Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH3:15])[CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[C:16](O)(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19].CCN=C=NCCCN(C)C>CC#N.CCOC(C)=O>[OH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[C:16]([NH:1][CH2:2][CH2:3][N:4]([CH3:15])[CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:24]
Reactant: O=C(O)c1ccccc1O
Reactant: CN(CCN)CCNC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN(CCNC(=O)OC(C)(C)C)CCNC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 49 %

Procedure:
tert-Butyl 2-((2-aminoethyl)(methyl)amino)ethylcarbamate (500 mg, 2.3 mmol) was taken up in CH3CN (10 mL) along with salicylic acid (310 mg, 2.3 mmol) and EDCI (485 mg, 2.53 mmol). The resulting reaction mixture was stirred at room temperature for 18 h and then diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by chromatography (MeOH—CH2Cl2, 5%) to afford tert-butyl 2-((2-(2-hydroxybenzamido)ethyl)(methyl)amino)ethylcarbamate (380 mg, 49%). Mass calculated for C17H27N3O4: 337.2. found: [M+H]+=338.
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[N:16]([CH:21]=[CH:22][CH:23]=3)[CH:17]=[C:18]([CH3:20])[N:19]=2)[CH2:10]1)(C)(C)C>CO>[ClH:1].[ClH:1].[CH3:20][C:18]1[N:19]=[C:14]([N:11]2[CH2:12][CH2:13][CH:9]([NH2:8])[CH2:10]2)[C:15]2[N:16]([CH:21]=[CH:22][CH:23]=2)[CH:17]=1
Reactant: Cc1cn2cccc2c(N2CCC(NC(=O)OC(C)(C)C)C2)n1
Agent: Cl
Solvent: CO
Product: Cc1cn2cccc2c(N2CCC(N)C2)n1
Reaction time: 8 h
Yield: 97.7 %

Procedure:
HCl (4 M in dioxane, 3.80 mL, 15.2 mmol) was added to [1-(3-methyl-pyrrolo[1,2-a]pyrazin-1-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (965 mg, 3.04 mmol) in MeOH (10 mL). This was stirred overnight then concentrated to give the product (860 mg, 2.97 mmol, 98%) as a white solid.
Reaction SMILES: [CH2:1]([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[N:17]=[CH:18][N:19]([CH2:21][CH3:22])[CH:20]=3)[S:15][C:8]=12.CI>O1CCCC1>[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[N:17]=[C:18]([CH3:1])[N:19]([CH2:21][CH3:22])[CH:20]=3)[S:15][C:8]=12.[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[N:17]=[CH:18][N:19]([CH2:21][CH3:22])[CH:20]=3)[S:15][C:8]=12
Reactant: [Li]CCCC
Agent: CCn1cnc(-c2cc3nccc(Cl)c3s2)c1
Solvent: CI
Solvent: C1CCOC1
Product: CCn1cc(-c2cc3nccc(Cl)c3s2)nc1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium was added to a solution at −78° C. of 7-chloro-2-(1-ethyl-1H-imidazol-4-yl)thieno[3,2-b]pyridine (13, scheme 4) in tetrahydrofuran and stirred for about 15 minutes. Methyl iodide was added slowly and the reaction mixture was stirred at −78° C. until completion of the reaction. The mixture was quenched with water then allowed to warm to room temperature. The aqueous solution was extracted three times with ethyl acetate. The combined organic extracts were washed with water and brine, then dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by flash chromatography (eluent: 100% DCM to 2% MeOH/98% DCM) to afford the title compound 107 (as a mixture with about 15% of the starting material 13) as a yellow solid (190 mg, 80% yield). MS (m/z): 278.0 (M+H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[CH:17][CH:16]=4)[C:13](=[O:27])[CH:12](C(OCC)=O)[C:11]3=[O:33])=[CH:9][C:4]=2[N:3]=[CH:2]1.Cl>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:22][CH2:23][O:24][CH2:25][CH2:26]5)=[CH:17][CH:16]=4)[C:13](=[O:27])[CH2:12][C:11]3=[O:33])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)C1C(=O)C(c2ccc(N3CCOCC3)cc2)N(c2ccc3[nH]cnc3c2)C1=O
Agent: Cl
Product: O=C1CC(=O)N(c2ccc3[nH]cnc3c2)C1c1ccc(N2CCOCC2)cc1

Procedure:
The compound was synthesized starting from ethyl 1-(1H-benzo[d]imidazol-5-yl)-5-(4-morpholinophenyl)-2,4-dioxo-pyrrolidine-3-carboxylate (which may be prepared in accordance with the procedure described for Intermediate 8; 0.12 g, 0.2676 mmol) and 5 N aqueous hydrochloric acid (6 ml) according to the method described in Method 1, step 3.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([C:12]12[CH2:19][CH2:18][N:15]([CH2:16][CH2:17]1)[C:14](=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:13]2=[O:27])[CH:10]=[CH2:11].C[Si](Cl)(C)C.CN(P(N(C)C)(N(C)C)=O)C>[Cu].C1(C)C=CC=CC=1>[CH2:9]([C:12]12[CH2:17][CH2:16][N:15]([CH2:18][CH2:19]1)[CH:14]([CH:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:13]2=[O:27])[CH:10]=[CH2:11]
Reactant: Br[Mg]c1ccccc1
Reactant: C=CCC12CCN(CC1)C(=Cc1ccccc1)C2=O
Agent: [Cu]
Agent: C[Si](C)(C)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCC12CCN(CC1)C(C(c1ccccc1)c1ccccc1)C2=O
Temperature: 0 °C
Yield: 67.5 %

Procedure:
Copper(I) bromide dimethyl sulfide complex (1.06 g, 5.16 mmol) and 100 ml of toluene were placed in a reaction vessel, which was immersed into an dry-ice acetone bath. Phenylmagnesium bromide (3.0M in ether, 42 ml, 126 mmol) was slowly added to the copper catalyst keeping the inner temperature below -60° C. To this yellow-white suspension was added a solution prepared from 4-allyl-2-benzylidene-1-azabicyclo-[2.2.2]octane-3-one (25.9 g, 103 mmol), trimethylsilyl chloride (31.4 ml, 247 mmol), HMPA (43 ml, 247 mmol) and toluene (120 ml) keeping below -60° C. After addition was completed, the reaction mixture was warmed up to 0° C. The reaction was quenched with 14.5 ml of acetic acid at -60° C. Water was added to the reaction mixture, which was neutralized with Na2CO3 (pH=6.5). The resulting solution was worked-up by an ordinal procedure (extraction with ether at pH=6.5, and then at pH=8.0, washing with brine, drying over Na2SO4, concentration by evaporation) to provide a crude product, which was triturated with ether to afford 4-allyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-one, 58 (23.04 g, 68%).
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4].[Cl:7][SiH:8]([Cl:10])[Cl:9]>[Cl-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1>[Cl:7][Si:8]([Cl:10])([Cl:9])[CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: Cl[SiH](Cl)Cl
Reactant: C[Si](C)(C)CCl
Agent: [Cl-]
Agent: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C[Si](C)(C)C[Si](Cl)(Cl)Cl
Yield: 72.2 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.29 g (0.75 mmol) of benyltriphenylphosphonium chloride, 0.92 g (7.5 mmol) of (chloromethyl)trimethylsilane, and 3.05 g (22.5 mmol ) of trichlorosilane were reacted at 150° C. for 10 hrs. The resulting mixture was distilled to give 1.20 g of 1,1,1-trichloro-3,3-dimethyl-1,3-disilabutane (yield; 72%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][OH:13])=[O:4].[OH-].[Na+]>C(O)(C)C>[NH:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:12][O:13][CH2:2][C:3]1=[O:4]
Reactant: O=C(CCl)Nc1ccccc1CO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C1COCc2ccccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To 2-chloro-N-(2-hydroxymethyl-phenyl)acetamide (7.0 g, 35 mmol) in isopropyl alcohol (100 mL) was added 50% w/w sodium hydroxide aqueous solution (4 mL, 50 mmol). The mixture was stirred at rt overnight. The mixture was extracted with DCM (50 mL×2). The resulting solution was then washed with brine (50 mL×2) and dried over MgSO4. The solvent was evaporated to afford 1,5-dihydro-4,1-benzoxazepin-2-one as a brown solid in 65% yield (3.7 g). MS: 163.0 (M+H)+; tR=1.56 min (method 1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:11])=[C:8]([OH:10])[CH:9]=1)([O-:3])=[O:2].[CH3:12][O:13][CH2:14][CH2:15]Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:11][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]=1[O:10][CH2:15][CH2:14][O:13][CH3:12]
Reactant: COCCCl
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cc([N+](=O)[O-])ccc1Cl
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 5-nitro-2-chlorophenol (1.0 g, 5.8 mmol) and 2-methyloxychloroethane (2.6 mL, 28.8 mmol) in DMF (20 mL) was added K2CO3 (2.4 g, 17.4 mmol). The suspension was stirred at 80° C. for 18 h. After cooling, the mixture was filtered, the salts washed with EtOAc and the solvents removed under vacuum. The residue was dissolved in EtOAc and washed twice with NaOH (1 N) and once with H2O. The EtOAc layer was dried over MgSO4 and concentrated under vacuum. The crude was purified on silica gel using a Hexanes/EtOAc gradient (100/0 to 50/50) to give 1-chloro-2-(2-methoxy-ethoxy)-4-nitro-benzene.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][C:15]([C:19]([O:21]CC)=[O:20])=[CH:14][C:13]=3[CH:24]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][C:15]([C:19]([OH:21])=[O:20])=[CH:14][C:13]=3[CH:24]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1=Cc2cc(-c3ccc(SC)cc3)ccc2OCC1
Agent: [Na+]
Agent: [OH-]
Product: CSc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Reaction time: 20 h
Yield: 93.3 %

Procedure:
To a solution of ethyl 7-(4-methylthiophenyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (132 mg) in ethanoltetrahydrofuran (5 ml-5 ml) was added 1N sodium hydroxide (1.0 ml) at room temperature, and the mixture was stirred for 20 hours and concentrated under reduced pressure. To the residue was added 1N hydrochloric acid (2 ml) and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The resulting crystal was collected by filtration to give 7-(4-methylthiophenyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (113 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][N:11]=[C:12]([Cl:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].[Cl:19]C(Cl)(N=NC1C(Cl)=CC(Cl)=CC=1Cl)C(OC)=O>>[Cl:18][C:12]([Cl:19])([N:11]=[N:10][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=1[Cl:9])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C(Cl)=NNc1c(Cl)cc(Cl)cc1Cl
Reactant: COC(=O)C(Cl)(Cl)N=Nc1c(Cl)cc(Cl)cc1Cl
Product: CCOC(=O)C(Cl)(Cl)N=Nc1c(Cl)cc(Cl)cc1Cl

Procedure:
Following the same procedure but substituting methyl-, isopropyl- and butyl-chloroglyoxylate-2-(2,4,6-trichlorophenyl)hydrazone for ethyl chloroglyoxylate 2-(2,4,6-trichlorophenyl)hydrazone there were prepared methyl dichloro[(2,4,6-trichlorophenyl)azo]acetate,
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH:39]([O:41][CH2:42][CH2:43][O:44][CH3:45])[CH3:40])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH:39]([O:41][CH2:42][CH2:43][O:44][CH3:45])[CH3:40])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn(C(C)OCCOC)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(C)cc(-c3cn(C(C)OCCOC)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-(2-methoxyethoxy-2-ethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[CH:8]=[CH:9][N:10]=2)[N:5]=[C:4]([CH3:21])[C:3]=1[CH2:22][CH2:23]Cl.[NH2:25][CH:26]([CH2:30][CH3:31])[CH2:27][O:28][CH3:29]>C(OC(=O)C)C.CCCCCC.C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:29][O:28][CH2:27][CH:26]([N:25]1[C:2]2[C:11]3[N:10]=[CH:9][CH:8]=[C:7]([C:12]4[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=4[CH3:20])[C:6]=3[N:5]=[C:4]([C:21]3[C:13]([CH3:14])=[CH:12][C:7]([CH3:8])=[CH:6][C:11]=3[CH3:2])[C:3]=2[CH:22]=[CH:23]1)[CH2:30][CH3:31]
Reactant: CCC(N)COC
Reactant: Cc1cc(C)c(-c2ccnc3c(Cl)c(CCCl)c(C)nc23)c(C)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCC(COC)n1ccc2c(-c3c(C)cc(C)cc3C)nc3c(-c4c(C)cc(C)cc4C)ccnc3c21
Reaction time: 8 h

Procedure:
A solution of 4-chloro-3-(2-chloroethyl)-8-mesityl-2-methyl[1,5]naphthyridine (200 mg, 0.557 mmol) in 2-amino-1-methoxybutane (2.0 mL) was stirred at 200° C. for four hours in a sealed tube. After overnight, the residue was purified by silica gel column chromatography (30-50% ethylacetate/hexane) Activated manganese dioxide (290 mg, 3.24 mmol) was added to a solution of the resulting product (130 mg, 0.33 mmol) in toluene (20 mL) and the mixture was heated under reflux for one day. After filtering through Celite, the mixture was evaporated. The residue was purified by silica gel column chromatography-(10% ethyl acetate/hexane), to give the title compound (108 mg) as white crystals.
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[CH3:47][C@@:48]12[C@H:56]([OH:57])[CH2:55][C@@H:51]([C:52]1([CH3:54])[CH3:53])[CH2:50][CH2:49]2>>[Cl:17][C:18]1[C:19]([O:57][C@@H:56]2[CH2:55][C@H:51]3[C:52]([CH3:54])([CH3:53])[C@:48]2([CH3:47])[CH2:49][CH2:50]3)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: CC1(C)[C@H]2CC[C@]1(C)[C@H](O)C2
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(O[C@@H]2C[C@@H]3CC[C@@]2(C)C3(C)C)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with [(1S)-endo]-(−)-borneol, the title compound was obtained as a colorless solid (0.17 g, 34%): 1H NMR (300 MHz, CDCl3) δ 8.64 (s, 1H), 8.20-8.00 (m, 1H), 6.67-6.43 (m, 1H), 4.47-4.25 (m, 1H), 3.03 (s, 6H), 2.55-2.20 (m, 2H), 1.92-1.69 (m, 2H), 1.51-1.19 (m, 2H), 1.19-0.74 (m, 10H); MS (ES−) m/z 431.2 (M−1), 433.2 (M−1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([C:25]([C:27]2[CH:36]=[C:35]([CH3:37])[C:30]3[NH:31][C:32](=[O:34])[O:33][C:29]=3[CH:28]=2)=[O:26])[CH:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:24][C:22]1[N:23]=[C:18]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]3=[O:16])[CH2:5][CH2:6]2)[CH:19]=[C:20]([C:25]([C:27]2[CH:36]=[C:35]([CH3:37])[C:30]3[NH:31][C:32](=[O:34])[O:33][C:29]=3[CH:28]=2)=[O:26])[N:21]=1
Reactant: Cc1nc(Cl)cc(C(=O)c2cc(C)c3[nH]c(=O)oc3c2)n1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)c2cc(C)c3[nH]c(=O)oc3c2)cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)n1

Procedure:
65 mg (0.30 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 91 mg (0.30 mmol) 6-(6-chloro-2-methyl-pyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one and 0.11 mL (0.60 mmol) DIPEA were stirred overnight in 3 mL DMF at RT. Then the reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent evaporated down. The residue was neutralised with 4N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=2)[C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]=2)[CH2:4][CH2:3]1.[Sn+2].O.O.[Cl-].[Cl-].O.[OH-].[Na+]>C(O)C>[NH:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[CH:9]([O:8][CH:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)[C:19]1[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=1
Reactant: CN1CCC(OC(c2cccc([N+](=O)[O-])c2)c2nc3ccccc3[nH]2)CC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1CCC(OC(c2cccc(N)c2)c2nc3ccccc3[nH]2)CC1

Procedure:
To a solution of 2-[(1-Methyl-piperidin-4-yloxy)-(3-nitro-phenyl)-methyl]-1H benzimidazole (110 mg) in ethanol (5 mL) is added Tin(II)dichloride-dihydrate (340 mg). The reaction mixture is heated at reflux for 2 hours. Water is added to the mixture as well as sodium hydroxide 1N solution to pH 10 The solution is extracted with chloroform. The pooled organic phases are dried with magnesium sulphate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 98/2/0.2 to 90/10/1) to give 3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylamine that is used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].C(O)(=O)C.C(OC(=O)C)(=O)C.C([O-])(O)=O.[Na+].[CH3:49][S:50]([CH3:52])=O>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C:11]([C@H:13]1[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])[C@H:20]1[CH2:25][CH2:24][C@H:23]([O:26][CH2:49][S:50][CH3:52])[CH2:22][CH2:21]1)=[O:4]
Reactant: CS(C)=O
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OCSC)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-cyclohex-1-enyl-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (25 mg, 0.054 mmol) in DMSO (0.2 mL) was added a mixture of acetic acid and acetic anhydride (1:5.6) (0.17 mL). After stirring for 1.5 h at room temperature it was held at 40° C. for 5 h. It was cooled to room temperature and stirred for 16 h. The mixture was cooled in ice-bath and NaHCO3 solution was added carefully. It was extracted with ether. The extract was washed with water and brine, dried over MgSO4 and evaporated. Pure 5-cyclohex-1-enyl-3-[(trans-4-methyl-cyclohexanecarbonyl)-(trans-4-methylsulfanylmethoxy-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester was obtained by chromatography over silica gel (hexane:EtOAc=−4:1) (22 mg, 77%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([NH2:13])=[C:6]([Cl:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCO.CO.[NH4+].[Cl-].C1COCC1>C(Cl)Cl.C1COCC1.O.[Zn]>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:13])=[C:6]([Cl:14])[C:5]=1[NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(Cl)c1Nc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(N)c(N)c(Cl)c1Nc1ccccc1
Reaction time: 20 h
Yield: 70.8 %

Procedure:
4-Amino-3-chloro-5-nitro-2-phenylamino-benzoic acid methyl ester 5c (0.50 g, 1.55 mmol) is dissolved into 2:1 EtOH/MeOH (15.5 mL). Saturated aqueous NH4Cl (15 mL), Zn powder (1.02 g, 15.6 mmol), and THF (10 mL) are added. After stirring for 20 hours, the reaction mixture is diluted with CH2Cl2/THF and water. The organic layer is washed with water (3×). The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure. The solids are triturated with ether to give 0.32 g (70%) clean desired product.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[S:9][C:10]([C:13]([NH2:15])=[O:14])=[CH:11][N:12]=2)=[CH:5][CH:4]=1)=O.[CH2:18]([NH2:23])[CH2:19][CH:20]([CH3:22])[CH3:21].[BH4-].[Na+]>CO>[CH3:21][CH:20]([CH3:22])[CH2:19][CH2:18][NH:23][CH2:1][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[S:9][C:10]([C:13]([NH2:15])=[O:14])=[CH:11][N:12]=2)=[CH:5][CH:4]=1
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2)s1
Reactant: CC(C)CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCNCc1ccc(Oc2ncc(C(N)=O)s2)cc1
Reaction time: 8 h

Procedure:
Place 2-(4-formylphenoxy)thiazole-5-carboxamide (0.187 g, 0.755 mmol), isoamylamine (0.072 g, 0.831 mmol) and 3 Å molecular sieves in a vial. Add methanol (3.8 mL), cap and stir overnight. Add NaBH4 (0.029 g, 0.755 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 5% (2.0 M NH3 in methanol) in ethyl acetate over 45 minutes to give the title compound: TOF MS ES+ 320.1 (M+H)+, HRMS calcd for C16H22N3O2S 320.1432 (M+H)+, found 320.1428, time 0.32 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min. 20-95% over 18], tR=9.7 min, 96.9% purity.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH:5]=[N:4][N:3]=1.[OH-].[Na+].Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[O:16]>CO>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:15](=[O:16])[CH2:14][S:1][C:2]2[N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH:5]=[N:4][N:3]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CCCCn1cnnc1S
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCn1cnnc1SCC(=O)c1ccc(OC)cc1

Procedure:
To a solution of 3-mercapto-4-n-butyl-1,2,4-triazole (10 g. or 0.063 mole) and sodium hydroxide (2.55 g. or 0.0637 mole) in 200 ml. of methanol was added α-bromo-p-methoxyacetophenone (15.3 g. or 0.067 mole). The reaction mixture was heated at reflux for 16 hours and the solvent removed in vacuum to leave a solid residue. The solid was washed with water and recrystallized from benzene-hexane to give 3-(p-methoxy-phenacylmercapto)-4-n-butyl-1,2,4-triazole melting at 79°-82° C. The structure was confirmed by its infrared and nuclear magnetic spectra.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:11])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.N([C:16]1[NH:17][CH2:18][CH2:19][N:20]=1)[N+]([O-])=O.C1(C)C(C)=CC=CC=1>CC(C)=O>[NH:20]1[CH2:19][CH2:18][N:17]=[C:16]1[NH:1][CH2:2][CH:3]([OH:11])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1
Reactant: Cc1ccc(C(O)CN)cc1
Reactant: O=[N+]([O-])NC1=NCCN1
Solvent: CC(C)=O
Solvent: Cc1ccccc1C
Product: Cc1ccc(C(O)CNC2=NCCN2)cc1
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
A mixture of 9.06 parts of α-(aminomethyl)-p-methylbenzyl alcohol, 7.8 parts of 2-(nitramino)-2-imidazoline and 8 parts of xylene is stirred for 30 minutes at 160°C (oil-bath). The reaction mixture is cooled and acetone is added. The precipitated product is filered off, washed with acetone and dried, yielding α-(2-imidazolin-2-ylaminomethyl)-p-methylbenzyl alcohol; 163.7°C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH:9]=2)=[CH:6][CH:7]=1.O.[NH3:22]>C(Cl)(Cl)Cl>[NH2:22][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: N
Reactant: COc1ccc(-c2ccc(Cl)nn2)cc1OCC(C)C
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2ccc(N)nn2)cc1OCC(C)C
Yield: 53.8 %

Procedure:
7.0 g (24 mmol) of 3-chloro-6-[4-methoxy-3-(2-methylpropoxy)phenyl]pyridazine are reacted as described in Example 1 in 40 ml of ammonia-saturated ethylene glycol. The crude product obtained by precipitation with water is dissolved in chloroform, the solution is dried with potassium carbonate, and the product is precipitated with petroleum ether (b.p. 50°-70° C.). 3.5 g (53.8%) of the title compound of m.p. 187° C. are obtained.