Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([Br:26])=[CH:14][C:10]=1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:39][O:40][CH2:41][CH2:42][CH2:43][NH2:44]>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15]([Br:26])=[CH:14][C:10]=1[C:11]([NH:44][CH2:43][CH2:42][CH2:41][O:40][CH3:39])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCCN
Reactant: O=C(O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: COCCCNC(=O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 2 h
Yield: 98.8 %

Procedure:
2,4-Bis-benzyloxy-5-bromobenzoic acid (13.5 g, 33 mmol) was dissolved in DMF (anhydrous, 100 ml), and carbonyldiimidazole (CDI) (6.1 g, 37 mmol) was added and the resulting solution was stirred at r.t for 2 h. 3-Methoxypropylamine (3.6 g, 40 mmol) solution in DMF (25 ml) was added and the resulting solution was stirred at r.t. until the reaction was complete. The reaction was diluted with water (250 ml), extracted with ethyl acetate (250 ml×3), and the combined organics were washed thoroughly with water to remove DMF and dried over sodium sulfate. After filtration and concentration, the residue was purified by flash chromatography on silica gel to give 2,4-bis-benzyloxy-5-bromo-N-(3-methoxy-propyl)-benzamide (15.8 g, 99%). M.p.: 104-106° C.; 400 MHz 1H NMR (CDCl3) δ: 8.41 (s, 1H), 7.85 (t, J=5.2 Hz, 1H), 7.45-7.32 (m, 10H), 6.53 (s, 1H), 5.14 (s, 2H), 5.09 (s, 2H), 3.47-3.41 (q, J=5.2 Hz, 2H), 3.30 (t, J=6.4 Hz, 2H), 3.22 (s, 3H), 1.72-1.65 (pent, J=6.4 Hz, 2H); LCMS: 484, 486 [M+H].
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:15]([N:19]4[S:23](=[O:25])(=[O:24])[NH:22][C:21](=[O:26])[CH2:20]4)=[CH:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.Cl[C:43]([O:45][CH3:46])=[O:44]>C1COCC1>[CH3:46][O:45][C:43](=[O:44])[NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]3[C:17](=[CH:16][C:15]([N:19]4[CH2:20][C:21](=[O:26])[NH:22][S:23]4(=[O:25])=[O:24])=[C:14]([O:27][CH2:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:13]=3)[CH:18]=2)[CH:4]=1
Reactant: COC(=O)Cl
Reactant: NCc1cccc(-c2ccc3cc(OCc4ccccc4)c(N4CC(=O)NS4(=O)=O)cc3c2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)NCc1cccc(-c2ccc3cc(OCc4ccccc4)c(N4CC(=O)NS4(=O)=O)cc3c2)c1
Reaction time: 0.5 h

Procedure:
To a stirring solution of 5-[7-(3-aminomethylphenyl)-3-benzyloxynaphthalen-2-yl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (0.046 g, 0.097 mmol) and triethylamine (0.014 mL, 0.098 mmol) in THF (3 mL) at 0° C. is added methyl chloroformate (0.008 mL, 0.104 mmol). The reaction is stirred for 30 min and then quenched with water and extracted with CH2Cl2 (3×25 mL). The organic layers are combined and concentrated. The residue is purified via Biotage Sp1 eluting with 5-60% CH3CN/H2O to afford {3-[6-benzyloxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-naphthalen-2-yl]-benzyl}-carbamic acid methyl ester: (M−H)−=530.
Reaction SMILES: [N:1]1[N:5]2[C:6]([CH:10]([OH:12])[CH3:11])=[CH:7][CH:8]=[N:9][C:4]2=[N:3][CH:2]=1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:44][C:45]1[CH:50]=[CH:49][C:48](O)=[CH:47][CH:46]=1>O1CCCC1>[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([O:12][CH:10]([C:6]2[N:5]3[N:1]=[CH:2][N:3]=[C:4]3[N:9]=[CH:8][CH:7]=2)[CH3:11])=[CH:47][CH:46]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(O)c1ccnc2ncnn12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1ccc(Cl)cc1)c1ccnc2ncnn12
Reaction time: 8 h

Procedure:
A mixture of (-)-1-(1,2,4-triazolo[1,5-a]pyrimidin-7-yl)ethanol (0.27 g), diethylazodicarboxylate (0.44 g), triphenylphosphine (0.68 g) and 4-chlorophenol (0.22 g) in dry tetrahydrofuran (20 ml) was stood overnight at ambient temperature until the reaction was complete. The solvent was removed under reduced pressure and the residue dissolved in ethyl acetate (100 ml). The solution was washed with 1M sodium hydroxide (40 ml) followed by brine (20 ml), and the solvent was evaporated. The residue was purified by flash chromatography on silica gel using as eluent a mixture of triethylamine and ethyl acetate (in the ratio 1:100 respectively) to give (-)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine. Yield 0.26 g.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]2[CH:10]=[C:11]([S:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[C:20](=O)[CH2:19][CH2:18]4)[S:12][CH:13]=2)[CH2:7][CH2:6][O:5][CH:4]1[CH3:8].Cl.[NH2:26][OH:27]>>[CH3:1][O:2][C:3]1([C:9]2[CH:10]=[C:11]([S:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)/[C:20](=[N:26]/[OH:27])/[CH2:19][CH2:18]4)[S:12][CH:13]=2)[CH2:7][CH2:6][O:5][CH:4]1[CH3:8]
Reactant: NO
Reactant: COC1(c2csc(Sc3ccc4c(c3)CCC4=O)c2)CCOC1C
Agent: Cl
Product: COC1(c2csc(Sc3ccc4c(c3)CC/C4=N\O)c2)CCOC1C
Yield: 64 %

Procedure:
Using an analogous procedure to that described in Example 66, 5-{4-[(2RS,3SR)-3-methoxy-2-methyltetrahydrofuran-3-yl]thien-2-ylthio}indan-1-one was reacted with hydroxylamine hydrochloride to give (E)-5-{4-[(2RS,3SR)-3-methoxy-2-methyltetrahydrofuran-3-yl]thien-2-ylthio}indan-1-one oxime in 64% yield, m.p. 149°-151° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1F)[CH:16]=[O:17]>>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:9][C:6]1[CH:7]=[N:8][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:4][CH:5]=1)[CH:16]=[O:17]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Oc1ccc(C(F)(F)F)nc1
Product: O=Cc1ccc(Oc2ccc(C(F)(F)F)nc2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 6-(trifluoromethyl)3-pyridinol and 3,4-difluorobenzaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[N+:15]([CH3:18])([O-])=O.[OH-].[Na+].C(O)(=O)C>C(O)C>[OH:7][CH:6]([C:5]1[CH:8]=[C:9]([O:13][CH3:14])[C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:18][NH2:15]
Reactant: C[N+](=O)[O-]
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(C(O)CN)cc(OC)c1OC
Temperature: 0 °C

Procedure:
A solution of 3,4,5-trimethoxybenzaldehyde (10 g, 51 mmol) and nitromethane (10 mL) in ethanol at 0° C. was treated with 10% sodium hydroxide (21.4 mL, 53.5 mmol), stirred for 45 sesonds, treated with 2% acetic acid (162 mL), stirred for 1 hour in the ice bath, and filtered. The solid was washed with water and dried under vacuum to provide 9.0 g of the desired product as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(N(CC)CC)C.[Cl:31]C(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[NH2:43][C:44]1[S:45][C:46]([CH3:49])=[CH:47][N:48]=1>C(Cl)(Cl)Cl.O>[ClH:31].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:35]([NH:43][C:44]2[S:45][C:46]([CH3:49])=[CH:47][N:48]=2)=[O:41])=[C:18]([F:23])[CH:17]=1
Reactant: Cc1cnc(N)s1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ncc(C)s4)c(F)c3)c2cc1OC
Product: Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 161.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (300 mg) was dissolved in chloroform (6 ml) and triethylamine (0.3 ml) to prepare a solution. A solution of triphosgene (142 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 2-amino-5-methylthiazole (119 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Iced water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine and was then dried over anhydrous sodium sulfate. The dried organic layer was filtered and was then concentrated. Ether was added to the residue for crystallization, and the crystal was collected by filtration. The crystal was purified by chromatography (chloroform:acetone=2:1). A 10% hydrogen chloride-methanol solution was added to the purified crystal, and the solution was then concentrated. The resultant crystal was washed with ether to give 380 mg of the title compound.
Reaction SMILES: [N:1]1([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3][CH2:2]1.[O:20]=[C:21]1[N:27]([CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C@@H:37]([C:48](O)=[O:49])[CH2:38][C:39]3[CH:44]=[C:43]([CH3:45])[C:42]([OH:46])=[C:41]([CH3:47])[CH:40]=3)=[O:35])[CH2:30][CH2:29]2)[CH2:26][CH2:25][C:24]2[CH:51]=[CH:52][CH:53]=[CH:54][C:23]=2[NH:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:20]=[C:21]1[N:27]([CH:28]2[CH2:29][CH2:30][N:31]([C:34]([O:36][C@H:37]([CH2:38][C:39]3[CH:40]=[C:41]([CH3:47])[C:42]([OH:46])=[C:43]([CH3:45])[CH:44]=3)[C:48]([N:17]3[CH2:16][CH2:15][CH:14]([N:1]4[CH2:2][CH2:3][CH:4]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:6]4)[CH2:19][CH2:18]3)=[O:49])=[O:35])[CH2:32][CH2:33]2)[CH2:26][CH2:25][C:24]2[CH:51]=[CH:52][CH:53]=[CH:54][C:23]=2[NH:22]1
Reactant: CCOC(=O)CCC1CCN(C2CCNCC2)CC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCC1CCN(C2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Reaction time: 2 h

Procedure:
410 mg (1.20 mmol) ethyl 3-[1,4′]bipiperidinyl-4-yl-propionate (used as the bis-hydrochloride salt) were added at RT to a solution of 500 mg (1.04 mmol) (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1h), 385 mg (1.20 mmol) TBTU and 0.48 mL (3.40 mmol) triethylamine in 10 mL DMF and the mixture was stirred for 2 h. The reaction mixture was purified by HPLC without any further working up. The fractions containing the product were combined, concentrated by evaporation i. vac. and the residue was stirred with saturated NaHCO3 solution.
Reaction SMILES: [N+:1]([C:4]1[CH:58]=[CH:57][CH:56]=[CH:55][C:5]=1[CH2:6][O:7][C:8]([CH:10]([PH:36]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[N:11]1[CH:14]([CH2:15][C:16](O)=[O:17])[CH:13]([CH:19]([NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])=[O:23])[CH3:20])[C:12]1=[O:35])=[O:9])([O-:3])=[O:2].C(Cl)(=O)C([Cl:62])=O>C(Cl)Cl.CN(C=O)C>[N+:1]([C:4]1[CH:58]=[CH:57][CH:56]=[CH:55][C:5]=1[CH2:6][O:7][C:8]([CH:10]([PH:36]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[N:11]1[C@@H:14]([CH2:15][C:16]([Cl:62])=[O:17])[C@H:13]([CH:19]([NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])=[O:23])[CH3:20])[C:12]1=[O:35])=[O:9])([O-:3])=[O:2]
Reactant: CC(NC(=O)OCc1ccccc1[N+](=O)[O-])C1C(=O)N(C(C(=O)OCc2ccccc2[N+](=O)[O-])[PH](c2ccccc2)(c2ccccc2)c2ccccc2)C1CC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(NC(=O)OCc1ccccc1[N+](=O)[O-])[C@@H]1C(=O)N(C(C(=O)OCc2ccccc2[N+](=O)[O-])[PH](c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1CC(=O)Cl
Reaction time: 0.08 h

Procedure:
1-(o-nitrobenzyloxycarbonyltriphenylphosphoranylmethyl)-3-(1-o-nitrobenzyloxycarbonylaminoethyl)-4-(carboxymethyl)-2-azetidinone (0.1320 g from the previous step) is dissolved in 5 ml CH2Cl2 and cooled to 0° under N2. Oxalyl chloride (0.040 ml, 0.44 mmole) is added dropwise over 5 minutes and then 1 drop of DMF is added. The mixture is stirred at 0° for 5 minutes and then at 25° C. for another 15 minutes. The solvent and excess oxalyl chloride are evaporated under reduced pressure. The residue is then desired acid chloride which is used without purification in the next step.
Reaction SMILES: [I:1][C:2]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([I:16])=[CH:10][C:3]=1[O:4][C:5](=[CH:8]C)[C:6]#[N:7].Cl.NC1C=CC=CC=1.O(C)[Na].Cl.[NH2:29][C:30]([NH2:32])=[NH:31]>C(O)C.CO>[I:1][C:2]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([I:16])=[CH:10][C:3]=1[O:4][C:5]1[C:6]([NH2:7])=[N:29][C:30]([NH2:32])=[N:31][CH:8]=1
Reactant: N=C(N)N
Reactant: CC=C(C#N)Oc1cc(I)c(OC)cc1I
Agent: CO[Na]
Agent: Cl
Solvent: CO
Solvent: Nc1ccccc1
Solvent: CCO
Product: COc1cc(I)c(Oc2cnc(N)nc2N)cc1I
Temperature: 85 °C
Reaction time: 18 h
Yield: 36.7 %

Procedure:
2-(2,5-Diiodo-4-methoxy-phenoxy)-but-2-enenitrile (3.47 g, 6.75 mmol) and aniline hydrochloride (3.5 g, 27 mmol) were dissolved in 27 mL ethanol. The reaction mixture was heated to 85° C. and stirred under nitrogen for 18 hours. The reaction mixture was cooled and 25% NaOCH3 in methanol (7.3 mL) was added, followed by guanidine hydrochloride (3.2 g), and ethanol (10 mL). The reaction mixture was heated to 100° C. for 21 hours, then cooled and concentrated under reduced pressure. The residue was poured into water and extracted with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give 1.2 g of 5-(2,5-Diiodo-4-methoxy-phenoxy)-pyrimidine-2,4-diamine, MS (M+H)=485.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[C:3]=1[CH3:9].[CH3:10][S-:11].[Na+].IC.O>CN(C)P(N(C)C)(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:11][CH3:10])[C:3]=1[CH3:9]
Reactant: C[S-]
Reactant: Cc1c(Cl)cccc1Cl
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CSc1cccc(Cl)c1C
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
200 g (1.24 mol) of 2,6-dichlorotoluene were dissolved in 600 ml of hexamethylphosphoramide and treated with 130.41 g (1.86 mol) of sodium thiomethoxide. The mixture was then heated at 100° C. for 3 h. It was allowed to cool, 88.2 g (0.5 mol) of iodomethane were added and it was stirred at room temperature for 0.5 h. The mixture was then added to 3.5 l of water and extracted with ethyl acetate. The combined organic phases were washed with water, dried over MgSO4 and completely concentrated on a rotary evaporator.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[C:13](Cl)(Cl)=[O:14].Cl[CH2:18]Cl>C(N(CC)CC)C>[C:6]([O:14][CH3:13])(=[O:8])[C:5]1[CH:4]=[CH:3][C:2]([C:1]([O:12][CH3:18])=[O:11])=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: O=C(Cl)Cl
Reactant: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)OC)cc1

Procedure:
Following the general procedure in Example 1 for the preparation of the diacid chloride, 10.13 parts of terephthalic acid were added to a mixture of 14.7 parts triethylamine and 14.4 parts phosgene in 200 parts dry dichloromethane at 25° to 30° C. The ratio of equivalents of triethylamine base/COOH acid group was 1.19. After carrying out the reaction and esterifying the resulting diacid chloride by the procedure described in Example 1, no dimethyl terephthalate was isolated. Instead, 100% recovery of unreacted terephthalic acid was obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:11][NH:10][CH2:9][C:7]=2[N:8]=1.Br[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[CH:23]=2)=[O:20])[CH:14]=1>>[CH:28]([C:24]1[CH:23]=[C:22]([NH:21][C:19]([C:15]2[CH:14]=[C:13]([N:10]3[CH2:11][C:6]4[CH:5]=[N:4][C:3]([S:2][CH3:1])=[N:8][C:7]=4[CH2:9]3)[CH:18]=[CH:17][N:16]=2)=[O:20])[CH:27]=[CH:26][CH:25]=1)([CH3:30])[CH3:29]
Reactant: CC(C)c1cccc(NC(=O)c2cc(Br)ccn2)c1
Reactant: CSc1ncc2c(n1)CNC2
Product: CSc1ncc2c(n1)CN(c1ccnc(C(=O)Nc3cccc(C(C)C)c3)c1)C2

Procedure:
In a manner similar to that describe in Example 126, 2-(methylthio)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine and 4-bromo-N-(3-isopropylphenyl)picolinamide were converted to the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[OH:25]O.O>C(O)(C)C>[CH3:1][C:2]1[C:7]([O:8][CH2:9][C:10]([F:12])([F:11])[F:13])=[CH:6][CH:5]=[N:4][C:3]=1[CH2:14][S+:15]([O-:25])[C:16]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Reactant: OO
Solvent: CC(C)O
Solvent: O
Product: Cc1c(OCC(F)(F)F)ccnc1C[S+]([O-])c1nc2ccccc2[nH]1
Reaction time: 1 h
Yield: 88 %

Procedure:
HCl, 1.376 g of 2-mercaptobenzimidazole, and 0.134 g of benzyl triethyl ammonium chloride as an interphase transfer catalyst were mixed in 24 ml of dichloromethane. 0.9534 g of NaOH (40%)/12 ml water mixture solution was dripped into the above mixture while stirring. The temperature of the resulting solution was raised to 40° C. for about 2 hours. Then, dichloromethane was removed from the mixture under a reduced pressure. The solid obtained was stirred with 50 ml of water, and filtered to obtain 3.28 g of solid Lansoprazole precursor: 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylthio]-1H-benzimidazole. At room temperature, 3.28 g of the above precursor, 0.1625 g of polyethylene glycol-400 as an interphase transfer catalyst, and 0.3936 g of Mo(acac)2 as an oxidation catalyst were mixed in 45 ml of isopropanol (abbreviated as IPA). To the resulting mixture 3.06 g of 35% H2O2 aqueous solution was added in 5–10 minutes. The reaction was carried out for about one hour, and then 60 ml of water was added, and the reaction was continued for another one hour while stirring. Finally, the precipitate formed was filtered, water washed, and dried to obtain Lansoprazole with a yield of about 88% (HPLC purity>98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6](/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10])=[C:5]([NH:15]S(C2C=CC(C)=CC=2)(=O)=O)[CH:4]=1.ClC1C=C2C(C(CC(O)=O)=[C:32]([C:36]([C:38]3[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][N:39]=3)=[O:37])N2)=CC=1>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:14][CH:13]=2)[NH:15][C:32]=1[C:36]([C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][N:39]=1)=[O:37]
Reactant: Cc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2CC(=O)O)c1
Reactant: COC(=O)/C=C/c1ccc(OC)cc1NS(=O)(=O)c1ccc(C)cc1
Product: COC(=O)Cc1c(C(=O)c2cc(C)ccn2)[nH]c2cc(OC)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-methoxy-2-(p-toluenesulfonylamino)cinnamate (step 3) and 2-bromoacetyl-4-methylpyridine hydrobromide (Preparation is described in step 2 of Example 31).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[NH2:38])[C:33]#[N:34]>CN(C=O)C.N1C=CC=CC=1>[C:33]([C:32]1[CH:35]=[CH:36][C:37]2[NH:38][C:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)=[N:29][C:30]=2[CH:31]=1)#[N:34]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: N#Cc1ccc(N)c(N)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc3cc(C#N)ccc3[nH]2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 37.4 %

Procedure:
To the solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (15 g, 65.5 mmol) in DMF (50 mL) and pyridine (50 mL) was added CDI (10.6 g, 65.5 mmol) at 45° C. and the mixture was stirred for another 2 h at this temperature. Then 3,4-diamino-benzonitrile (8.7 g, 65.5 mmol) was added and the mixture was stirred at RT overnight. Solvents were removed in vacuo and the residue was dissolved in HOAc (20 mL) and heated for 1 h at 100° C. Then the reaction mixture was concentrated and the residue was partitioned between DCM and aqueous of Na2CO3. The organic layer was dried over Na2SO4 and concentrated to give the crude product which was purified by column chromatography (ethyl acetate:petroleum ether=1:2) to give the compound tert-butyl 4-(5-cyano-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (8 g, 65%) as pale solid.
Reaction SMILES: [F:1][C:2]1([F:31])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([C:24]5[CH:29]=[CH:28][C:27](=[O:30])[NH:26][CH:25]=5)[N:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.Cl[CH2:33][C:34]([O:36][CH3:37])=[O:35].C(=O)([O-])[O-].[K+].[K+].ClC(Cl)C>ClCCl>[F:31][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:18]=[C:19]([C:24]5[CH:29]=[CH:28][C:27](=[O:30])[N:26]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH:25]=5)[C:20]([CH3:23])=[CH:21][CH:22]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(=O)[nH]c1
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: COC(=O)Cn1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)ccc1=O
Temperature: 100 °C
Yield: 74.7 %

Procedure:
To a flask containing 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide (0.15 g, 0.35 mmol), methyl chloroacetate (0.19 g, 1.8 mmol), and potassium carbonate (0.5 g, 3.5 mmol) was added dichloroethane (7 mL) and the reaction mixture was heated to 100° C. in a sealed tube overnight. The reaction was diluted with dichloromethane (15 mL) and washed with water (10 mL). The organics were dried over sodium sulfate and evaporated to dryness. The crude reaction was purified by silica gel chromatography (eluting with 0-10% methanol in dichloromethane) to give the product (0.13 g, 76%). ESI-MS m/z calc. 497.14. found 498.3 (M+1)+ Retention time 1.73 minutes.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2.[H-].[Na+].Cl.Cl[CH2:15][C:16]1[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[C:19]([CH3:25])=[CH:18][N:17]=1.O>CN(C)C=O>[CH3:22][C:21]1[C:16]([CH2:15][S:1][C:2]2[NH:3][C:4]3[C:5]([N:10]=2)=[N:6][CH:7]=[CH:8][CH:9]=3)=[N:17][CH:18]=[C:19]([CH3:25])[C:20]=1[O:23][CH3:24]
Reactant: COc1c(C)cnc(CCl)c1C
Reactant: Sc1nc2ncccc2[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C)cnc(CSc2nc3ncccc3[nH]2)c1C
Reaction time: 0.5 h

Procedure:
1.5 Grams of 2-mercaptoimidazo[4,5-b]pyridine was dissolved in 50 ml of dimethylformamide, to this solution was added, under ice-cooled condition, 0.88 g of 60% sodium hydride (in oil), and the mixture was stirred at the same temperature for 30 minutes. Then, to this reaction mixture was added 2.2 g of 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride and the whole mixture was heated at 70° to 80° C. under stirring condition for 3 hours. After the reaction was completed, dimethylformamide was removed by evaporation, and to the residue thus obtained was added water, and then extracted with chloroform. The chloroform extract was washed with water, and dried with anhydrous magnesium sulfate. Chloroform was removed by evaporation, then the residue thus obtained was recrystallized from ethanol to obtain 1.3 g of 2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylthio]imidazo[4,5-b]pyridine in the form of white powdery crystals. Melting point: 186°-188° C.