Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([C:8]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:16]3[C@@H:12]([CH2:13][NH:14][CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:32]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](O)=[O:39])=[CH:33]1>>[C:26]1([C:8]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:16]3[C@@H:12]([CH2:13][N:14]([C:38](=[O:39])[CH2:37][C:34]4[CH:35]=[CH:36][S:32][CH:33]=4)[CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)Cc1ccsc1
Reactant: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Agent: Cl
Product: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CN(C(=O)Cc3ccsc3)C[C@H]21
Yield: 55.2 %

Procedure:
By working in accordance with Example 4, starting from 0.8 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydroisoindol-4-ol hydrochloride and 0.34 g of 3-thienylacetic acid, 0.53 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(3-thienyl)acetyl]perhydroisoindol-4-ol is obtained in the form of white crystals which melt with decomposition at 106° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].C1(C2[NH:24][CH2:23][CH:22]([CH2:25][Cl:26])[O:21]2)C=CC=CC=1.Cl>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([NH:24][CH2:23][CH:22]([OH:21])[CH2:25][Cl:26])=[O:7]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: ClCC1CNC(c2ccccc2)O1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)NCC(O)CCl)cc1OC
Temperature: 25 °C
Yield: 72.3 %

Procedure:
A solution of 15.2 g of 3,4-dimethoxybenzoyl chloride in 40 ml of chloroform is added dropwise to a solution of 15.0 g 2-phenyl-5-chloromethyloxazolidine in a mixture of 200 ml of chloroform and 6 ml of pyridine at a temperture of -40° C. under agitation. This solution is then heated to room temperature. After a reaction period of 14 hours, 20 ml of concentrated hydrochloric acid are added, the phases are thoroughly mixed for a period of 10 minutes and then are separated. The separated aqueous phase is diluted with water to twice its volume and then is saturated with sodium chloride and extracted with chloroform. After drying the chloroform-extract and evaporating the solvent, 15.0 g of N-(3,4-dimethoxybenzoyl)-3-chloro-1-aminopropan-2-ol is obtained as an oil which can be further reacted without any purification. After crystallization from ethanol/toluene the compound exhibits a melting point of 104°-106° C.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]([C:6]([O:8][C@@H:9]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[O:7])[CH2:2]1.ClC1C=CC=C(C(OO)=[O:35])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[O:35]=[S:1]1[CH2:5][CH2:4][N:3]([C:6]([O:8][C@@H:9]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])=[O:7])[CH2:2]1
Reactant: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)OC(=O)N1CCSC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)OC(=O)N1CCS(=O)C1
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
To a solution of benzyl 2(S)-(3-thiazolidine-carbonyloxy)-3-phenylpropionate (371 mg) in methylene chloride (7 ml), which was cooled to 0° C., was added 80% m-chloroperbenzoic acid (215 mg). The mixture was stirred at same temperature for 30 minutes. Then 10% sodium sulfite aqueous solution and methylene chloride were added thereto, and the mixture was separated. The separated aqueous layer was extracted with methylene chloride (2 times). The combined extract was washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution successively, dried over magnesium sulfate, and concentrated under reduced pressure. Obtained crystals were washed with n-hexane to give benzyl 2(S)-(1-oxo-thiazolidine-3-carbonyloxy)3-phenylpropionate (350 mg).
Reaction SMILES: C([Li])CCC.[CH2:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CO[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1>CCCCCC.C1COCC1>[CH2:6]([N:13]1[CH2:18][CH2:17][N:16]([C:30]2[CH:31]=[CH:32][C:27]([C:24]3[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=3)=[CH:28][CH:29]=2)[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COc1ccc(-c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: c1ccc(CN2CCN(c3ccc(-c4ccccc4)cc3)CC2)cc1
Reaction time: 1 h

Procedure:
1.6 ml (0.05 mol) of butyllithium solution in n-hexane is added dropwise to a solution of 8.81 g (0.05 mol) of 1-benzylpiperazine in 50 ml of anhydrous THF under argon at 0° C. and stirred for one hour. Then 9.21 g (0.05 mol) of 4-methoxybiphenyl are added and the reaction mixture is refluxed for 12 hours. The solvent is then evaporated off, the residue is combined with 150 ml of 2 N hydrochloric acid followed by diethyl ether and the precipitate formed is filtered off. The precipitate is washed with diethyl ether, suspended in 20% sodium carbonate solution and extracted several times with dichloromethane. After drying over magnesium sulphate the solvent is removed and the residue is washed with ethyl acetate and diethyl ether.
Reaction SMILES: C[O:2][C:3]1[N:4]=[C:5]2[CH2:13][CH2:12][CH2:11][O:10][C:6]2=[N:7][C:8]=1[CH3:9].I[Si](C)(C)C>S1(CCCC1)(=O)=O.C(OCC)(=O)C>[CH3:9][C:8]1[N:7]=[C:6]2[O:10][CH2:11][CH2:12][CH2:13][C:5]2=[N:4][C:3]=1[OH:2]
Reactant: COc1nc2c(nc1C)OCCC2
Agent: C[Si](C)(C)I
Solvent: CCOC(C)=O
Solvent: O=S1(=O)CCCC1
Product: Cc1nc2c(nc1O)CCCO2
Temperature: 42.5 °C
Reaction time: 48 h

Procedure:
To a suspension of 2-methoxy-3-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazine (1.95 g, 10.8 mmol) in sulfolane (25 mL) was added iodotrimethylsilane (15.0 g, 75.0 mmol) at 30° C. The reaction mixture was heated at 40-45° C. for 8 h, and then cooled to ambient temperature and stirred for 2 days. And the reaction mixture was diluted with ethyl acetate and washed with 2% aqueous sodium sulfite. The aqueous layer was extracted with ethyl acetate and chloroform. The organic layer was combined, dried over sodium sulfate, filtrated and concentrated in vacuo. The crude was purified by silica gel column chromatography (ethyl acetate to ethyl acetate:methanol=93:7) to give 3-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin-2-ol and recovered starting material. MS (APCI): m/z 177 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14](Cl)(=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCC(=O)Cl
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.9 %

Procedure:
A solution of 1-benzylpiperazine (352 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and pentanoyl chloride (301 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:1). The fractions containing 1-(4-benzylpiperazin-1-yl)pentan-1-one are collected and the solvent is removed in vacuo to give 416 mg of colorless oil.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22]C(=O)C)=[C:18]([CH2:26][CH3:27])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH2:26][CH3:27])[CH:17]=3)[O:7][C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)ccc1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 299 %

Procedure:
A mixture of acetic acid 4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-ethyl-phenyl ester (0.92 g, 2.47 mmol, from Step 3), potassium carbonate (0.68 g, 4.9 mmol) in MeOH (10 mL) was stirred at rt for 1 h. The reaction mixture was partitioned between 1 N HCl and EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated to a yellow oil. The oil was purified by silica gel chromatography (20% to 40% EtOAc in hexanes) to give the title compound (2.44 g, 59%).
Reaction SMILES: N[C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:10])[CH2:8][Br:9])[N:6]=1.N([O-])=O.[Na+].[ClH:15]>O.[Cu]Cl>[Cl:15][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:10])[CH2:8][Br:9])[N:6]=1
Reactant: Nc1nc(C(=O)CBr)cs1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(CBr)c1csc(Cl)n1
Temperature: 0 °C

Procedure:
7.6 g (6.0344 mol) of 2-Amino-4-bromoacetyl-thiazole are dissolved in 20 ml of water and 50 ml of concentrated hydrochloric acid. Now, at 0° C. and with stirring, a solution of 3.44 g (0.0499 mol) of sodium nitrite in 15 ml of water is added dropwise. The resulting diazonium salt solution is then introduced in portions into a vigorously stirred cold solution of 4.93 g (0.0449 mol) of copper(I) chloride in 15 ml of concentrated hydrochloric acid, and the mixture is stirred at room temperature for 20 hours. It is then diluted with 100 ml of water and extracted with ether. The ether extract is dried over sodium sulphate and evaporated. For purification, the crude product is purified on a silica gel column using methylene chloride as the eluant.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10]C)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.C[O-].[Na+]>C1COCC1>[N:1]1([C:7]([O:9][CH3:10])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)N1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Polymer-bound piperidinecarboxylic acid, ethyl ester resin (0.25 g, 0.283 mmol) was swollen with a solution of MeOH (1 ml) in THF (4 ml) in a QUICKFIT test-tube. After addition of sodium methoxide (0.28 ml, 0.028 mmol, 1M solution in MeOH) the resulting suspension was stirred overnight at reflux. The reaction suspension was cooled down to room temperature and the resin was washed using VACMASTER station with DCM (4×3 ml), MeOH (2×3 ml) and then dried under vacuum. FT-IR (2% w/w KBr disk): C=0 1736 cm−1 (ester); 163 cm−1 (amide).
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[Na+].[C:6]1([CH3:15])[C:7]([S:12]([O-:14])=[O:13])=[CH:8][CH:9]=[CH:10][CH:11]=1>CN(C=O)C>[C:6]1([CH3:15])[C:7]([S:12]([CH2:2][C:3]#[N:4])(=[O:14])=[O:13])=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: N#CCCl
Reactant: Cc1ccccc1S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1S(=O)(=O)CC#N
Reaction time: 1 h
Yield: 51.6 %

Procedure:
2.2 ml (34.5 mmol) of chloroacetonitrile were added to a suspension of 4.5 g (28.8 mmol) of toluene-2-sulphinic acid sodium salt in 100 ml of DMF and stirred at 1000 for 1 hr. The reaction solution was evaporated and the residue was partitioned between H2O and CH2Cl2. The aqueous phase was washed three times with CH2Cl2. The combined organic phases were washed once with H2O, dried (MgSO4). filtered and evaporated. Chromatography (SiO2, CH2Cl2) yielded 2.9 g (50%) of (toluene-2-sulphonyl)-acetonitrile as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([O:26]C)=O)=[CH:15][C:13]=2[N:14]=1.[F:28][C:29]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:30]=1[NH2:31].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:31][C:30]3[CH:32]=[C:33]([F:37])[C:34]([F:36])=[CH:35][C:29]=3[F:28])=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: COC(=O)c1cc2nc(Nc3c(C)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Reactant: Nc1cc(F)c(F)cc1F
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)Nc3cc(F)c(F)cc3F)c3c(c2[nH]1)CC(C)(C)O3
Yield: 33.8 %

Procedure:
The title compound was prepared by following the procedure described for Example-137 by using methyl 2-[(2-chloro-6-methylphenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-35, 0.200 g, 0.414 mmol) and 2,4,5-trifluoroaniline (0.090 g, 0.602 mmol), trimethyl aluminium (2M solution in toluene) (1 mL) and dry toluene (5.0 mL) to afford 0.070 g of the desired product. 1HNMR (DMSO-d6): δ 1.54 (s, 6H), 2.24 (s, 3H), 3.17 (s, 2H), 7.25-7.33 (m, 2H), 7.42 (d, J=8.80 Hz, 1H), 7.52 (s, 1H), 7.72 (q, J=8.4 Hz, 10.8 Hz, 1H), 8.48-8.58 (m, 1H), 9.13 (br s, 1H), 10.16 (s, 1H), 10.98 (br s, 1H): MS [M+H]+: 501.0
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])C.[NH2:20][C:21]1[CH:28]=[C:27]([Br:29])[CH:26]=[CH:25][C:22]=1[CH:23]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:29][C:27]1[CH:28]=[C:21]2[C:22]([CH:23]=[C:5]([N:6]3[C:7](=[O:16])[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:14]3=[O:15])[CH:4]=[N:20]2)=[CH:25][CH:26]=1
Reactant: Nc1cc(Br)ccc1C=O
Reactant: CCOC(CN1C(=O)c2ccccc2C1=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1c1cnc2cc(Br)ccc2c1
Yield: 45.3 %

Procedure:
A mixture of 2-(2,2-diethoxyethyl)isoindoline-1,3-dione (3.16 g, 12.00 mmol), 2-amino-4-bromobenzaldehyde (2 g, 10.00 mmol) and p-toluenesulfonic acid monohydrate (1.902 g, 10.00 mmol) in toluene (60 mL) was heated under reflux using Dean-Stark apparatus overnight. A very dark/black solid precipitated overnight and was collected, washed with toluene and hexanes, then dissolved in chloroform fortified with DMF. The mixture was washed with aq. NaHCO3 solution (×2), ensuring any precipitate was dissolved in additional chloroform during separation. The organic layer was dried (sodium sulfate) and evaporated onto silica gel. Purification by flash chromatography (0-2% methanol in dichloromethane) afforded the title compound (1.6 g, 45%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.05 (d, 1 H), 8.57 (d, J=2.3 Hz, 1 H), 8.35 (d, J=1.8 Hz, 1 H), 8.11 (d, J=8.6 Hz, 1 H), 8.09-8.02 (m, 2 H), 8.02-7.93 (m, 2 H), 7.87 (dd, J=1.9, 8.7 Hz, 1 H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.C1(C)C=C(C)C=C(C)C=1S(O)(=O)=[O:24].O.C1C=C(Cl)C=C(C(OO)=O)C=1>CC(C)=O>[CH2:1]([N:8]1[CH2:12][CH:11]2[O:24][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(S(=O)(=O)O)c(C)c1
Reactant: C1=CCN(Cc2ccccc2)C1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: CC(C)=O
Product: c1ccc(CN2CC3OC3C2)cc1
Yield: 94.7 %

Procedure:
To a solution of 15.9 g (0.1 mol) of 1-benzyl-3-pyrroline, 56.7 g (0.24 mol) of 2-mesitylenesulfonic acid dihydrate (produced by Aldrich Chemical Co., Inc.), 15.0 g of water, and 60.0 g of acetone in a round flask reactor, 31.1 g (0.13 mol) of 70% m-CPBA (m-chloroperbenzoic acid produced by Tokyo Chemical Industry Co., Ltd.) was added with stirring and allowed to react for 10 hours at room temperature without irradiation by lamps. After completion, acetone was evaporated under reduced pressure, neutralized by NaOH (aq), and extracted with toluene and water. After the solvent was evaporated under reduced pressure, 16.6 g of 1-benzyl-3,4-epoxypyrrolidine (yield 94.7%) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH2:9][OH:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Li+].[Cl-].C[CH2:15][O:16]C(C)=O>FC(F)(F)C(O)=O.CO.Cl[Pd]Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]2[C:15](=[O:16])[O:10][CH2:9][C:4]=2[C:3]=1[CH3:11]
Reactant: CCOC(C)=O
Reactant: Cc1cc(Br)c(C)c(CO)c1
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1cc(Br)c(C)c2c1C(=O)OC2
Reaction time: 8 h

Procedure:
To a solution of (3-bromo-2,5-dimethylphenyl)methanol (1.6 g, 7.4 mmol) in trifluoroacetic acid (20 mL) was added Tl(OOCF3)3 (4 g, 7.4 mmol) at r.t, then the reaction was stirred at r.t overnight under N2. The mixture was concentrated under pressure. The residue solids, LiCl (0.6 g, 14.9 mmol), MgO (0.6 g, 14.9 mmol) and PdCl2 (0.13 g, 0.74 mmol) in MeOH were stirred under CO at 1 Mpa over night. EtOAc was added to the mixture and filtered. The organic phase was concentrated to afford 5-bromo-4,7-dimethyl-2-benzofuran-1(3H)-one.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[C@H:14]1([OH:23])[CH2:21][CH2:20][CH2:19][C@@H:18]([OH:22])[CH2:17][CH2:16][CH2:15]1>CN(C1C=CN=CC=1)C.C1COCC1>[C:9]([Si:6]([CH3:8])([CH3:7])[O:22][C@@H:18]1[CH2:19][CH2:20][CH2:21][C@H:14]([OH:23])[CH2:15][CH2:16][CH2:17]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: O[C@H]1CCC[C@@H](O)CCC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCC[C@@H](O)CCC1
Reaction time: 2 h

Procedure:
21.4 g (312 mmol) of imidazole, 34.5 g (229 mmol) of t-butyldimethylsilyl chloride and 10 mg of DMAP were added to a solution of cis-1,5-cyclooctanediol in 500 mL of THF. The reaction mixture was stirred for 2 h before quenching with water followed by extraction with ethyl acetate. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate. Filtration and evaporation under reduced pressure gave crude product which was purified by silica gel chromatography (n-heptane/ethyl acetate, 4:1) to give 26.0 g of the desired product as a colourless oil. Rt=3.00 min (Method J). Detected mass: 259.2 (M+H+).
Reaction SMILES: [CH:1]([N:3]([CH2:12][C@@H:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14](O)=[O:15])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2].N1C=CC=CC=1.[F:27]C1N=C(F)N=C(F)N=1>C(Cl)Cl>[CH:1]([N:3]([CH2:12][C@@H:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]([F:27])=[O:15])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2]
Reactant: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)F
Reaction time: 4 h
Yield: 99.1 %

Procedure:
To a solution of (2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)hexanoic acid (9) (1.7 g, 6.1 mmol) in DCM (20 mL) was added pyridine (0.53 g, 6.7 mmol), followed by 2,4,6-trifluoro-1,3,5-triazine (0.86 g, 6.4 mmol) dropwise. The reaction mixture was stirred for 4 h and TLC indicated completion of the reaction. The reaction mixture was washed with 10% aqueous citric acid and brine, dried over Na2SO4, and concentrated to provide the title compound (1.7 g, 100%) as red oil. 1H NMR (300 MHz, DMSO) δ ppm 0.86 (t, J=6.7 Hz, 3H), 1.16-1.38 (m, 4H), 1.57 (m, 2H), 3.03 (m, 1H), 3.87 (m, 2H), 4.91 (s, 2H), 7.41 (m, 5H).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[CH:27]=[CH:26][C:25]2[C:11]3[NH:12][C:13](=[O:24])[C:14]4[N:15]([CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=4)[C:10]=3[CH2:9][C:8]=2[CH:7]=1>CN(C)C=O>[CH3:1][NH:2][C:3](=[O:4])[NH:5][C:6]1[CH:27]=[CH:26][C:25]2[C:11]3[NH:12][C:13](=[O:24])[C:14]4[N:15]([CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=4)[C:10]=3[CH2:9][C:8]=2[CH:7]=1
Reactant: CCOC(=O)c1cn2c3c([nH]c(=O)c2n1)-c1ccc(N)cc1C3
Reactant: CN=C=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c3c([nH]c(=O)c2n1)-c1ccc(NC(=O)NC)cc1C3
Reaction time: 12 h

Procedure:
0.44 ml of methyl isocyanate is added dropwise with stirring to a suspension of 580 mg of ethyl 8-amino-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylate in 10 ml of dimethylformamide and stirring is continued for 12 hours at a temperature close to 20° C. The reaction mixture is then filtered, rinsed with dimethylformamide and dried at 35° C. under vacuum (1 mm Hg; 0.13 kPa). 320 mg of ethyl 8-(3-methylureido)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylate are obtained as a dihydrate in the form of a beige solid melting above 260° C. (analysis % calculated C: 53.59, H: 5.25, N: 17.36; % found C: 53.2, H: 4.7, N: 17.7).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]([OH:12])=[O:11])[NH2:9])=[CH:4][CH:3]=1.ClCCl.C[Si](C)(C)Cl.Cl.[OH:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][N:31]=2)[N:26]=[CH:25][C:24]=1[C:33](Cl)=[O:34]>C(N(CC)CC)C>[OH:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][N:31]=2)[N:26]=[CH:25][C:24]=1[C:33]([NH:9][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[C:10]([OH:12])=[O:11])=[O:34]
Reactant: O=C(Cl)c1cnc2cccnc2c1O
Reactant: NC(C(=O)O)c1ccc(O)cc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC(C(=O)O)c1ccc(O)cc1)c1cnc2cccnc2c1O

Procedure:
To a mixture of 1.35 g of DL-2-p-hydroxyphenylglycine, 50 ml of anhydrous dichloromethane and 4.05 g of triethylamine, 2.62 g of trimethylchlorosilane were added, and the resulting mixture was refluxed for 20 minutes. After the addition of 2.1 g of 4-hydroxy-1,5-naphthyridine-3-carbonyl chloride hydrochloride, the reaction was effected while cooling with ice for 4 hours. The reaction mixture was concentrated under reduced pressure, 50 ml of water were added to the residue, and the resulting mixture was adjusted to pH 1 with 4N hydrochloric acid. The precipitated crystals were collected by filtration, suspended in 50 ml of water and potassium carbonate was added thereto. After removal of insoluble materials by filtratior, the filtrate was adjusted to pH 1. The precipitated crystals were collected by filtration, washed with water and dried to give 2.1 g of DL-α-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-p-hydroxyphenylacetic acid. M.P. 310° to 320° C (decomp.).
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]([NH:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)=[O:14])=O)C1C=CC=CC=1>[C].[Pd].CO>[NH2:11][CH2:12][C:13]([NH:15][CH2:16][CH:17]1[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)CNC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)CN)CC1

Procedure:
A methanol (100 mL) solution of 4-[[(N-(benzyloxycarbonyl)glycyl)amino]methyl]-1-(tert-butoxycarbonyl)piperidine (6.26 g, 15.4 mmol) was hydrogenated in the presence of a 5% palladium carbon (620 mg) at room temperature for 7 hours. The catalyst was removed by filtration through Celite, and the filtrate was then concentrated to thereby afford 4-[(glycylamino)methyl]-1-(tert- butoxycarbonyl)piperidine as a solid (3.84 g, 92%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH:16]([CH3:30])[CH2:15]1)=[O:13].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[C:3]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH:16]([CH3:30])[CH2:15]2)=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: C1COCCN1
Reactant: CC1CN(C(=O)c2cc(S(C)(=O)=O)ccc2I)CCN1c1ccc(C(F)(F)F)cc1
Product: CC1CN(C(=O)c2cc(S(C)(=O)=O)ccc2N2CCOCC2)CCN1c1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
(2-Iodo-5-methanesulfonyl-phenyl)-[3-methyl-4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (50 mg, 0.09 mmol) was poured into morpholine (2.0 ml) and the reaction mixture was stirred for 24 h at 100° C. before being concentrated in vacuo. The residue was then purified by column chromatography (SiO2, 20 g, Heptane/EtOAc 0-100%) to give the title compound as a light brown solid (43.5 mg, 94%). MS (m/e): 512.3 (M+H+).