Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([CH3:8])[CH:7]=1)#[CH:2].[Br:9][C:10]1[CH:15]=[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:13](I)=[CH:12][N:11]=1.C(N(CC)CC)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:9][C:10]1[N:11]=[CH:12][C:13]2[CH:2]=[C:1]([C:3]3[CH:4]=[N:5][N:6]([CH3:8])[CH:7]=3)[N:16]([S:17]([CH3:20])(=[O:19])=[O:18])[C:14]=2[CH:15]=1
Reactant: C#Cc1cnn(C)c1
Reactant: CS(=O)(=O)Nc1cc(Br)ncc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1cc(-c2cc3cnc(Br)cc3n2S(C)(=O)=O)cn1
Temperature: 60 °C
Yield: 45.2 %

Procedure:
4-Ethynyl-1-methyl-1H-pyrazole (20) (4.11 g, 38.7 mmole) was dissolved in DMF (95 mL) and N-(2-bromo-5-iodopyridin-4-yl)methanesulfonamide 8 (12.18 g 32.3 mmole) was added. To the solution was added triethylamine (19.6 mL, 14.1 g 139 mmole) and copper(I) iodide (214 mg 1.12 mmole). The reaction was sealed and flushed with nitrogen. Bis(triphenylphosphine)palladium dichloride (797 mg 1.13 mmole) was added and the reaction was again flushed with nitrogen and heated at 60° C. for 105 minutes. Most of the DMF was evaporated and the residue taken up in ethyl acetate (350 ml). The solution was washed with water (3×100 mL) and brine. Each aqueous fraction was backwashed with the same 100 mL portion of ethyl acetate. The combined organics were dried and evaporated. The residue was flash chromatographed (silica) eluting with dichloromethane, 1:4 ethyl acetate:dichloromethane, 1:1 ethyl acetate:dichloromethane and ethyl acetate to give the title compound (5.19 g 45.9%). 1H-NMR (CDCl3, 500 MHz): δ 2.98 (s, 3H), 4.01 (s, 3H), 6.69 (d, J=0.95 Hz, 1H), 7.73 (s, 1H), 7.78 (s, 1H), 8.25 (t, J=0.95 Hz, 1H), 8.64 (d, J=0.95 Hz, 1H).
Reaction SMILES: [CH:1]([C:3]1[N:7]([CH3:8])[CH:6]=[N:5][C:4]=1[C:9]#[N:10])=O.Cl.[NH2:12][CH2:13][CH:14]([C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[C:22]=1[F:29])[CH2:15][C:16](OCC)=[O:17]>>[CH3:8][N:7]1[C:3]([CH2:1][N:12]2[CH2:13][CH:14]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[C:22]=3[F:29])[CH2:15][C:16]2=[O:17])=[C:4]([C:9]#[N:10])[N:5]=[CH:6]1
Reactant: Cn1cnc(C#N)c1C=O
Reactant: CCOC(=O)CC(CN)c1cc(F)cc(F)c1F
Agent: Cl
Product: Cn1cnc(C#N)c1CN1CC(c2cc(F)cc(F)c2F)CC1=O
Yield: 25.8 %

Procedure:
1-methyl-5-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile 127 is prepared according to the method described in 10.1 starting from 5-formyl-1-methyl-1H-imidazole-4-carbonitrile x86 and ethyl 4-amino-3-(2,3,5-trifluorophenyl)butanoate hydrochloride x60.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[C:15]1([N:6]2[C:5]3[CH:21]=[CH:22][C:2]([N:1]([S:31]([C:28]4[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=4)(=[O:33])=[O:32])[S:31]([C:28]4[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=4)(=[O:33])=[O:32])=[CH:3][C:4]=3[N:8]=[C:7]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1
Product: COc1ccc(S(=O)(=O)N(c2ccc3c(c2)nc(-c2ccccc2)n3-c2ccccc2)S(=O)(=O)c2ccc(OC)cc2)cc1

Procedure:
5-Amino-1,2-diphenyl-1H-benzimidazole was reacted with 4-methoxybenzenesulfonic acid chloride according to general operating instructions 13.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][NH:48][C:49]1[CH:50]=[C:51]([CH3:55])[CH:52]=[CH:53][CH:54]=1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:48]([CH3:47])[C:49]4[CH:50]=[C:51]([CH3:55])[CH:52]=[CH:53][CH:54]=4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CNc1cccc(C)c1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(C)c2cccc(C)c2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with N-methyl-N-m-tolylamine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C44H52Cl2N5O3 [(M+H)+] 768.3442, observed 768.3440.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12]C(=O)[NH:10][CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:16]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C(O)C>[NH2:10][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:16]=1)[CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[OH:12]
Reactant: O=C1NC(Cc2cccc(OC(F)(F)C(F)F)c2)C(c2cccc(F)c2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(F)c1

Procedure:
To a solution of (4RS,5SR)-5-(3-fluorophenyl)-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one (3.30 g, 8.52 mmol) in ethanol (12 ml) was added 8N aqueous sodium hydroxide solution (5.3 ml, 42 mmol), and the mixture was heated under reflux for 5 hrs. The reaction solutions was concentrated, diluted with water (100 ml), and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give the objective substance (2.60 g, 84%).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].[OH:6][C@@H:7]1[C@@H:31]([N:32]2[CH2:37][CH2:36][O:35][C:34]([CH3:39])([CH3:38])[CH2:33]2)[CH2:30][C@@:29]2([CH3:40])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:41])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C:17](=[O:24])[CH2:18]OS(C)(=O)=O)[CH2:8]1.O>C(O)C>[C:1]([O:4][CH2:18][C:17](=[O:24])[C@@H:16]1[C@:25]2([CH3:41])[C@H:13]([C@H:12]3[C@H:28]([CH2:27][CH2:26]2)[C@:29]2([CH3:40])[C@H:9]([CH2:8][C@H:7]([OH:6])[C@@H:31]([N:32]4[CH2:37][CH2:36][O:35][C:34]([CH3:39])([CH3:38])[CH2:33]4)[CH2:30]2)[CH2:10][CH2:11]3)[CH2:14][CH2:15]1)(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CC1(C)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](C(=O)COS(C)(=O)=O)CC[C@@H]43)C[C@@H]2O)CCO1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(=O)OCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N5CCOC(C)(C)C5)C[C@]4(C)[C@H]3CC[C@]12C
Yield: 35.4 %

Procedure:
Anhydrous potassium acetate (470 mg) was added to (2β,3α,5α)-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)-21-[(methylsulfonyl)oxy]pregnan-20-one (1.0 g) in ethanol (15 ml) and the solution was heated under reflux for 1.5 h. The reaction mixture was poured into water (150 ml) and the precipitated solid was filtered off, washed with water and the solid was dissolved in dichloromethane. After drying the solution over sodium sulfate, the solvent was removed under reduced pressure and the residue was chromatographed on silica gel. The purified product was crystallised from methanol to give (2β,3α,5α)-21-(acetyloxy)-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)pregnan-20-one (330 mg). m.p. 174°-175° C.; [α]D +13.9° (c 0.5).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=[O:18]>C(#N)C>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:18])=[CH:10][CH:9]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C(=O)COc2ccc(Br)cc2)cc1
Yield: 96.1 %

Procedure:
24 g of potassium carbonate are added to a solution of 20 g (0.115 mol) of 4-bromophenol and 26.5 g (0.115 mol) of 2-bromo-4′-methoxyacetophenone in 400 of acetonitrile, and the reaction mixture is heated under reflux for five hours. The precipitate is subsequently filtered off, the filtrate is evaporated to dryness, the residue is taken up in 10 ml of water, and the aqueous solution is extracted twice with 10 ml of ethyl acetate each time. The combined organic phases are washed with 10 ml of saturated sodium chloride solution and dried over sodium sulfate. After the solvent has been stripped off, the residue is triturated with 50 ml of diethyl ether, and the resultant crystalline product is filtered off with suction in vacuo, giving 35.5 g of 2-(4-bromophenoxy)-1-(4-methoxyphenyl)ethanone as beige solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[F:32])[CH2:16][CH2:15][CH:14]([NH:17][S:18]([C:21]([F:24])([F:23])[F:22])(=[O:20])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>[Pd]>[C:5]1([S:8]([C:11]2([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[F:32])[CH2:12][CH2:13][CH:14]([NH:17][S:18]([C:21]([F:23])([F:24])[F:22])(=[O:20])=[O:19])[CH2:15][CH2:16]2)(=[O:9])=[O:10])[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: O=S(=O)(NC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1)C(F)(F)F
Agent: [Pd]
Product: O=S(=O)(NC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccccc2)CC1)C(F)(F)F
Reaction time: 16 h
Yield: 96.5 %

Procedure:
A solution of the product from Example 47 (0.28 g, 0.6 mmol) was flushed with nitrogen, 10% palladium on carbon (0.03 g, 10% w/w) was added, and the mixture was hydrogenated at 40 psi for 16 hours. Filtration and evaporation in vacuo gave the product (0.28 g, 99%). 1H NMR (CDCl3, 400 MHz): 1.61-1.68 (2H, m), 2.03-2.07 (2H, m), 2.44 (2H, bt, J=13.2), 2.63 (2H, bd, J=13.5), 3.78-3.82 (1H, m), 5.64 (1H, d, J=8.4), 6.78-6.85 (1H, m), 6.99-7.08 (2H, m), 7.38-7.43 (4H, m), 7.60-7.65 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:11]Br)=[CH:8][C:9]=1[Cl:10])=[O:4].C([O-])(O)=[O:14].[Na+]>CS(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:11][OH:14])=[CH:8][C:9]=1[Cl:10])=[O:4]
Reactant: O=C([O-])O
Reactant: COC(=O)c1sc(CBr)cc1Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1sc(CO)cc1Cl
Temperature: 115 °C
Yield: 44.6 %

Procedure:
A mixture of 5-Bromomethyl-3-chloro-thiophene-2-carboxylic acid methyl ester (3.8 g, 14.1 mmol) and NaHCO3 (20 g, 238 mmol) in DMSO (100 ml) was heated at 115° C. for 4 h. The reaction mixture was cooled. The reaction mixture was diluted with water and extracted with DCM (3×100 mL), washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by column (0-30% EtOAc in hexane) to give 1.30 g (45%) product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1.[ClH:24].O1CCOCC1>ClCCl>[ClH:24].[ClH:24].[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2Br)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(N2CCNCC2)c(Br)c1
Temperature: 20 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
A solution of tert-butyl 4-(2-bromo-4-nitrophenyl)piperazine-1-carboxylate (2.3 g, 5.9 mmol) in dichloromethane (15 mL) was treated with 4 M HCl in 1,4-dioxane (15 mL, 59 mmol) and stirred at 20° C. for 3 h. The reaction mixture was concentrated, diluted with a minimal amount of methanol (˜15 mL), and added dropwise to ether (300 mL) that was cooled 0° C. The solid that precipitated was collected by filtration and dried to give the desired product (1.9 g, 89%) which was used in the next step without further purification.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24].O>C(O)(=O)C>[Br:1][C:12]1[CH:11]=[C:10]2[C:6]([C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:9]2)=[CH:5][C:4]=1[Cl:3]
Reactant: BrBr
Reactant: CCOC(=O)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1F
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c2cc(Br)c(Cl)cc2c1-c1ccccc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Add 1.0 ml of bromine to 4.6 g of ethyl 5-chloro-3-(2-fluorophenyl)indole-2-carboxylate in 250 ml of glacial acetic acid. Stir for 16 hours at room temperature, add water and collect the precipitate. Ws the precipitate with warm methanol. Collect the dry ethyl 6-bromo-5-chloro-3-(2-fluorophenyl)indole-2-carboxylate, m.p. 193°-194°.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]([C:10]1[CH:14]=[C:13]([NH2:15])[O:12][N:11]=1)([CH3:9])([CH3:8])[CH3:7].N1C=CC=CC=1>ClCCl>[C:6]([C:10]1[CH:14]=[C:13]([NH:15][C:3](=[O:4])[CH2:2][Cl:1])[O:12][N:11]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)c1cc(N)on1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)CCl)on1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
Chloroacetic acid chloride (0.25 ml; 3.14 mmol) is dropped slowly into a stirred solution of 3-t-Butyl-5-amino isoxazole (400 mg; 2.85 mmol) in pyridine (0.3 ml; 3.71 mmol) and dichloromethane (2 ml), cooled to 0° C. Stirring is continued for 2 h at room temperature. The reaction mixture is diluted with dichloromethane, washed twice with 1 N aqueous hydrochloric acid, twice with an aqueous solution of NaHCO3 and with water. The reaction mixture is then dried over Na2SO4, filtered and evaporated to yield 600 mg (97%) brownish solid of 11.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([O:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[CH3:15])=[O:6])[CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:24][C:25]([NH2:27])=[O:26]>CN(C=O)C>[CH3:3][C:2]([CH3:16])([O:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:24][C:25]([NH2:27])=[O:26])=[CH:10][C:9]=1[CH3:15])=[O:6])[CH3:1]
Reactant: NC(=O)CBr
Reactant: Cc1cc(O)ccc1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(OCC(N)=O)ccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.2 %

Procedure:
To a 200 mL round bottomed flask with a stirring bar, and an argon inlet was added 4-(1,1-dimethylethoxycarbonyl)amino-3-methylphenol (5.00 g, 22.39 mmot), Cs2CO3 (14.59 g, 44.78 mmol), DMF (50 mL), and bromoacetamide (3.24 g, 23.51 mmol). This mixture was stirred vigorously at ambient temperature for 24 h. The mixture was filtered through a frit and the DMF was removed under high vacuum. The residue was dissolved in EtOAc (300 mL) and washed wit H2O (2×) and brine (1×). Drying (MgSO4), filtration, and removal of the solvent in vacuo gave a solid. This material was triturated with EtOAc, the solid was collected by filtration and dried in vacuo to give 4.91 g (78%) of 4-(1,1-dimethyl-ethoxycarbonyl)amino-3-methylphenoxyacetamide as a white, crystalline solid.
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8]([CH3:10])[C@H:7]([C:11]([O:13]C)=[O:12])[CH2:6]1)(=O)C.[ClH:15]>O>[ClH:15].[SH:4][C@@H:5]1[CH2:9][N:8]([CH3:10])[C@H:7]([C:11]([OH:13])=[O:12])[CH2:6]1
Reactant: COC(=O)[C@@H]1C[C@H](SC(C)=O)CN1C
Agent: Cl
Solvent: O
Product: CN1C[C@@H](S)C[C@H]1C(=O)O
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
A mixed solution of methyl (2S,4S)-4-acetylthio-1-methyl-2-pyrrolidinecarboxylate (10.7 g), concentrated hydrochloric acid (14.9 g) and water (16 mL) was stirred at from 75 to 85° C. for 5 hours. After completion of the reaction, the water in the reaction mixture was removed by distillation under reduced pressure. Acetic acid (10 mL) and ethyl acetate (20 mL) were added to the residue, which was stirred at from 0 to 5° C. for 1 hour. The crystals which precipitated were collected by filtration to give the title compound (9.2 g, yield 95%). Nuclear magnetic resonance spectrum (400 MHz, CDCl3) δ(ppm): 2.11–2.20 (m, 1H), 2.97–3.05 (m, 1H), 3.02 (s, 3H), 3.56–3.68 (m, 2H), 3.80–3.88 (m, 1H), 4.35–4.41 (m, 1H).
Reaction SMILES: Cl.C([NH:4][C@H:5]([C:10]([NH:12][C@H:13]([C:21]([OH:23])=O)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[CH2:6][C:7](=[O:9])[OH:8])=O.[CH2:24](N(CC)CC)C>CO>[CH3:24][O:8][C:7](=[O:9])[CH2:6][CH:5]1[C:10](=[O:11])[NH:12][CH:13]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:21](=[O:23])[NH:4]1
Reactant: CCN(CC)CC
Reactant: O=CN[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Solvent: CO
Product: COC(=O)CC1NC(=O)C(Cc2ccccc2)NC1=O
Temperature: 25 °C
Yield: 72.8 %

Procedure:
To a solution having 9.6 g of hydrogen chloride dissolved in 400 ml of methanol was fed 61.6 g of N-formyl-α-L-aspartyl-L-phenylalanine and the resulting mixture was reacted at 50°-60° C. for 6 hours. The resulting reaction solution was cooled to room temperature, added dropwise with 30.4 g of triethylamine, and then subjected to further reaction under reflux for 8 hours. The reaction mixture was cooled to room temperature and the crystal thereby deposited was filtered and washed with methanol to obtain 40.2 g of 5-benzyl-3,6-dioxo-2-piperazine acetic acid methyl ester having a melting point of 216°-218° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:13])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[CH2:14]1CCN2C(=NCCC2)CC1.IC>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9](=[O:13])[C:10]([O:12][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(O)C(=O)Cc1ccc(Br)cc1
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C(=O)Cc1ccc(Br)cc1
Reaction time: 2.5 h
Yield: 68 %

Procedure:
To a solution of 3-(4-bromophenyl)-2-oxopropionic acid (70.0 mg, 0.288 mmol) in DMF (2 mL) at 0° C. was added DBU (72.2 mg, 0.288 mmol) and iodomethane (204 mg, 1.440 mmol). The reaction mixture was stirred for 2.5 hours at the same temperature. The reaction was acidified with 1 M HCl and extraction with ether (3×25 mL), drying (MgSO4), concentrated under reduced pressure and dried on vacuum to get the light brown oily compound B18 in 68% yield and used as such in next step.
Reaction SMILES: O.S(=O)(=O)(O)O.[CH2:7]([N:14]1[CH2:21][CH:20](O)[CH2:19][N:18](S(C2C=CC=CC=2)(=O)=O)[CH2:17][CH:16]([OH:32])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:7]([N:14]1[CH2:15][CH:16]2[O:32][CH:20]([CH2:19][NH:18][CH2:17]2)[CH2:21]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=S(=O)(c1ccccc1)N1CC(O)CN(Cc2ccccc2)CC(O)C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(CN2CC3CNCC(C2)O3)cc1
Temperature: 95 °C

Procedure:
Water (11.2 mL) and concentrated sulfuric acid (24.5 mL) were added to 5-benzyl-3,7-dihydroxy-1-phenylsulfonyl-1,5-diazacyclooctane (2.92 g, 7.76 mmol; see step (ii) above). The reaction mixture was heated for 24 hours at 95° C. The temperature was adjusted to 60° C., and toluene (40 mL) was added. Sodium hydroxide solution was then added (150 mL of 5 M), causing the internal temperature to rise to 85° C. The pH of the reaction mixture was then checked, and was found to be 2. A few pellets of solid sodium hydroxide were then added. The pH was measured again, and was found to be 13. The layers were separated, and the aqueous phase extracted with toluene (50 mL). The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo to provide 3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane as an orange-brown oil. This can be converted to the title compound (dihydrochloride salt) by reaction with hydrochloric acid under standard conditions.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[N:15]=2)[C:3]=1[CH2:21][CH2:22][CH3:23].[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C=O)C>[N:24]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[N:15]=2)[C:3]=1[CH2:21][CH2:22][CH3:23])=[N+:25]=[N-:26]
Reactant: CCCc1c(Cl)ncnc1Cn1ccnc1-c1cccc(F)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(Cn2ccnc2-c2cccc(F)n2)ncnc1N=[N+]=[N-]

Procedure:
A solution of 103 (2.25 mmol) and NaN3 (731 mg, 11.25 mmol) in DMF (15 ml) is heated at 70° C. in a sealed tube overnight. The solvent is removed in vacuo and water (10 ml) and EtOAc (10 ml) are added to the residue. The layers are separated and the aqueous layer is extracted with EtOAc (2×10 ml). The combined extracts are washed with brine (15 ml) and dried with Na2SO4. The solvent is removed in vacuo and the resulting yellow oil (104) is used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([C:24]([F:27])([F:26])[F:25])=[N:22][N:23]=2)[N:20]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([C:24]([F:25])([F:27])[F:26])=[N:22][N:23]=3)[N:20]=2)[CH2:10][CH2:9]1
Reactant: Cc1ccccc1N1CCNCC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Product: Cc1ccccc1N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
A mixture of 1-(2-methylphenyl)piperazine and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(2-methylphenyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:9][C:10]1[CH:23]=[CH:22][C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1.[Na]>C(O)C>[Cl:9][C:10]1[CH:23]=[CH:22][C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)Oc1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
20.9 g (0.115 mol) of ethyl 2-bromo-propionate are run over the course of 30 minutes into a hot solution of 23 g (0.1045 mol) of p-(p-chlorophenoxy)-phenol and 2.4 g (0.1045 mol) of sodium in 90 ml of anhydrous ethanol and the mixture is then heated to the reflux temperature for 2 hours. The inorganic salts are removed by filtration and the ethanol is driven off under reduced pressure. After having dissolved the residue in diethyl ether, washed the solution with water, dried the organic phase over dry sodium sulphate and evaporated the solvent, 32.5 g of an orange-coloured oil which is insoluble in water are obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1)=[O:4].Br[CH2:12][CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:15][CH2:14][CH2:13][CH2:12][N:6]1[CH2:7][CH2:8][CH2:9][C@H:5]1[C:3](=[O:4])[N:2]([CH3:10])[CH3:1]
Reactant: OCCCBr
Reactant: CN(C)C(=O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(C)C(=O)[C@@H]1CCCN1CCCO
Yield: 48.3 %

Procedure:
A mixture of (S)-2(N,N-dimethylcarbamoyl)pyrrolidine (426 mg, 3 mmol), (Chem. pharm. Bull. 1973, 21, 2112-2116), 3-bromo-1-propanol (0.41 ml, 4.5 mmol) and potassium carbonate (829 mg, 6 mmol) in acetonitrile (6 ml) was heated at reflux for 8 hours. The mixture was allowed to cool and was partitioned between methylene chloride and water. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography, eluting with methylene chloride/methanol (a gradient from 90/10 to 60/40) to give (S)-1-(3-hydroxypropyl)-2(N,N-dimethylcarbamoyl)pyrrolidine (290 mg, 48%).