]3=[O:35])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1
Reactant: O=C(NC[C@H]1CN(c2ccc(C3C=CS(=O)(=O)CC3)cc2)C(=O)O1)C(F)F
Reactant: CCC(=O)OC(=O)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)NC[C@H]1CN(c2ccc(C3C=CS(=O)(=O)CC3)cc2)C(=O)O1
Reaction time: 4 h
Yield: 84.1 %

Procedure:
Propionic anhydride (0.136 ml, 1.06 mmol) is added dropwise to the crude amine hydrochloride prepared in Step 1 of Example 15 (0.316 g, 0.88 mmol) in a mixture of pyridine (4 mL) and dichloromethane (4 mL). The mixture is stirred for 4 hours and then evaporated to dryness. The residue is purified by PTLC (10% methanol/dichloromethane) to give the title compound as white solid (0.28 g, 80%). M.p. 144–7° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[CH2:11][CH:10]([CH2:12][OH:13])[O:9][N:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[S:6][C:5]([C:7]2[CH2:11][CH:10]([CH2:12][O:13][S:22]([CH3:21])(=[O:24])=[O:23])[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CC(c2ccc(Br)s2)=NO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CC(c2ccc(Br)s2)=NO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
[3-(5-Bromo-thien-2-yl)-4,5-dihydro-isoxazol-5-yl]-methanol (10.7 g, 40.6 mmol) was added to anhydrous dichloromethane (200 ml) followed by addition of triethylamine (7.9 ml, 56.9 mmol). The solution was cooled to 0° C. followed by dropwise addition of methane sulfonyl chloride (3.8 ml, 48.7 mmol). The reaction was stirred for 2 hours at 0° C. and then aqueous sodium bicarbonate (100 ml) was added. After further extraction with dichloromethane (2×100 ml), the organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give the desired product (9 g).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH:5]([C:12]1[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[C:15]([CH3:21])=[C:14]([CH3:22])[C:13]=1[O:23][CH3:24])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C-:25]#[N:26].[Na+].C(OC(C)C)(C)C.O>CS(C)=O>[CH3:24][O:23][C:13]1[C:14]([CH3:22])=[C:15]([CH3:21])[C:16]([O:19][CH3:20])=[C:17]([CH3:18])[C:12]=1[CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][CH2:3][CH2:2][C:25]#[N:26]
Reactant: COc1c(C)c(C)c(OC)c(C(CCCI)c2ccccc2)c1C
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(C)OC(C)C
Product: COc1c(C)c(C)c(OC)c(C(CCCC#N)c2ccccc2)c1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 163 %

Procedure:
To a solution of 4.19 g (5.0 mmole) of 1-iodo-4-(2,5-dimethoxy-3,4,6-trimethylphenyl)-4-phenylbutane in dimethylsulfoxide (30 ml) was added 0.74 g (5×3 mmole) of sodium cyanide, and the mixture was stirred at 50° C. for 2 hours. The reaction solution was cooled with ice, and isopropyl ether and water were added to it, followed by stirring. The isopropyl ether layer was separated out, washed with aqueous sodium chloride solution, dried (magnesium sulfate) and evaporated. The residual solution was chromatographed on a silica gel column to perform purification (elution with isopropyl ether/hexane) to thereby give 1.65 g (98%) of 5-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-phenylvaleronitrile. Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 14.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH3:30])[CH:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[C:18]3[C:19]4[CH2:20][NH:21][CH2:22][CH2:23][C:24]=4[S:25][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:12][CH2:11]1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH3:31][S:32]([N:21]1[CH2:20][C:19]2[C:18]3[C:17]([O:16][CH:13]4[CH2:12][CH2:11][CH:10]([N:9]([CH3:30])[CH3:8])[CH2:15][CH2:14]4)=[N:29][CH:28]=[N:27][C:26]=3[S:25][C:24]=2[CH2:23][CH2:22]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)C1CCC(Oc2ncnc3sc4c(c23)CNCC4)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C1CCC(Oc2ncnc3sc4c(c23)CN(S(C)(=O)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N,N-dimethyl-4-[8-thia-4,6,12-triazatricyclo[7.4.0.0-[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yloxy]cyclohexan-1-amine trifluoroacetate (30 mg, 0.09 mmol, 1.00 equiv) in 5 mL of anhydrous dichloromethane was added TEA (40 mg, 0.40 mmol, 4.38 equiv) and MsCl (14 mg, 0.12 mmol, 1.36 equiv) at 0° C. under nitrogen. The resulting solution was stirred for 2 h at room temperature. The reaction mixture was concentrated under vacuum and the residue was purified by preparative HPLC under the following conditions (Waters): Column: XBridge Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase: water with 0.05% NH4HCO3 and CH3CN (16% CH3CN increasing to 23% in 10 min, up to 100% in 2 min, down to 16% in 2 min); flow rate: 20 mL/min; UV Detection at 254/220 nm. This resulted in 8.0 mg (22%) of 4-([12-methanesulfonyl-8-thia-4,6,12-triazatricyclo[7.4.0.0-[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy)-N,N-dimethylcyclohexan-1-amine as a white solid. MS (ES): m/z 411 (M+H)+; 1H NMR (300 MHz, CD3OD): δ 1.59-1.71 (m, 4H), 2.05-2.10 (d, 2H, J=15 Hz), 2.34-2.50 (m, 9H), 2.98 (s, 3H), 3.08 (t, 2H, J=5.7 Hz), 3.06 (t, 2H, J=5.7 Hz), 4.67 (t, 2H, J=1.8 Hz), 5.26 (m, 1H), 8.53 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:11])[CH:3]=1.CN.C(Cl)CCl.[CH2:18]([N:20](CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:20][CH3:18])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: CN
Solvent: ClCCl
Solvent: ClCCCl
Product: CNC(=O)c1ccc(Br)cc1F
Reaction time: 24 h
Yield: 31.4 %

Procedure:
A solution of 4-bromo-2-fluorobenzoic acid (0.8 g, 3.7 mmol), methylamine (3.65 mL, 7.3 mmol), EDC (1.4 g, 7.3 mmol), triethylamine (1.0 mL, 7.3 mmol) dissolved in CH2Cl2(15 mL) was stirred under N2 for 24 h. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layers were washed with saturated NaHCO3, brine, dried over dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (40% EtOAc in hexanes) to give the title compound as a white solid (0.27 g, 32%).
Reaction SMILES: [OH:1][CH2:2][CH:3]=[C:4]([CH3:23])[CH2:5][CH:6]([O:21][CH3:22])[CH:7]=[C:8]([CH3:20])[CH:9]=[CH:10][C:11]1[C:16]([CH3:18])([CH3:17])[CH2:15][CH2:14][CH2:13][C:12]=1[CH3:19]>C(Cl)Cl.CCOCC.[O-2].[O-2].[Mn+4]>[CH3:22][O:21][CH:6]([CH:7]=[C:8]([CH3:20])[CH:9]=[CH:10][C:11]1[C:16]([CH3:18])([CH3:17])[CH2:15][CH2:14][CH2:13][C:12]=1[CH3:19])[CH2:5][C:4]([CH3:23])=[CH:3][CH:2]=[O:1]
Reactant: COC(C=C(C)C=CC1=C(C)CCCC1(C)C)CC(C)=CCO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCOCC
Product: COC(C=C(C)C=CC1=C(C)CCCC1(C)C)CC(C)=CC=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 91 %

Procedure:
1.34 g (4.2 mmol) of 1-hydroxy-5-methoxy-3,7-dimethyl-9-(2,6,6-trimethylcyclohexene-1-yl)-2,6,8-nonatriene (IV) was dissolved in 40 ml of methylene chloride, to which was then added 3.66 g (42 mmol) of manganese dioxide and the mixture was stirred at an ambient temperature for 24 hours. After the resulting mixture was diluted with an ether, it was dried over anhydrous magnesium sulfate and filtered, followed by evaporation of the solvent to obtain 5-methoxy-3,7-dimethyl-9-(2,6,6-trimethylcyclohexene-1-yl)-nona-2,6,8-trienal (V) as a mixture of E and Z isomers in a yield of 91%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][N+:9](=[N:12]C(=O)C2C=CC=CC=2)[CH2:8][CH:7]=1)=[O:5])[CH3:2].[Br:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/I)=[CH:24][CH:23]=1>[Pd](Br)Br.[O-]S(C(F)(F)F)(=O)=O.[Ag+].O1CCOCC1>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[C:8]3[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=[CH:10][N:9]3[N:12]=2)=[CH:24][CH:23]=1
Reactant: Brc1ccc(/C=C/I)cc1
Reactant: CCOC(=O)C1=CC[N+](=NC(=O)c2ccccc2)C=C1
Agent: Br[Pd]Br
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: C1COCCO1
Product: CCOC(=O)c1ccn2nc(-c3ccc(Br)cc3)cc2c1
Temperature: 127.5 °C
Yield: 54 %

Procedure:
Related procedures are described in Org. Lett. 2010, 12, 516): 4-Ethoxycarbonyl-N-benzoyliminopyridinium ylid (JOC 2003, 68, 7119) (3.50 g, 13.0 mmol), para-tris-methoxyphenylphosphine (686 mg, 1.95 mmol), Palladium (II) bromide (173 mg, 0.65 mmol), silver triflate (8.93 g, 39.0 mmol) and (E)-1-Bromo-4-(2-iodovinyl)benzene (Org. Lett. 2008, 10, 5485) (4.02 g, 13.0 mmol) were placed in a 250 mL round bottom flask equipped a with magnetic stirrer. Dioxane (52 mL) was added. The mixture was degassed by bubbling nitrogen for 10 minutes with vigorous stirring and heated to 125-130° C. for 15-20 h. The mixture was then cooled to room temperature, diluted with CH2Cl2, filtered over Celite. The organic layer was then washed with saturated aqueous sodium bicarbonate and the organic phase was concentrated under reduced pressure. The crude product was triturated with methanol to afford 2.40 g (54%) of the title compound. LCMS m/z 345.0, 347.0 (M+H)+, ret. time=3.05 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[C:8]=1[CH3:24].[OH-].[Na+].[O-:27]S([O-])(=S)=O.[Na+].[Na+].C(O)(=O)C>CO.O.OO>[CH3:24][C:8]1[C:9]([CH2:13][S+:14]([O-:27])[C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)=[N:10][CH:11]=[CH:12][C:7]=1[O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: O=S([O-])([O-])=S
Reactant: COCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COCCCOc1ccnc(C[S+]([O-])c2nc3ccccc3[nH]2)c1C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
2 g of 2-[[[4-(3-methoxy-propoxy)-3-methyl-2-pyridinyl]methyl]thio]-1H-benzimidazole was suspended in 36 ml of methanol at room temperature, to which 1.93 g of45% NaOH in 14 ml water was added while stirring. 0.09 g of Na2WO4·2H2O oxidation catalyst was dissolved in 0.66 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 Rabeprazole with a yield of about 88% (LC purity>95%).
Reaction SMILES: [C:1](Cl)(=[O:9])[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+].O.[NH2:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([S:27][C:28]#[N:29])[CH:24]=[CH:23][C:21]=2[N:22]=1>O1CCCC1>[S:27]([C:25]1[CH:24]=[CH:23][C:21]2[N:22]=[C:18]([NH:17][C:1](=[O:9])[O:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[S:19][C:20]=2[CH:26]=1)[C:28]#[N:29]
Reactant: N#CSc1ccc2nc(N)sc2c1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CSc1ccc2nc(NC(=O)Oc3ccccc3)sc2c1
Temperature: 20 °C
Reaction time: 20 h
Yield: 87.4 %

Procedure:
7.5 g of phenyl chlorocarbonate and then 4.05 g of sodium hydrogen carbonate and 9.4 cm3 of water are added, at 20° C., to a solution of 2.5 g of commercial 2-amino-1,3-benzothiazol-6-yl thiocyanate in 94 cm3 of tetrahydrofuran. The resulting mixture is subsequently stirred at 20° C. for 20 h and then extracted with 2×150 cm3 of ethyl acetate. The organic phases are combined and then washed with 3×50 cm3 of a saturated aqueous solution of sodium hydrogen carbonate. The organic phase obtained is dried over magnesium sulphate and then concentrated to dryness under reduced pressure. The residue is taken up in 50 cm3 of water and the product is spin-filter-dried and dried under vacuum at 20° C. 3.45 g of phenyl (6-thiocyanato-1,3-benzothiazol-2-yl)carbamate are thus obtained in the form of a pale yellow solid, the characteristics of which are as follows:
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[O:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=2)[CH2:30][CH2:29]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:39]([C:38]3[CH:37]=[CH:36][C:35]([CH2:34][N:31]4[CH2:32][CH2:33][O:28][CH2:29][CH2:30]4)=[CH:42][CH:41]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Reactant: Cc1nc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)cs1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1nc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(CN6CCOCC6)cc5)nc34)CC2)cs1
Temperature: 85 °C
Yield: 28.1 %

Procedure:
To a mixture of 5-bromo-4-(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.062 g, 0.15 mmol), EtOH (2.6 mL) and DMF (0.35 mL), 4-(morpholinomethyl)-benzaldehyde (0.034 g, 0.165 mmol) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.45 mL, 0.45 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM, and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 96:4) to give the title compound as a pale yellow solid (0.024 g, 29%); 1H-NMR (500 Mz, DMSO-d6): δ 2.33-2.42 (m, 4H), 2.62-2.71 (m, 7H), 3.54 (s, 2H, NCH2), 3.59 (t, J=4.5 Hz, 4H), 3.62-3.74 (m, 6H), 7.32 (s, 1H, thiazole 5-H), 7.47 (d, J=8.0 Hz, 2H, ArH, C6H4), 8.14 (d, J=8.0 Hz, 2H, ArH, C6H4), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.51 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 2.12 min—568/570 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 568.1504, calculated for C26H31N7BrOS (M+H)+: 568.1494.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.C(Cl)(=O)OCC.[N+:27](=[CH2:29])=[N-:28]>C1COCC1.CCOCC>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH3:13])[C:10](=[O:12])[CH:29]=[N+:27]=[N-:28])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: C=[N+]=[N-]
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(NC(=O)OC(C)(C)C)C(=O)C=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
To a −15° C. solution of 2-((tert-butoxycarbonyl)amino)propanoic acid (2.5 g, 13.21 mmol) in THF (66 mL) was added Et3N (1.337 g, 13.21 mmol) and ethyl carbonochloridate (1.434 g, 13.21 mmol). The reaction mixture was stirred for 15 min then allowed to warm to 0° C. A solution of diazomethane (prepared according to the standard procedure (Organic Syntheses, Coll. Vol. 5, p. 351 (1973); Vol. 41, p. 16 (1961)) in Et2O (150 mL) was added, until the rich yellow color persisted. The reaction mixture was allowed to warm to rt and stirred for 3 h. Excess CH2N2 was destroyed by the addition of a small amount of aqueous AcOH (20%, 3 mL). The reaction mixture was extracted with saturated NaHCO3 (20 mL), and the organic portion was separated and washed with saturated aqueous NH4Cl (20 mL) and brine (20 mL). The organic portion was separated, dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5-20% EtOAc in petroleum ether) to give (3-diazo-1-methyl-2-oxo-propyl)-carbamic acid tert-butyl ester (2.8 g, 99%) as a brown solid. 1H NMR (DMSO-d6, 400 MHz): δ 7.27 (d, J=7.2, 1H), 6.02 (s, 1H), 4.01 (m, 1H), 1.39 (s, 9H), 1.20 (m, 3H).