Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[C:44]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([CH2:53][CH2:54]O)=[CH:49][CH:48]=2)[C:43]([Cl:56])=[CH:42][C:41]=1[O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(=O)[NH:88]C(=O)C2=CC=CC=C12.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(C)C=CC=CC=1.O.NN.[OH-].[Na+]>CO.O1CCCC1>[NH2:88][CH2:54][CH2:53][C:50]1[CH:51]=[CH:52][C:47]([CH2:46][C:44]2[C:43]([Cl:56])=[CH:42][C:41]([O:57][CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[C:40]([C@@H:10]3[O:11][C@H:12]([CH2:31][O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C@@H:13]([O:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C@H:14]([O:15][CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C@H:9]3[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:45]=2)=[CH:48][CH:49]=1
Reactant: OCCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OCc3ccccc3)cc2Cl)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: NN
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: NCCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OCc3ccccc3)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 49.8 %

Procedure:
To a tetrahydrofuran solution (2.0 mL) of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[2-(benzyloxy)-4-chloro-5-[4-(2-hydroxyethyl)benzyl]phenyl]-D-glucitol (79.0 mg, 0.090 mmol), triphenyl phosphine (53.1 mg, 0.203 mmol), and phthalimide (23.9 mg, 0.162 mmol) cooled in ice was added a 40% diisopropyl azodicarboxylate solution in toluene (386 μL, 0.203 mmol) under nitrogen atmosphere. After the reaction solution was stirred at room temperature for 1.5 hours, methanol (1 mL) was added thereto. Then hydrazine monohydrate (43.7 μL, 0.90 mmol) was added, and the reaction mixture was stirred at 60° C. for 3 hours. After the mixture was cooled to room temperature, a 2 M sodium hydroxide aqueous solution was added thereto, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (chloroform:methanol=9:1) to obtain the title compound (39.2 mg, 50%) as a colorless oily compound.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14]>>[C:13]([N:17]1[CH2:22][CH2:21][N:20]([C:10]([C@@H:8]2[CH2:9][C@H:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:11])[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: CC(C)(C)N1CCNCC1
Product: CC(C)(C)N1CCN(C(=O)[C@@H]2C[C@H]2c2ccccc2)CC1

Procedure:
This example was prepared according to Example 1 employing trans-2-phenyl-1-cyclopropanecarbonyl chloride and 1-tert-butylpiperazine, which is commercially available from, for example, Beta Pharma. m/z (ES+) M+1=287.2; HPLC tR=1.60 min. 1H NMR (500 MHz, CDCl3) δ 7.34-7.23 (m, 2H), 7.23-7.15 (m, 1H), 7.11 (d, J=7.0 Hz, 2H), 3.73-3.53 (m, 4H), 2.64-2.50 (m, 4H), 2.47 (ddd, J=8.9, 6.4, 4.3 Hz, 1H), 1.96 (td, J=4.5, 3.5 Hz, 1H), 1.65 (ddd, J=9.2, 5.2, 4.3 Hz, 1H), 1.25 (ddd, J=8.2, 6.4, 4.3 Hz, 1H), 1.06 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:19]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:4][C:5]([CH3:18])=[C:6]([CH3:17])[C:7]=1[NH:8][CH2:9][C:10]1([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[CH2:34]([O:36][CH2:37][C:38](Cl)=O)[CH3:35]>>[CH2:20]([N:19]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:3]1[C:2]2[N:1]=[C:35]([CH2:34][O:36][CH2:37][CH3:38])[N:8]([CH2:9][C:10]3([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:7]=2[C:6]([CH3:17])=[C:5]([CH3:18])[N:4]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1nc(N(Cc2ccccc2)Cc2ccccc2)c(N)c(NCC2(O)CCCCC2)c1C
Reactant: CCOCC(=O)Cl
Product: CCOCc1nc2c(N(Cc3ccccc3)Cc3ccccc3)nc(C)c(C)c2n1CC1(O)CCCCC1

Procedure:
1-[(3-Amino-2-dibenzylamino-5,6-dimethylpyridin-4-ylamino)methyl]cyclohexanol (0.94 g, 2.1 mmol, prepared as described in Parts A through C of Example 59 was reacted with ethoxyacetyl chloride (0.31 g, 2.52 mmol) according to the general method of Part A of Example 58. The resulting amide was cyclized according to the general method of Part A of Example 58 to provide 0.67 g of 1-[(4-dibenzylamino-2-ethoxymethyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]cyclohexanol as a white solid.
Reaction SMILES: C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:33])[CH3:32])[C:21]=2[CH2:20][CH2:19]1>C(O)(=O)C>[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:33])[CH3:32])[C:21]=2[CH:20]=[CH:19]1
Reactant: CC(=O)NCCCc1cccc2c1CCO2
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CC(=O)O
Product: CC(=O)NCCCc1cccc2occc12
Yield: 41.4 %

Procedure:
Lead tetraacetate (210 mg) was added to a solution of N-[3-(2,3-dihydro-benzofuran-4-yl)-propyl]-acetamide (100 mg) in acetic acid (1.5 ml) at 100. The mixture was stirred at room temperature for 2h and at 50° for 16 h. The solvent was evaporated and the residue purified by chromatography to give the title compound as an oil (41 mg).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][CH:8]=1.[Li+].[OH-].CCO>C1COCC1.O>[F:1][C:2]([F:18])([F:19])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1ccc(OCCCC(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(OCCCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.7 %

Procedure:
To a stirred solution of ethyl 4-(4,4,4-trifluorobutoxy)benzoate (0.60 g, 2.17 mmol) in THF/water (3:1 v/v, 15 ml) at room temperature was added LiOH (0.11 g, 4.34 mmol) in one portion. The reaction mixture was stirred at room temperature for 18 h, then EtOH (15 ml) was added to give a clear solution and stirring was continued for 48 h. The solvents were removed under reduced pressure and to the residue was added water (30 ml). This was extracted with DCM (30 ml) and the aqueous phase was then acidified with 1 M HCl and extracted with EtOAc (3×30 ml). The combined organic extracts were washed with brine (30 ml) and dried (Na2SO4). The solvent was removed under reduced pressure to give the title compound (0.51 g, 95%) as a colourless solid which was used without further purification.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C.[Cl:51]C1C=CC(S)=CC=1>>[Cl:51][C:7]1[CH:6]=[CH:5][C:4]([S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]2[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]2)[C:14](=[O:28])[NH:15][C:16]2[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=2)=[CH:3][CH:8]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: COc1ccccc1SCCCN(C(=O)Nc1ncc(SC(C)(C)C(=O)O)s1)[C@H]1CC[C@H](C)CC1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCCSc2ccc(Cl)cc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis 2-{2-[3-[3-(2-methoxy-phenylsulfanyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester and 4-chloro-thiophenol.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.CN1CCOCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cu]I.[Cu].C(OCC)(=O)C.CN(C)C=O>[CH:18]1([NH:24][C:2]2[CH:10]=[C:9]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1I
Reactant: NC1CCCCC1
Agent: [Cu]
Agent: [Cu]I
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(Oc2ccccc2)cc1NC1CCCCC1
Temperature: 180 °C
Reaction time: 0.25 h

Procedure:
To N,N-dimethylformamide 1.0 mL solution of 2-iodo-4-phenoxybenzoic acid 40 mg, were added cyclohexylamine 0.027 mL, copper(I) iodide 3 mg, copper powder 3 mg and N-methylmorpholine 0.040 mL, and it was stirred under application of pressure at 180° C. for 15 minutes. After the reaction mixture was cooled to room temperature,10% citric acid aqueous solution and ethyl acetate were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate:acetic acid=20:10:1] to give 2-(cyclohexylamino)-4-phenoxybenzoic acid 5 mg of white solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].Cl[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(OCC)(=O)C.CCCCCC>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[C:3]=1[NH:4][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)Cl
Reactant: Nc1c(F)cc(F)cc1Br
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)Nc1c(F)cc(F)cc1Br
Temperature: 25 °C
Yield: 93.7 %

Procedure:
To a vigorously stirred solution of 2-bromo-4,6-difluoro aniline (100 g, 0.48 mol) in pyridine (400 mL), at 0° C., is added ethyl chloroformate (70 ml, 0.73 mol) at a rate to keep the temperature below 5° C. When addition is complete, the mixture is stirred at 0° C.–5° C. an additional 2 hours while monitoring by TLC (20% ethyl acetate/hexane, UV). The reaction is then allowed to warm to room temperature, filtered and the filtrate concentrated. The residue is dissolved in diethyl ether/ethyl acetate (500 ml/250 ml) and washed with H2O, 2.5 N HCl, aqueous NaHCO3, brine, dried (Na2SO4), filtered, concentrated, and triturated with petroleum ether to give 126 g of 2-bromo-4,6-difluoro-N-carbethoxy aniline (94%).
Reaction SMILES: C([O:3][CH:4]1[CH:8]([NH:9][C:10]([C@H:12]2[N:17]3[C:18](=[O:33])[C@@H:19]([NH:24][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:20][CH:21]=[CH:22][CH2:23][C@@H:16]3[CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:7][C:6](=[O:34])[O:5]1)C.FC(F)(F)C(O)=O>C(#N)C.O>[OH:3][CH:4]1[CH:8]([NH:9][C:10]([C@H:12]2[N:17]3[C:18](=[O:33])[C@@H:19]([NH:24][C:25](=[O:32])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:20][CH:21]=[CH:22][CH2:23][C@H:16]3[CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:7][C:6](=[O:34])[O:5]1
Reactant: CCOC1OC(=O)CC1NC(=O)[C@@H]1CCC[C@H]2CC=CC[C@H](NC(=O)c3ccccc3)C(=O)N21
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1CC(NC(=O)[C@@H]2CCC[C@@H]3CC=CC[C@H](NC(=O)c4ccccc4)C(=O)N32)C(O)O1
Reaction time: 0.5 h

Procedure:
A solution of (4S,7S,11aS)-7-benzoylamino-6-oxo-1,3,4,6,7,8,11,11a-octahydro-2H-pyrido[1,2-a]azocine-4-carboxylic acid (2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide, 45, (32 mg) in 10 mL of 1:1 acetonitrile/water is treated with 2 mL of trifluoroacetic acid. After stirring for 30 minutes the solution is concentrated in vacuo and the crude product purified by preparative reverse phase HPLC to afford 21 mg of the desired product as a white solid. 1H NMR (CD3OD) δ 7.92 (d, J=7.0 Hz, 2H), 7.54 (m, 3H), 5.75 (m, 1H), 5.63 (m, 1H), 5.42 (dd, J=8.1, 4.8 Hz, 1H), 5.01 (d, J=6.2 Hz, 1H), 4.72 (m, 1H0, 4.65 (d, J=4.0 Hz, 0.5H), 4.64 (d, J=4.0 Hz, 0.5 H), 4.31 (m, 1H), 3.18 (m, 1H), 2.68 (m, 2H), 2.45 (m, 3H), 2.26 (br d, J=13.9 Hz, 1H), 2.10 (m, 1H), 1.94 (m, 1H), 1.80 (br d, J=13.2 Hz, 1H), 1.61 (m, 2H); MS 442 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][CH:4]=[N:3]1.Br[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C(OCC)(=O)C.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.CN(C)C=O>[CH3:1][N:2]1[C:6]([CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: BrC=Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cn1nccc1C=Cc1ccccc1
Temperature: 75 °C
Reaction time: 6 h
Yield: 74.5 %

Procedure:
Under a nitrogen atmosphere, a mixture of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.50 g), β-bromostyrene (1.45 g), bis(triphenylphosphine)palladium(II) dichloride (506 mg), potassium carbonate (1.30 g), ethanol (3.8 mL) and dimethylformamide (7.5 mL) was stirred at 75° C. for 6 hours. Thereafter, 13-bromostyrene (1.45 g) was further added to the reaction solution, and the obtained solution was then stirred at 75° C. for 4 hours. Subsequently, the reaction solution was diluted with ethyl acetate, and was then washed with water. The organic layer was dried over anhydrous magnesium sulfate, and was then concentrated under a reduced pressure. The residue was purified by column chromatography (silica gel 60N, hexane:ethyl acetate=4:1 to 3:1), so as to obtain the title compound (990 mg) in the form of a light yellow solid.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:21])[NH:6][C@@H:7]1[CH2:20][C:10]2[NH:11][C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].CC1C=CC(S(O[CH2:33][C@@H:34]2[C@@H:38]([OH:39])[CH2:37][CH2:36][O:35]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1.C(OCC)(=O)C>[CH:1]([O:4][C:5](=[O:21])[NH:6][C@@H:7]1[CH2:20][C:10]2[N:11]([CH2:33][C@@H:34]3[C@@H:38]([OH:39])[CH2:37][CH2:36][O:35]3)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2OCC[C@@H]2O)cc1
Reactant: CC(C)OC(=O)N[C@@H]1Cc2[nH]c3ccc(C#N)cc3c2C1
Agent: CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)N[C@H]1Cc2c(n(C[C@H]3OCC[C@@H]3O)c3ccc(C#N)cc23)C1
Temperature: 65 °C
Yield: 72.7 %

Procedure:
A mixture of ((S)-7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid isopropyl ester (2.50 g, 8.82 mmol), [(2R,3S)-3-hydroxytetrahydrofuran-2-yl]methyl 4-methylbenzenesulfonate (3.10 g, 11.38 mmol), and cesium carbonate (5.00 g, 15.35 mmol) in N-methylpyrrolidine (25 mL) is heated in a 65° C. oil bath overnight. After cooling to ambient temperature, the reaction is diluted with ethyl acetate (120 mL) and washed with water (3×100 mL) and brine. The organic portion is dried over sodium sulfate, filtered, and concentrated to dryness. The resulting residue is purified by medium pressure liquid chromatography, eluting with ethyl acetate. Fractions containing pure product are combined and concentrated to afford 2.46 g (72%) of the title compound. LC-ES/MS m/z 384.2 [M+H]+, TR=1.90 min. (Symyx Draw 3.1 (IUPAC Name) provides the following name for the compound of Example 1: Isopropyl N-[(2S)-7-cyano-4-[[(2R,3S)-3-hydroxytetrahydrofuran-2-yl]methyl]-2,3-dihydro-1H-cyclopenta[b]indol-2-yl]carbamate.)
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].[B-]C#[N:24].[Na+]>O1CCCC1.CO>[NH2:24][CH:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: [B-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(N)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
To a solution of tert-butyl 4-acetylpiperidine-1-carboxylate (10 g, 44.05 mmol) in tetrahydrofuran (100 ml) and methanol (100 ml) were added ammonium acetate (20 g, 264.3 mmol) and sodium cyanotrihydroborate (20 g, 264.3 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuum. The crude product was added water (100 ml), and extracted with ethyl acetate (50 mL×3). The organic layer was dried over sodium sulfate and concentrated to give tert-butyl 4-(1-aminoethyl)piperidine-1-carboxylate (6 g, yield: 60%) as a colorless liquid. LRMS (M+H+) m/z: calcd 228.15. found 229.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:21][CH3:22])=[CH:5][C:6]2[NH:12][C:11](=[O:13])[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1.[H-].[Na+].C1(=O)O[CH2:28][CH2:27][O:26]1.O>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([O:21][CH3:22])=[CH:5][C:6]2[N:12]([CH2:28][CH2:27][OH:26])[C:11](=[O:13])[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)=NCC(=O)N2
Reactant: O=C1OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)N(CCO)C(=O)CN=C2c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a solution of 150 mg (0.50 mmol) of 7,8-dimethoxy-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one XXIIaa in 5 ml of DMF, add at 0° C. under an inert atmosphere 21 mg (0.52 mmol) of 60% NaH in oil. Stir at room temperature for 1 hour. Add at 0° C., 53 mg (0.60 mmol) of ethylene carbonate. Stir at room temperature overnight. Add 50 ml of H2O and extract three times with 50 ml of AcOEt; dry on MgSO4, evaporate the AcOEt and purify by silica chromatography (AcOEt 3/hexane 1, then AcOEt). Recrystallize in CHCl3/cHexane. Yield: 40%. M: 128–130° C. 1H-NMR (DMSO, 300 MHz): d 3.36–3.52 (m, 2H, HOCH2), 3.60 (s, 3H, OCH3), 3.70–3.86 (m, 5H, NCH2+OCH3), 4.11 (AB system, ? d=0.77, JAB=9.96, 2H, CH2), 4.77 (m, 1H, OH), 6.60 (s, 1H Ar), 7.39 (s, 1H Ar), 7.42–7.58 (m, 4H Ar). Mass: (M+H)+=341.16.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[CH:11][C:10]([C:20]([O:22]CC)=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.O1CCOCC1.[OH-].[Li+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[CH:11][C:10]([C:20]([OH:22])=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2F)n(-c2cccc(Cl)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(-c2ccccc2F)n(-c2cccc(Cl)c2)n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
2.30 g (6.67 mmol) of the compound of Example 36A are provided in 32 ml of a 2:1 mixture of 1,4-dioxane and water, 17 ml (33.4 mmol) of a 2N solution of lithium hydroxide in water are added, and the mixture is stirred at 50° C. for 2 h. The mixture is concentrated, a 2N aqueous hydrogen chloride solution is subsequently added to the residue until the pH is acidic, the mixture is extracted with ethyl acetate, and the organic phase is dried over sodium sulfate, filtered and concentrated. The residue is stirred in a little of a mixture of petroleum ether and diethyl ether, collected by filtration and dried under high vacuum. 1.58 g (75% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:18][S:19]([O:22][C:23]1[CH:24]=[C:25]([CH2:29][CH2:30]CS([O-])(=O)=O)[CH:26]=[CH:27][CH:28]=1)(=[O:21])=[O:20]>>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:30][CH2:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([O:22][S:19]([CH3:18])(=[O:20])=[O:21])[CH:24]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CS(=O)(=O)Oc1cccc(CCCS(=O)(=O)[O-])c1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Product: CCOC(=O)C(Cc1ccc(OCCc2cccc(OS(C)(=O)=O)c2)cc1)OCC

Procedure:
2-Ethoxy-3-{4-[2-(3-methanesulfonyloxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester was synthesized using the same method as in example 1(b) from 2-ethoxy-3-(4-hydroxyphenyl)propanoic acid ethyl ester (described in Example 20b) and 2-(3-methanesulfonyloxyphenyl)-ethylmethanesulfonate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]#[N:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[NH4+].Cl>CN(C=O)C>[NH:21]1[C:19]([C:13]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=2[NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[N:20][N:23]=[N:22]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(C#N)c(NS(=O)(=O)c2ccc(F)cc2)c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nnn[nH]2)c(NS(=O)(=O)c2ccc(F)cc2)c1
Temperature: 0 °C

Procedure:
The title compound was synthesized by reacting 2-{[(4-fluorophenyl)sulfonyl]amino}-4-methylbenzenecarbonitrile (13) (0.1 g, 0.34 mmol), sodium azide (0.09 g, 1.37 mmol), and ammonium chloride (0.74 g, 1.37 mmol) in 3 mL of DMF at 120° C. for 20 h.23 Reaction mixture was poured into ice cold water (30 mL) and acidified with dilute HCl solution. The white precipitate obtained on acidification was extracted with ethyl acetate. The organic layer was washed (H2O) dried (Na2SO4) and concentrated to give crude product (0.1 g), which was purified by FCC (silica gel, CH2Cl2, MeOH, CH3COOH, 10:2:0.1, v/v/v) to give 13 as white solid (0.086 g, 74.9%) mp: 152-154° C.; IR (CHCl3) 3136, 1457, 1376, 1348, 1165, 1153 cm−1; 1H NMR (500 MHz, DMSOD6) δ 2.36 (s, 3H, CH3), 7.17-7.81 (m, 6H, aromatic) and 10.81 (br, 1H, NH). HRMS calcd 356.0587 (C14H12FN5O2S.Na+), found 356.0587.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15](=O)[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[N:31]1([C:36]([NH2:38])=[NH:37])[CH2:35][CH2:34][CH2:33][CH2:32]1.CC(C)([O-])C.[Na+]>CC(O)(C)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:37]=[C:36]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[N:38]=[C:15]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N=C(N)N1CCCC1
Reactant: Cc1ccc(C(=O)C2CN(C(=O)OC(C)(C)C)CCC2=O)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1ccc(-c2nc(N3CCCC3)nc3c2CN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 25 °C
Yield: 36.7 %

Procedure:
To a mixture of 3-(4-Methyl-benzoyl)-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.24 g, 0.74 mmol) and pyrrolidine-1-carboxamidine trifluoroacetate (0.14 g, 0.58 mmol) in t-BuOH (7.5 mL) was added sodium tert-butoxide (0.10 g, 1.1 mmol). The mixture was heated at reflux for 2 h, then cooled to rt, diluted with H2O and extracted with CH2Cl2 (2×). The combined organic extracts were dried and concentrated. The residue was purified by FCC to give the title compound (0.084 g, 29%) as a clear oil. MS (ESI): mass calcd. for C23H30N4O2, 394.5; m/z found, 395.5 [M+H]+.