Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9]([C:11]1[CH:12]=[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[CH:16]=1)=[O:10].O>O1CCCC1>[OH:10][CH:9]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:11]1[CH:12]=[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:14]=[C:15]([C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[CH:16]=1
Reactant: CCOC(=O)c1cc(C=O)cc(-c2ccc(C)cc2)c1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(C)cc2)cc(C(O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Phenylmagnesium bromide (850 mg, 4.7 mmol) was added to a solution of ethyl 5-formyl-4′-methylbiphenyl-3-carboxylate (360 mg, 1.3 mmol) in tetrahydrofuran (8 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 h, and then water (10 mL) was added. The mixture was extracted with EtOAc (20 mL×2). The combined organic layers were dried over anhydrous MgSO4 and concentrated. The residue was purified by silica gel column chromatography to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[S:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:29]([C:34](O)=[O:35])#[C:30][C:31]([OH:33])=[O:32]>>[O:35]=[C:34]1[C:29](=[CH:30][C:31]([OH:33])=[O:32])[S:15][C:14](=[N:13][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)[N:16]1[C:17]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=1
Reactant: COc1cc(NC(=S)Nc2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Reactant: O=C(O)C#CC(=O)O
Product: COc1cc(N=C2SC(=CC(=O)O)C(=O)N2c2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Yield: 57.1 %

Procedure:
Prepared by the method described in Example 1 from N,N'-bis(3,4,5-trimethoxyphenyl)thiourea (26.8 g, 66 mmoles) and acetylenedicarboxylic acid (9.8 g, 86 mmoles). Recrystallization from ethanol gave the product (19 g), mp 250°-252° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].C([O:15][C:16]([CH:18]1[CH2:20][CH2:19]1)=O)C.C(O)(=O)C>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]([CH:18]2[CH2:20][CH2:19]2)=[O:15])[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CCOC(=O)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#CC(C(=O)C1CC1)c1ccc(Cl)cc1
Reaction time: 0.17 h

Procedure:
2-(4-Chlorophenyl)acetonitrile (5.74 g) is dissolved in 120 mL of THF at 0° C. After adding 60% NaH (4.2 g, 2.7 eq), the reaction mixture is stirred for 10 minutes. Ethylcyclopropane carboxylate is added and the mixture is stirred overnight. The reaction is stopped by adding acetic acid (5 mL) and water. The aqueous layer is extracted with ethyl acetate (50 mL×3). The collected organic layer is washed with brine and dehydrated with MgSO4. The dehydrated organic layer is concentrated by distillation under reduced pressure and purified by column chromatography to yield 7.74 g of the target compound. 1H NMR (CDCl3, 300 MHz): δ 7.42 (d, J=8.7 Hz, 2H), 7.34 (d, J=8.7 Hz, 2H), 4.79 (s, 1H), 2.10 (m, 1H) 1.16 (m, 2H), 1.03 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43][C:44]([OH:46])=O)=[O:10])C1C=CC=CC=1.[CH3:47][NH:48][CH3:49]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43][C:44](=[O:46])[N:48]([CH3:49])[CH3:47])=[O:10])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:33]=1
Reactant: CNC
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCC(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCC(=O)N(C)C)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
Similar to example 6a, 80.0 mg of (2R,4R,5R)-2-(2-carboxy-ethyl)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester (from example 19b) are reacted with dimethylamine to afford the title compound as a yellow oil. Rf=0.35 (dichlormethane-methanol 9:1); Rt=4.93.
Reaction SMILES: Br[CH2:2][CH2:3][Cl:4].[OH:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[C:13](=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[Cl:4][CH2:3][CH2:2][O:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[C:13](=[O:15])[CH3:14]
Reactant: ClCCBr
Reactant: CC(=O)c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)c1ccc(F)cc1OCCCl

Procedure:
40.5 ml of 1-bromo-2-chloroethane (490 mmol) are added at room temperature to a solution of 25 g of 1-[2-hydroxy-4-fluorophenyl]ethanone (162 mmol) in 2-butanone (400 ml), followed by addition of 45 g of potassium carbonate (320 mmol) and 1.26 g of potassium iodide (7.59 mmol).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([NH2:9])=O)[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:19])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7](=[S:19])[NH2:9])[CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1cc(C(N)=O)no1
Solvent: Cc1ccccc1
Product: Cc1cc(C(N)=S)no1
Temperature: 25 °C
Yield: 103.8 %

Procedure:
A suspension of 525 mg (4.16 mmol) of 5-methylisoxazole-3-carboxamide and 1.85 g (4.58 mmol, 1.1 equiv) of Lawesson's reagent in 15 mL of dry toluene was heated to reflux for 5 h, during which time the reaction mixture became a clear yellow color. The reaction mixture was cooled to RT and the solvent was removed in vacuo. Purification of the material by silica gel flash column chromatography using a gradient of hexane/EtOAc 5/1 to hexane/EtOAc 1/1 as eluent followed by trituration with acetonitrile, filtration to remove the solid Lawesson's reagent byproducts and removal of solvent afforded 614 mg of the title compound as a yellow oil: 1H NMR (CDCl3, 300 MHz) δ 8.05 (s, br, 2H), 6.52 (s, 1H), 2.46 (s, 3H).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[O-]CC.[Na+].Br[CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25]>C(O)C>[C:1]([NH:4][C:5]([CH:21]=[CH:22][CH2:23][CH2:24][CH3:25])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: C=CCCCBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCC=CC(NC(C)=O)(C(=O)OCC)C(=O)OCC

Procedure:
Diethyl acetamidomalonate (6.0 g) was dissolved in 50 ml of dehydrated ethanol and 2.26 g of sodium ethoxide and 5.22 g of 5-bromo-1-pentene were added thereto. The mixture was refluxed under a nitrogen atmosphere overnight. The reaction mixture was neutralized and concentrated. The concentrate was purified by silica gel column chromatography using hexane-ethyl acetate (5:1→2:1) as an eluent to give 4.871 g of colorless, oily diethyl 2-acetamido-2-pentenylmalonate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][CH:27]=2)[C:8]2[C:13]([C:14]=1[CH:15]=[O:16])=[CH:12][C:11](B1OC(C)(C)C(C)(C)O1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][CH:27]=2)[C:8]2[C:13]([C:14]=1[CH:15]=[O:16])=[CH:12][C:11]([C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C=O)c2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1-c1ccc(OC(C)C)cc1
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(C=O)c2cc(-c3ccc(C(F)(F)F)cn3)ccc2n1-c1ccc(OC(C)C)cc1
Temperature: 80 °C

Procedure:
A mixture of 3-formyl-1-(4-isopropoxyphenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)indole-2-carboxylic acid ethyl ester (600 mg, 1.26 mmol; see step (a) above), 2-bromo-5-(trifluoromethyl)pyridine (426 mg, 1.89 mmol), Na2CO3 (aq, 2 M, 1.89 mL, 3.78 mmol), Pd(PPh3)4 (70 mg, 0.06 mmol), EtOH (5 mL) and toluene (20 mL) was heated at 80° C. for 24 h, allowed to cool, poured into H2O and extracted with EtOAc. The combined extracts were washed with H2O and brine, dried (Na2SO4), concentrated and purified by chromatography to give the sub-title compound. Yield 500 mg (80%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][NH:14][C@H:13]([CH3:17])[CH2:12]2)=[N:4][CH:5]=[C:6]([CH2:8][O:9][CH3:10])[CH:7]=1.Cl[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([C:28]([F:31])([F:30])[F:29])[CH:26]=[CH:27][C:21]=2[N:20]=1>O1CCOCC1>[Cl:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][N:14]([C:19]3[NH:20][C:21]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:22]=4[N:23]=3)[C@H:13]([CH3:17])[CH2:12]2)=[N:4][CH:5]=[C:6]([CH2:8][O:9][CH3:10])[CH:7]=1
Reactant: FC(F)(F)c1ccc2nc(Cl)[nH]c2c1
Reactant: COCc1cnc(N2CCN[C@H](C)C2)c(Cl)c1
Solvent: C1COCCO1
Product: COCc1cnc(N2CCN(c3nc4cc(C(F)(F)F)ccc4[nH]3)[C@H](C)C2)c(Cl)c1

Procedure:
A mixture of (3R)-1-(3-chloro-5-methoxymethyl-pyridin-2-yl)-3-methyl-piperazine from step (b) above (153 mg, 0.6 mmol) and 2-chloro-6-trifluoromethyl-1H-benzoimidazole (153 mg, 0.48 mmol, Example 1c) in dioxane (2 mL) reacted under the conditions of Example 3c to give the title compound. MS (ESI, pos. ion) m/z: 440 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][CH:22]2[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: N[C@H]1CC[C@H](O)CC1
Product: O=C(NC1CCC(O)CC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) and trans-4-aminocyclohexanol (59 mg, 0.51 mmol). The title compound was obtained as a solid (45 mg, 23% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, m), 8.58 (1H, m), 8.47 (1H, s), 4.56 (1H, d), 3.55 (1H, m), 3.37 (1H, m), 1.78 (4H, m), 1.20 (6H, m). MS m/z: 446.19, 448.18 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][CH:4]=1.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K]>CN(C)C=O>[C:8]1([C:6]2[O:7][C:3]([CH2:2][N:18]3[C:14](=[O:24])[C:15]4[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:17]3=[O:19])=[CH:4][N:5]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCc1cnc(-c2ccccc2)o1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1cnc(-c2ccccc2)o1
Yield: 99.8 %

Procedure:
Dissolve 5-bromomethyl-2-phenyloxazole (1.17 g, 4.94 mmol) in dimethylformamide (15 mL) and add dropwise to a solution of potassium phthalimide (1.1 g, 5.93 mmol) in dimethylformamide (15 mL). Stir the reaction under nitrogen at room temperature overnight, concentrate to remove dimethylformamide, dissolve in ethyl acetate (75 mL), wash with saturated Na2CO3 (50 mL), and brine (75 mL). Dry the organic phase (Na2SO4), filter, and concentrate. Perform flash chromatography on silica gel eluting with 4:1 to 1:1 Hex/ethyl acetate to afford 1.5 g of 2-(2-phenyloxazol-5-ylmethyl)isoindole-1,3-dione as an off-white solid. MS: m/e=305 (MH+)
Reaction SMILES: O.[CH2:2]([S:9][CH:10]1[NH:13][C:12](=[O:14])[CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:16][C:17](=[O:26])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[CH2:2]([S:9][CH:10]1[N:13]([CH2:16][C:17](=[O:26])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12](=[O:14])[CH2:11]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CC(SCc2ccccc2)N1
Reactant: O=C(CBr)CCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCc1ccccc1)CN1C(=O)CC1SCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.3 %

Procedure:
To a cooled (cold water bath) solution of 4-(benzylthio)azetidin-2-one (5.5 g, 28.5 mmol), tetra-n-butylammonium bromide (0.9 g, 2.85 mmol) and 1-bromo-4-phenylbutan-2-one (7.1 g, 31.3 mmol) in dry THF (100 ml) was added freshly powdered potassium hydroxide (1.8 g, 31.3 mmol), and the mixture stirred vigorously for 2 hr at ambient temperature. Water was added and the product extracted into ethyl acetate, dried (MgSO4) and evaporated to an oil. Treatment with ether gave the product as a white crystalline solid (3.12 g, 32%) mp 79-81° C.
Reaction SMILES: FC(F)(F)C(O)=O.C[O:9][C:10](=[O:48])[C@H:11]([CH2:44][CH2:45][S:46][CH3:47])[NH:12][C:13](=[O:43])[CH2:14][N:15]([CH2:27][C@@H:28]([NH:33][C:34](=[O:42])[C@@H:35]1[CH2:39][CH2:38][C:37](=[O:40])[N:36]1[CH3:41])[C@@H:29]([CH3:32])[CH2:30][CH3:31])[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.[Li+].[OH-].Cl>CO>[CH3:41][N:36]1[C:37](=[O:40])[CH2:38][CH2:39][C@H:35]1[C:34]([NH:33][C@@H:28]([C@@H:29]([CH3:32])[CH2:30][CH3:31])[CH2:27][N:15]([CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)[CH2:14][C:13]([NH:12][C@H:11]([C:10]([OH:48])=[O:9])[CH2:44][CH2:45][S:46][CH3:47])=[O:43])=[O:42]
Reactant: CC[C@H](C)[C@@H](CN(CC(=O)N[C@@H](CCSC)C(=O)OC)Cc1cccc2ccccc12)NC(=O)[C@@H]1CCC(=O)N1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H](CN(CC(=O)N[C@@H](CCSC)C(=O)O)Cc1cccc2ccccc12)NC(=O)[C@@H]1CCC(=O)N1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-[2(S)-((N-Methylpyroglutamyl)-amino)-3(S)-methylpentyl]-N-(1-naphthylmethyl)-glycyl-methionine methyl ester trifluoroacetate salt (prepared in Example 25, 112 mg, 0.19 mmol) was dissolved in methanol (5 ml) and treated with 0.76 ml of 1N LiOH. The mixture was stirred for 4 hours at room temperature, then treated with 0.76 ml of 1N HCl. The solvent was evacuated in vacuo. The crude product was purified by preparative HPLC (Waters PrepPak C-18 eluting with CH3CN/0.1% TFA in H2O) to give, after lyophilization, the title compound.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][C:38]=1[CH3:44])=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][C:38]=3[CH3:44])=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: Cc1ccc(C(=O)CCCCCBr)c(C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccc(C)cc2C)CC1
Yield: 42.5 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.1 g) as starting compound, potassium carbonate (2.0 g) and 6-bromo-1-(2,4-dimethylphenyl)-1-hexanone (0.94 g) were reacted and treated in the same manner as in Example 172 to give 0.63 g of 4-amino-5-chloro-N-((1-(6-(2,4-dimethylphenyl)-6-oxohexyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [CH3:1][NH:2]/[C:3](/[NH:8][CH2:9][CH2:10][S:11]CC1N=C(CN(C)C)SC=1)=[CH:4]\[N+:5]([O-])=[O:6].ClCC1N=C(CN(C)C)SC=1.SCCNC(NC)=C[N+]([O-])=O>>[CH3:1][NH:2][C:3]1[C:4](=[N:5][OH:6])[S:11][CH2:10][CH2:9][N:8]=1
Reactant: CN/C(=C\[N+](=O)[O-])NCCSCc1csc(CN(C)C)n1
Agent: CN(C)Cc1nc(CCl)cs1
Agent: CNC(=C[N+](=O)[O-])NCCS
Product: CNC1=NCCSC1=NO

Procedure:
The preparation of nizatidine by fusing 4-chloromethyl-2-dimethylaminomethylthiazole with N-(2-mercaptoethyl)-N'-methyl-2-nitro-1,1-ethenediamine has been suggested generically in EP 49618. However, we have found that N-(2-mercaptoethyl)-N'-methyl-2-nitro-1,1-ethenediamine cannot be isolated and stored. Our attempts to prepare this compound have always produced the disulphide, N-methyl-[N'-[2-(N"-methyl-2-nitro-1,1-ethenediamine)ethyldisulphanyl]ethyl]-2-nitro-1,1-ethenediamine and 3-methylamino-5,6-dihydro-[1,4]-thiazin-2-one oxime.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5](=[O:17])[CH:6]([CH2:11][CH:12]1[O:16][CH2:15][CH2:14][O:13]1)[C:7]([O:9]C)=[O:8]>CO>[CH3:3][O:4][C:5](=[O:17])[CH:6]([CH2:11][CH:12]1[O:16][CH2:15][CH2:14][O:13]1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)C(CC1OCCO1)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C(CC1OCCO1)C(=O)O
Temperature: 85 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
To a solution of 1.03 g (18 mmol) potassium hydroxide in 15 ml methanol were added 4.00 g (18 mmol) (1,3-dioxolan-2-ylmethyl)propanedioic acid dimethyl ester. After stirring overnight at 85° C. the solvent was distilled off. The residue was extracted with water/ethylacetate. The aqueous phase was then acidified with concentrated hydrochloric acid. Extraction with ethylacetate gave 2.11 g (56%) 2-[1,3]dioxolan-2-ylmethyl-malonic acid monomethyl ester as light yellow oil, 1H-NMR (ppm, CDCl3) δ 2.38–2.42 (m, 2H), 3.65 (t, 1H, J=6.9 Hz), 3.77 (s, 3H), 3.79–3.97 (m, 4H), 5.03 (t, 1H, J=3.6 Hz).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)([CH:13]=[O:14])[CH2:12][CH:7]2[CH2:6]1)=[O:4].O.O.P([O-])(O)(O)=[O:26].[Na+].Cl([O-])=O.[Na+].CC(=CC)C>O1CCCC1.O>[CH:16]1([CH2:15][C:11]2([C:13]([OH:26])=[O:14])[CH2:12][CH:7]3[CH2:6][N:5]([C:3](=[O:4])[N:2]([CH3:1])[CH3:22])[CH2:9][CH:8]3[CH2:10]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=P([O-])(O)O
Reactant: CN(C)C(=O)N1CC2CC(C=O)(CC3CCCCC3)CC2C1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)N1CC2CC(CC3CCCCC3)(C(=O)O)CC2C1
Temperature: 0 °C
Yield: 99.8 %

Procedure:
5-Cyclohexylmethyl-5-formyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 15b (0.713 g, 2.33 mmol) was dissolved in the solvent mixture of 60 mL of tetrahydrofuran and 30 mL of water. Upon cooling to 0° C., sodium dihydrogenphosphate dihydrate (1.09 g, 6.99 mmol), sodium chlorite (0.79 g, 6.99 mmol) and 2-methyl-2-butene (0.62 mL, 7.0 mmol) were added. The reaction mixture was reacted at 0° C. for 2 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated to remove tetrahydrofuran and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 5-cyclohexylmethyl-2-dimethylcarbamoyl-octahydro-cyclopenta[c]pyrrole-5-carboxylic acid 15c (0.75 g, yield 100%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Cl:12])[CH:9]=[C:10]([Cl:11])[C:2]=1[NH2:1]
Reactant: Nc1c(Cl)cc(Cl)cc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Cl)cc(Cl)c1N
Temperature: 64 °C
Yield: 78.6 %

Procedure:
To a 500 mL round-bottom flask, 0.2 mol of 2-amino-3,5-dichlorobenzoic acid having a structural formula of IV-4, 300 mL of methanol, and 5 mL of concentrated sulfuric acid were added, heated to 64° C. and reacted for 12 hours (into which 3 mL of concentrated sulfuric acid was added twice), after cooling most of the solvent was removed under reduced pressure, and 300 mL of water was added, the pH was adjusted to 9-10 with a saturated sodium hydroxide solution, extracted with 200 mL of ethyl acetate, washed with water for one time, dried over anhydrous sodium sulfate, filtered and the solvent was remove to obtain a crude product, 34.6 grams of 2-amino-3,5-dichlorobenzoic acid methyl ester having a structure as shown by VIII-1 was obtained by column chromatography, and the yield was 78.6%;
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[CH3:9][O:10][C:11]1[C:16](B(O)O)=[CH:15][CH:14]=[CH:13][N:12]=1>>[Br:8][C:4]1[CH:3]=[C:2]([C:16]2[C:11]([O:10][CH3:9])=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1ncccc1B(O)O
Reactant: Brc1cccc(Br)c1
Product: COc1ncccc1-c1cccc(Br)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using 1,3-dibromo-benzene and 2-methoxy-3-pyridineboronic acid.
Reaction SMILES: C[Si]([I:5])(C)C.F[B-](F)(F)F.[F:11][S:12]([F:24])([F:23])([F:22])([F:21])[C:13]1[CH:18]=[CH:17][C:16]([N+]#N)=[CH:15][CH:14]=1>>[I:5][C:16]1[CH:17]=[CH:18][C:13]([S:12]([F:24])([F:23])([F:22])([F:21])[F:11])=[CH:14][CH:15]=1
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Reactant: C[Si](C)(C)I
Agent: F[B-](F)(F)F
Product: FS(F)(F)(F)(F)c1ccc(I)cc1
Reaction time: 0.08 h
Yield: 40.3 %

Procedure:
(Bowden, et al., Tetrahedron 2000, 56, 3393-3408) Trimethylsilyl iodide (15.0 mg, 0.0750 mmol) was added to a solution of 1 (11.0 mg, 0.0346 mmol) in [BMIM][BF4] (67.6 mg). After stifling for 5 min the mixture was extracted with hexane (0.5 mL×3) and the combined extracts was evaporated to give pure 25b as a colorless oil (4.6 mg, 40%): MS (GC, EI): m/z=330 [M+], 311 [M+ F], 222, 96. 1H NMR (500 MHz, CDCl3): δ=7.82 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.8 Hz, 2H) ppm. 13C NMR (125 MHz, CDCl3): δ=137.9 (2CH), 127.5 (2CH), 98.2 (C) ppm. 19F NMR (470 MHz, CDCl3): δ=83.5 (quint, J=151 Hz, 1 F), 62.8 (d, J=151 Hz, 4 F) ppm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][NH2:15])[N:12]=2)[CH:2]=1.[C:16](O)(=O)C.C=O>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[S:9][C:10]3[CH2:16][NH:15][CH2:14][CH2:13][C:11]=3[N:12]=2)[CH:2]=1
Reactant: CC(=O)O
Reactant: NCCc1csc(Nc2cccnc2)n1
Agent: C=O
Solvent: CO
Product: c1cncc(Nc2nc3c(s2)CNCC3)c1
Reaction time: 2 h
Yield: 57.3 %

Procedure:
2-(3-Pyridyl)amino-4-(2-aminoethyl)thiazole (0.50 g, from preceding preparation) and acetic acid (0.19 ml, 3.3 mmol) were dissolved in methanol (23 ml) and treated with formaldehyde (0.19 ml of a 37% aqueous solution, 2.3 mmol). The reaction was allowed to stir at room temperatue for 18 hours, at which point additional formaldehyde (0.02 ml of a 37% aqueous solution, 0.25 mmol) was added. After an additional 2 hours, the reaction mixture was filtered; the filtrate was concentrated in vacuo, dissolved in aqueous base, and extracted with methylene chloride. The organic extracts were dried over sodium sulfate and concentrated to provide the title product (310 mg, 1.3 mmol, 57% yield).