Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8]CCN)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:12]([N:15](C(C)C)CC)(C)[CH3:13].[Br:21][C:22]([CH3:27])([CH3:26])[C:23](Br)=[O:24].C(OCC)(=O)C.ClCCl>ClCCl>[C:1]([NH:8][C:23](=[O:24])[C:22]([Br:21])([CH3:27])[CH2:26][CH2:13][CH2:12][NH2:15])([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: CC(C)(Br)C(=O)Br
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(=O)C(C)(Br)CCCN
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of N-Boc-ethylenediamine (5.0 mL, 32 mmol), and diisopropylethylamine (5.8 mL, 33 mmol) in anhydrous dichloromethane (35 mL) was cooled in a NaCl/ice bath (−10° C., bath temperature). Over a period of 15 minutes, 2-bromoisobutyryl bromide (4.1 mL, 33 mmol) was added to this solution. After 1 h, the ice bath was removed and the reaction was allowed to warm to room temperature and stirring was continued for 18 h. The reaction mixture was concentrated to dryness under reduced pressure giving a tan colored solid which was dry-loaded onto a silica gel column. The product was isolated by elution with ethyl acetate:dichloromethane (3:2) as an off-white solid (7.84 g, 80%). 1H NMR (CDCl3, 300 MHz): δ 7.2 (bs, 1H), 4.91 (bs, 1H), 3.33 (m, 4H), 1.93 (s, 6H), 1.43 (s, 9H). 13C NMR (CDCl3, 300 MHz): δ 172.9, 157.1, 80.1, 61.9, 42.0, 40.0, 32.5, 28.6. EIMS m/z: 331 ([M+Na]+), 333 ([M+Na]+).
Reaction SMILES: [Na].[C:2]1(C=CC=C(O)C=1O)[OH:3].Br[C:12]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:15]=[C:14](Br)[C:13]=1[OH:23].[CH3:24][O-:25].[Na+]>[Cu](I)I.CN(C)C=O>[CH3:2][O:3][C:12]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:15]=[C:14]([O:25][CH3:24])[C:13]=1[OH:23]
Reactant: C[O-]
Reactant: CC(C)(C)c1cc(Br)c(O)c(Br)c1
Reactant: Oc1cccc(O)c1O
Agent: I[Cu]I
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1cc(C(C)(C)C)cc(OC)c1O
Yield: 89 %

Procedure:
Processes are well known for preparing alkoxyphenols from phenol halides, in other words, for substituting alkoxyl groups for the halogen substituents in phenols. Usually alkoxyphenols are produced by reacting with heating a phenol halide with an alcoholate prepared by dissolving metallic sodium in an alcohol, in a suitable solvent, such as dimethylformamide or an amine, in the presence of a copper halide serving as a catalyst. Laid-Open West German Patent Application No. 2627874 and Chemical Abstract 86, 171074 (1974), for example, disclose a process for synthesizing pyrogallol in which 2,6-dibromo-4-tert-butylphenol is reacted with sodium methoxide with use of copper iodide as a catalyst and dimethylformamide as a solvent to afford 2,6-dimethoxy-4-tert-butylphenol in a yield of 89%. Journal of Chemical Society (C), 312 (1969) further discloses that several kinds of aromatic halides, including phenol bromide, are reacted with sodium methoxide in a mixture of methanol and collidine with use of copper iodide as a catlyst to give the corresponding methoxidated aromatic compounds in yields of 37 to 99%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[C:18]1([C:24]2[CH:29]=[CH:28]N=C[CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1.[CH3:30][N:31]1CCCC1=O>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH:23]3[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]3[C:24]3[CH:25]=[N:31][CH:30]=[CH:28][CH:29]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C1=C(c2ccncc2)CCCC1
Reactant: CN1CCCC1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CN1CCc2c(c3cc(Cl)ccc3n2C2CCCCC2c2cccnc2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.45 mmol) in N-methyl-2-pyrrolidone (1.0 mL) was added powdered KOH (0.140 g, 2.5 mmol) and stirred for 10 min. at RT. 4-cyclohexenylpyridine (1.25 mol) was added and the reaction mixture was stirred for additional 4 h at 100° C. After completion of reaction (as analyzed by TLC), the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3×20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product.
Reaction SMILES: [OH:1][C:2]([CH3:23])([CH3:22])[CH:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]1[CH3:21])[CH3:4].[H-].[Na+].I[CH3:27]>C1COCC1>[CH3:27][O:1][C:2]([CH3:22])([CH3:23])[CH:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]1[CH3:21])[CH3:4]
Reactant: CI
Reactant: Cc1c(C(=O)OC(C)(C)C)c2ccccc2n1C(C)C(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)(C)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2ccccc21
Temperature: 45 °C
Yield: 95.2 %

Procedure:
To a solution of (±)-tert-butyl 1-(3-hydroxy-3-methylbutan-2-yl)-2-methyl-1H-indole-3-carboxylate (0.2594 g, 0.817 mmol) and THF (8 mL), in a 50 mL round bottom flask, cooled to 0° C. was added sodium hydride (0.065 g, 1.634 mmol). The reaction was then heated at 45° C. for 2 h then iodomethane (0.102 ml, 1.634 mmol) was added and the reaction was heated at that temperature overnight. The reaction was quenched with 1N HCl and brine, extracted with EtOAc, dried over Na2SO4, filtered, concentrated, deposited onto silica gel with aid of DCM, and purified by column chromatography using 5% EtOAc in Hex as eluent to provide (±)-tert-butyl 1-(3-methoxy-3-methylbutan-2-yl)-2-methyl-1H-indole-3-carboxylate (257.8 mg, 95%). LRMS (M+H+) m/z: calcd 332.45. found 332.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[S-:12][C:13]#[N:14].[NH4+]>CO.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([S:12][C:13]#[N:14])=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: N#C[S-]
Reactant: COc1ccc2cc[nH]c2c1
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COc1ccc2c(SC#N)c[nH]c2c1
Yield: 28.8 %

Procedure:
Using the procedure described in Tetrahedron Letters 40 (1999), 1195-1196, 6-methoxy-1H-indole (1.0 g, 6.8 mmole) and ammonium thiocyanate (0.621 g, 8.1 mmole) were dissolved in methanol (35 ml) and treated with ceric ammonium nitrate (8.56 g, 15.6 mmole)in methanol (175 ml) at room temperature. The reaction mixture was stirred for 15 m and then diluted with water (700 ml) and extracted with methylene chloride (4×125 ml). The combined organic extracts were dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by column chromatography (silica gel) using ethyl acetate:hexane (1:9) as the eluting solvent to afford 6-methoxy-3-thiocyanato-1H-indole (0.40 g 29% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[CH:4][CH:3]=1.[Br:16]Br>CCOCC.C(Cl)Cl>[Br:16][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:9]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)=[O:10]
Reactant: O=C(Cc1ccc(F)cc1)c1cccs1
Reactant: BrBr
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(c1cccs1)C(Br)c1ccc(F)cc1

Procedure:
To a solution of 70.0 g (0.32 mole) of 2-(4-fluorophenyl-1-(2-thienyl)ethanone in 600 ml of ether was added dropwise a solution of 56.0 g (0.35 mole) of bromine in 120 ml of methylene chloride at room temperature. The reaction mixture was concentrated under vacuum to give 123.0 g of 2-bromo-2-(4-fluorophenyl)-1-(2-thienyl)ethanone as an oil.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:14]([C:18](O)=[O:19])=[C:15]([CH3:17])[N:16]=2)[CH:9]=[C:10]([C:12]#[CH:13])[CH:11]=1.N[C@H:27]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:28][OH:29].C([N:37](C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[F:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:14]([C:18]([NH:37][C@@H:32]([CH2:31][CH2:30][CH2:27][CH2:28][OH:29])[CH3:33])=[O:19])=[C:15]([CH3:17])[N:16]=2)[CH:9]=[C:10]([C:12]#[CH:13])[CH:11]=1
Reactant: C#Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)O)n2c1
Reactant: CCCC[C@@H](N)CO
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: C#Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)N[C@H](C)CCCCO)n2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, 50 mg (0.15 mmol) of 8-[(2,6-difluorobenzyl)oxy]-6-ethynyl-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid were dissolved in 0.5 ml of dry dimethylformamide, 20.54 mg (0.18 mmol, 1.2 equivalents) of (R)-(−)-2-aminohexanol, 72 μl of diisopropylethylamine (0.44 mmol, 3 equivalents) and 72 mg of HATU (0.19 mmol, 1.3 equivalents) were added and the mixture was stirred at room temperature overnight. A little water was then added, and the mixture was purified directly by preparative HPLC (Method 8). This gave 37.5 mg of the target compound (58% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][C:16]=1[C:22]([F:25])([F:24])[F:23])([O-:14])=[O:13]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([N+:12]([O-:14])=[O:13])=[C:16]([C:22]([F:23])([F:24])[F:25])[CH:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Product: O=C(Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1)c1cc(Cl)ccc1O
Yield: 44.8 %

Procedure:
Using 5-chlorosalicylic acid and 4-nitro-3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)=[O:32]>>[CH3:41][O:40][C:37]1[CH:38]=[CH:39][C:34]([O:33][C:31](=[O:32])[N:14]([C@@H:13]2[C@@H:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12]2)[CH3:15])=[CH:35][CH:36]=1
Reactant: COc1ccc(OC(=O)Cl)cc1
Reactant: CN[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Product: COc1ccc(OC(=O)N(C)[C@H]2CN(C(=O)C3CCN(C(=O)C4(C)CC4)CC3)C[C@@H]2c2ccc(Cl)c(Cl)c2)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 2 (step b), the title compound rac-{(3R,4S)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid p-methoxy-phenyl ester was prepared from rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using p-methoxyphenyl chloroformate instead of 4-fluorophenyl chloroformate and was obtained as a light brown foam. MS m/e: 588.2 [M]+.
Reaction SMILES: [CH:1]([NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([NH:13][C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16][C:15]=2[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=2)=[O:24])=[O:12])[CH2:7][CH2:6]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:40](Cl)(=[O:42])[CH3:41].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:40]([N:4]([C@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]([NH:13][C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16][C:15]=2[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=2)=[O:24])=[O:12])[CH2:9][CH2:10]1)[CH:1]([CH3:3])[CH3:2])(=[O:42])[CH3:41]
Reactant: CC(C)N[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N(C(C)C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trans-3-[4-(isopropylamino)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (100 mg) obtained in Example 310 and triethylamine (61 μl) is dissolved in chloroform (5 ml), and thereto is added acetyl chloride (24 μl). The mixture is stirred at room temperature for one hour, and thereto is poured a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is washed successively with water and a saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1, then ethyl acetate). The resulting residue is suspended in n-hexane, and collected by filtration to give the title compound (60 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[C:3]=1[F:10].C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]([CH3:20])=[O:19]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH:18]2[CH2:20][O:19]2)=[C:4]([F:9])[C:3]=1[F:10]
Reactant: Oc1ccc(Br)c(F)c1F
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1c(Br)ccc(OCC2CO2)c1F
Yield: 71 %

Procedure:
A solution of the crude 4-bromo-2,3-difluorophenol (0.40 g) [prepared using published procedure, WO0121606] and (2R)-glycidyl 3-nitrobenzenesulfonate (0.49 g) in dry acetone (19 mL) was treated with potassium carbonate (0.79 g) and refluxed under nitrogen for 12 h. The reaction was cooled, filtered and filtrate was concentrated in vacuo and the residue was flash chromatographed (20% ethyl acetate/hexanes) to yield the desired product (0.33 g) in 71% yield. 1H-NMR (400 MHz, CDCl3) δ: 7.23-7.19 (m, 1H), 6.74-6.71 (m, 1H), 4.35-4.32 (m, 1H), 4.03-3.99 (m, 1H), 3.38-3.35 (m, 1H), 2.93-2.92 (m, 1H), 2.77-2.76 (m, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:23][CH2:22][N:12]2[C:13]3[C:18]([NH:19][C:20](=[O:21])[CH:11]2[CH2:10]1)=[CH:17][CH:16]=[CH:15][CH:14]=3.O.Cl.[H][H]>O=[Pt]=O.C(O)C>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][N:9]1[CH2:23][CH2:22][N:12]2[C:13]3[C:18]([NH:19][C:20](=[O:21])[CH:11]2[CH2:10]1)=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: [H][H]
Reactant: O=C1Nc2ccccc2N2CCN(CCc3ccccn3)CC12
Agent: O=[Pt]=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C1Nc2ccccc2N2CCN(CCC3CCCCN3)CC12

Procedure:
A solution of 2,3,4,4a-tetrahydro-3-[2-(2-pyridinyl)-ethyl]-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one in 120 ml. water and 60 ml. ethanol containing 14 ml. conc. hydrochloric acid, was shaken with 1.2 g. of PtO2 under 45 psi. hydrogen pressure. Solution was filtered, concentrated under vacuum, and residue crystallized once from ethanol and then from methanol. After filtration and drying the dihydrochloride salt of the title compound had a m.p. of 268°-271° C. (dec.); yield: 3.5 g.
Reaction SMILES: Br[C:2]1[C:3]([Cl:10])=[CH:4][C:5]([Cl:9])=[C:6]([F:8])[CH:7]=1.[Cu][C:12]#[N:13].CC(CC(O)CO)C.C1(C)C(C)=CC=CC=1>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC>[Cl:10][C:3]1[CH:4]=[C:5]([Cl:9])[C:6]([F:8])=[CH:7][C:2]=1[C:12]#[N:13]
Reactant: N#C[Cu]
Reactant: Fc1cc(Br)c(Cl)cc1Cl
Agent: CC(C)CC(O)CO
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1C
Product: N#Cc1cc(F)c(Cl)cc1Cl

Procedure:
97.6 g (0.4 mol) of 5-bromo-2,4-dichlorofluorobenzene, 35.8 g (0.4 mol) of copper(I)cyanide, 10.0 g (0.014 mol) of trimethyl(ethoxypolyoxypropyl)ammonium chloride, 5.0 g (0.015 mol) of tetrabutylphosphonium bromide and 5.0 g (0.01 mol) of polyethylene glycol dimethyl ether 500 were introduced together with 20.0 g (0.19 mol) of xylene into a 250 ml 3-neck flask fitted with a reflux condenser and blade stirrer and azeotropically dried at up to 150° C. under reduced pressure. Amount of 2,4-dichloro-5-fluorobenzonitrile formed: after 5 hours: 19 GC area-%. after 26 hours: 75 GC area-%.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:10]1[CH2:16][N:15]2[C:17]([CH2:20][C:21]([F:24])([F:23])[F:22])=[N:18][N:19]=[C:14]2[C@H:13]([NH:25]C(=O)OC(C)(C)C)[CH2:12][CH2:11]1>O1CCOCC1>[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:10]1[CH2:16][N:15]2[C:17]([CH2:20][C:21]([F:24])([F:22])[F:23])=[N:18][N:19]=[C:14]2[C@H:13]([NH2:25])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)nnc21
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)nnc21
Reaction time: 1 h

Procedure:
Hydrochloric acid (4.0 M in dioxane; 10 mL, 40.1 mmol) was added to a solution of tert-butyl [(6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-yl]carbamate (618 mg, 1.384 mmol, described in Intermediate 13) in 1,4-dioxane (5 mL). After 1 h, the reaction was concentrated in vacuo to give the title compound as a bis hydrochloride salt. MS: m/z=347 (M+1).
Reaction SMILES: O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[Cl:16][CH2:17][CH2:18][O:19][CH:20]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[C:21]([OH:23])=O.[C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:34])[NH:32][NH2:33].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[Cl:16][CH2:17][CH2:18][O:19][CH:20]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[C:21]([NH:33][NH:32][C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:23]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)C(OCCCl)c1ccc(F)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NNC(=O)C(OCCCl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.9 %

Procedure:
Bis(2-oxo-3-oxazolidinyl)phosphinic acid chloride (4.38 g) was added to a solution of (2-chloroethoxy)-(4-fluorophenyl)acetic acid (2 g), tert-butyl carbazate (2.27 g) and triethylamine (3.58 mL) in tetrahydrofuran (20 mL), and the reaction solution was stirred at room temperature for 16 hours. Saturated aqueous ammonium chloride and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex, elution solvent: heptane/ethyl acetate) to obtain the title compound (2.8 g). The property values of the compound are as follows.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[CH:24]=[C:25]([CH3:27])[CH3:26])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7]2)=[O:28])=[C:18]([CH:24]=[C:25]([CH3:27])[CH3:26])[CH:19]=1
Reactant: CCOC(=O)C1(NC(=O)c2ccc(C)cc2C=C(C)C)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)=Cc1cc(C)ccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
2-[4-Methyl-2-(2-methyl-propenyl)-benzoylamino]-indan-2-carboxylic acid ethyl ester (764 mg, 2.02 mmol) is dissolved in EtOH (25 mL), and solid KOH (2.32 g, 40 mmol) and water (2.5 mL) are added. The mixture is stirred at RT for 30 min then concentrated in vacuo. The residue is dissolved in a mixture of water (40 mL) and EtOAc (20 mL) and the organic layer is separated. The aqueous layer is adjusted to approximately pH 7 with conc. HCl then extracted with EtOAc (2×15 mL). The combined organic layers are concentrated in vacuo to yield product (279) as off-white solid (544 mg, 78%).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=1[S:17]([O-:20])(=[O:19])=[O:18])[CH2:2][CH3:3].[Na+].[Cl-].[NH4+].C(O)(C)C>O>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][O:4][CH2:1][CH2:2][CH3:3])=[C:9]([S:17]([OH:20])(=[O:19])=[O:18])[CH:10]=1
Reactant: CCCOCCOc1ccc([N+](=O)[O-])cc1S(=O)(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CCCOCCOc1ccc(N)cc1S(=O)(=O)O
Temperature: 77 °C
Reaction time: 2 h

Procedure:
A mixture of 10 g of sodium 2-(2-propoxyethoxy)-5-nitrobenzenesulfonate, 5 g of reduced iron, 0.2 g of ammonium chloride, 20 ml of isopropyl alcohol and 20 ml of water was stirred at 77° C. for 2 hours. After the reaction was completed, the reaction solution was filtered to remove insoluble products. After addition of 10 ml of concentrated hydrochloric acid (36%), the filtrate was cooled. Precipitated crystals were collected by filtration and dried by air. Yield: 7.1 g.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[N+:17]([O-:19])=[O:18])[C:10]([N+:20]([O-:22])=[O:21])=[CH:9][CH:8]=1>>[ClH:6].[N+:17]([C:15]1[C:16]2[C:11](=[C:10]([N+:20]([O-:22])=[O:21])[CH:9]=[CH:8][CH:7]=2)[C:12]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:13][CH:14]=1)([O-:19])=[O:18]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1ccc(Cl)c2c([N+](=O)[O-])cccc12
Product: Cl
Product: O=[N+]([O-])c1ccc(N2CCCC2)c2c([N+](=O)[O-])cccc12
Reaction time: 0.08 h
Yield: 21 %

Procedure:
Pyrrolidine (5.0 mL) was added to 1-chloro-4,8-dinitronaphthalene (50 mg, 0.20 mmol, Bassilios et al, Recueil, 1962, 81, 209-214) which resulted in an immediate, highly exothermic reaction. The reaction was further agitated for 5 min while heating using a heatgun. Volatiles were removed in vacuo and purification as in 159JP06 (dichloromethane/n-heptane 4:1, 5× eluted) afforded 12 mg (21%) of 159JP29 as an orange solid. The product was converted to the corresponding hydrochloride salt as described above.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][CH:23](N)[CH:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]1.C([N:34](CC)CC)C>>[Cl:11][C:12]1[CH:13]=[C:14]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][CH:23]([C:4]2([CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH2:3]2)[C:7]([NH2:34])=[O:8])[CH:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]1
Reactant: CCN(CC)CC
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)C(N)CC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Product: CC1=CCC(C(N)=O)(C(CC2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)C(C)C)C=C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.4 %

Procedure:
p-Toluoyl chloride (0.077 ml, 0.58 mmol) was added to a solution of 1(RS)-[1-(3,4-dichlorobenzyl)piperidin-4-ylmethyl]-2-methylpropylamine (0.16 g, 0.49 mmol) in dichlororhethane (2 ml) and triethylamine (0.12 ml, 1.63 mmol). The reaction mixture was stirred at room temperature for 1.5 h and was quenched with water. The product was then extracted with dichloromethane and the organic layer was washed with brine and dried over sodium sulfate. The crude product was purified on preparative TLC with 25% acetone, 25% dichloromethane in hexanes to give 0.21 g of N-{1-[1(RS)-[1-(3,4-dichlorobenzyl)piperidin-4-ylmethyl]-2-methylpropyl}-4-methylbenzamide as an oil, which was then converted to its dihydrochloride salt (0.15 g); m.p. 233.9-235.5° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C:9]1=[O:17]>>[OH:8][C:16]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:10][C:9]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:17]
Reactant: CN1CCNCC1
Reactant: O=C1Cc2ccccc2O1
Product: CN1CCN(C(=O)Cc2ccccc2O)CC1
Temperature: 85 °C
Reaction time: 3.5 h
Yield: 101.7 %

Procedure:
N-Methylpiperazine (1.52 g) was added to 2-coumaranone (2.01 g) and stirred for 3.5 hours at 85° C., thereby yielding the entitled compound (3.57 g) as pale brown solid.