Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[NH2:24][CH:25]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[CH2:26][OH:27]>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:24][CH:25]([CH2:26][OH:27])[CH2:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: NC(CO)Cc1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Product: O=C(NC(CO)Cc1ccc(Cl)cc1)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chlorobenzoic acid was coupled with (±)-2-amino-3-(4-chloro-phenyl)-propan-1-ol as in EXAMPLE 1, Part C. HPLC: RT=9.71 min. MS (ESI−): mass calcd. for C22H18Cl2N4O4S2, 536.01; m/z found, 535/537 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.57 (s, 1H), 8.38 (br d, J=6.2, 1H), 8.22 (br d, J=8.4, 1H), 7.71 (br m, 2H), 7.35-7.10 (br m, 5H), 6.92 (br d, J=6.0, 1H), 6.30 (br m, 1H), 4.36-4.27 (br m, 1H), 3.76-3.62 (br m, 2H), 2.98-2.85 (br m, 2H), 1.92 (br s, 1H).
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([N:10]1[C@@H:14]([CH:15]2[CH2:17][CH2:16]2)[C@H:13]([C:18]([O:20]CC)=[O:19])[O:12][CH:11]1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO.O>[C:3]([O:7][C:8]([N:10]1[C@@H:14]([CH:15]2[CH2:17][CH2:16]2)[C@H:13]([C:18]([OH:20])=[O:19])[O:12][CH:11]1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CCOC(=O)[C@@H]1OC(c2ccc(OC)cc2)N(C(=O)OC(C)(C)C)[C@H]1C1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C2O[C@@H](C(=O)O)[C@H](C3CC3)N2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 125.5 %

Procedure:
(1)Ethyl (4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-cyclopropyl-5-oxazolidinecarboxylate (diastereomeric mixture) obtained in Example 6(1) is purified by column chromatography to give ethyl (4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-cyclopropyl-5-oxazolidinecarboxylate. A 87 mg of lithium hydroxide is added under ice-cooling to a solution of 1.03 g of ethyl (4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-cyclopropyl-5-oxazolidinecarboxylate in a mixture of 20 ml of methanol and 10 ml of water. The mixture is stirred at room temperature for 30 minutes. The reaction mixture is evaporated under reduced pressure to remove methanol. The pH of the solution of the residue in ethyl acetate is adjusted to pH 2 with 1N hydrochloric acid under ice-cooling. After the mixture is extracted with ethyl acetate, the extract is washed with brine, dried and evaporated to remove the solvent to give 1.20 g of (4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-cyclopropyl-5-oxazolidinecarboxylic acid quantitatively. ESI-MS(m/z): 386(M+ +Na) IR(neat,cm-1): 3080,1755,1702
Reaction SMILES: [CH3:1][N:2]([C@@H:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[C@H:10]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:9]1)C(=O)OCC.[OH-].[K+]>C(O)CCC>[CH3:1][NH:2][C@@H:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[C@H:10]([O:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=2)[CH2:9]1
Reactant: CCOC(=O)N(C)[C@@H]1CCc2ccccc2[C@H](Oc2ccc(C(F)(F)F)cc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CN[C@@H]1CCc2ccccc2[C@H](Oc2ccc(C(F)(F)F)cc2)C1
Yield: 94.1 %

Procedure:
A solution of 7.1 g of the product of Step A in 70 ml of n-butanol was mixed with stirring under nitrogen with 7 g of potassium hydroxide pastilles and the mixture was then refluxed for 17 hours. The mixture was evaporated to dryness and the residue was taken up in methylene chloride. The solution was washed with water and dried and evaporated to dryness to obtain 5.5 g of cis N-methyl-5-[4-trifluoromethylphenoxy]-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-amine in the form of an orange oil. The latter was dissolved in 30 ml of ethyl acetate and the solution was made acidic by addition of a solution of gaseous hydrogen chloride in ethyl acetate. Crystallized was effected and the mixture was vacuum filtered. The recovered product was washed with ethyl acetate and was dried to obtain 5.4 g of the hydrochloride of the cis product in the form of white crystals melting at ≈220° C.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CCOCC>[N:24]([CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)Cl
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCCN=[N+]=[N-]
Temperature: 60 °C
Reaction time: 3 h
Yield: 26.6 %

Procedure:
To a solution of 1,1-dimethylethyl (2-hydroxyethyl)carbamate (1.483 g, 9.2 mmol) in toluene (40 mL) cooled with an ice bath was added triethylamine (1.282 mL, 9.20 mmol) then methanesulfonyl chloride (0.717 mL, 9.20 mmol) and the resulting mixture was stirred for 5 min at this temperature then tetrabutylammonium bromide (0.297 g, 0.920 mmol) was added followed by a solution of sodium azide (5 g, 77 mmol) in water (20 mL). The resulting mixture was stirred at 60° C. for 3 h then cooled to room temperature and diluted with Et2O (150 mL). The organic layer was washed with water then brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by SP4 using a 50G silica cartridge gave 1,1-dimethylethyl (2-azidoethyl)carbamate (456 mg, 2.449 mmol, 26.6% yield) as a colourless oil.
Reaction SMILES: C(N(CC)CC)C.[O:8]([C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]2[C@@H:31]([CH2:32][CH2:33][C@@H:34]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[OH:35])[C:30](=[O:43])[N:29]2[C:44]2[CH:49]=[CH:48][C:47](I)=[CH:46][CH:45]=2)=[CH:24][CH:23]=1)[C@@H:9]1[O:17][C@H:16]([C:18]([O:20][CH3:21])=[O:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]1[OH:11].[CH2:51]([NH:54][S:55]([CH3:58])(=[O:57])=[O:56])[C:52]#[CH:53]>CN(C=O)C.[Cu](I)I>[O:8]([C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]2[C@@H:31]([CH2:32][CH2:33][C@@H:34]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[OH:35])[C:30](=[O:43])[N:29]2[C:44]2[CH:49]=[CH:48][C:47]([C:53]#[C:52][CH2:51][NH:54][S:55]([CH3:58])(=[O:57])=[O:56])=[CH:46][CH:45]=2)=[CH:24][CH:23]=1)[C@@H:9]1[O:17][C@H:16]([C:18]([O:20][CH3:21])=[O:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]1[OH:11]
Reactant: COC(=O)[C@H]1O[C@@H](Oc2ccc([C@@H]3[C@@H](CC[C@H](O)c4ccc(F)cc4)C(=O)N3c3ccc(I)cc3)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: C#CCNS(C)(=O)=O
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1O[C@@H](Oc2ccc([C@@H]3[C@@H](CC[C@H](O)c4ccc(F)cc4)C(=O)N3c3ccc(C#CCNS(C)(=O)=O)cc3)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 18 h

Procedure:
Triethylamine (0.07 mL, 0.502 mmol) was added to a stirred solution of 4-[(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-(4-iodophenyl)-4-oxoazetidin-2-yl]phenyl methyl β-D-glucopyranosiduronate (i-7) (0.050 g, 0.071 mmol), N-prop-2-yn-1-ylmethanesulfonamide (i-5) (0.014 g, 0.105 mmol), tetrakistriphenylphosphine palladium(0) (0.012 g, 0.010 mmol) and copper iodide (0.005 g, 0.026 mmol) in DMF (0.5 mL) under a nitrogen atmosphere and the resulting solution aged at room temperature for 18 h. The volatiles were evaporated in vacuo and the crude residue purified by flash chromatography on silica gel (gradient elution; 0-25% methanol/methylene chloride as eluent) to afford the title compound; m/z (ES) 713 (MH+), 505.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:17])=[C:7]([CH2:13][C:14](O)=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:17])=[C:7]([CH2:13][C:14]([Cl:20])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(CC(=O)O)c(=O)oc2cc(N)ccc12
Solvent: Cc1ccccc1
Product: Cc1c(CC(=O)Cl)c(=O)oc2cc(N)ccc12

Procedure:
The reaction was carried out in a 500 ml two-necked reaction flask, containing 50 ml toluene, 7-amino-4-methylcoumarin-3-acetic acid (prepared as per Example 1 above), 699 mg (3 mmol) and thionyl chloride, 0.278 ml (446 ng, 3.75 mmol, BDH Chemicals, U.K.). Nitrogen was passed through the mixture during the reaction. The mixture was refluxed for 2 hours on an oil bath (temperature 130°-150° C.). The solvent was removed by rotatory evaporation and the precipitate was dried in vacuo.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCOC(=O)CBr
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 67.3 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (200 mg) in N,N-dimethylformamide (1.3 mL) was added cesium carbonate (615 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added ethyl bromoacetate (326 mg), and the mixture was stirred at room temperature for 2.5 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×3). The organic layer was washed with saturated brine (20 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=90/10→0/10). The object fraction was concentrated under reduced pressure and dried to give the title compound (210 mg) as white powder crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[CH:18](O)[CH3:19]>>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH:18]([C:12]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=2[Cl:10])[CH3:19])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)cc1O
Reactant: CC(O)c1cc(F)ccc1Cl
Product: CC(Oc1cc(Br)cnc1N)c1cc(F)ccc1Cl
Reaction time: 18 h

Procedure:
The title compound was prepared by a similar method to that of preparation 18 using commercially available 5-bromo-3-hydroxy-2-amino-pyridine and 1-(2-chloro-5-fluoro-phenyl)-ethanol (prepared according to WO 2009087305 A1) except the reaction time was 18 hr and the crude reaction was purified by chromatography on silica gel eluting initially with ethyl acetate in dichloromethane (2:98) followed by a second purification on silica gel eluting with tert-butyl methyl ether in heptane (45:55) to give a white solid (3.82 g, 49%).
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]3[S:13][C:14]4[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+].C(OCC)(=O)C.CO.Cl>O1CCCC1.CO.O.O1CCOCC1>[N:1]1([C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]3[S:13][C:14]4[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)sc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)sc2c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A solution of (R)-ethyl 2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazole-6-carboxylate (Example 53, 1.38 g, 3.85 mmol) in tetrahydrofuran (50 mL) and methanol (25 mL) was added to a stirred solution of lithium hydroxide monohydrate (0.504 g, 12.00 mmol) in water (20 mL). The reaction mixture was stirred at ambient temperature for 19 hours. An aliquot was checked by TLC (99:1 ethyl acetate/methanol). A lower Rf spot was apparent, however, considerable starting ester remained, so the reaction mixture was heated to 40° C. for 7 hours. Starting ester was still present so the reaction mixture was stirred at ambient temperature for approximately 65 hours. Starting ester appeared to be consumed so the reaction mixture was concentrated under reduced pressure. The residue was treated with methanol (100 mL), water (200 mL), and three equivalents (3.0 mL, 12.0 mmol) of 4 M HCl in dioxane. This mixture was stirred overnight at ambient temperature. A precipitate had formed overnight. Most of the methanol was removed under reduced pressure, then the mixture was diluted with additional water and the precipitate was collected by filtration. This solid was azeotroped with benzene to remove residual water then dried in a vacuum oven to provide the title compound as the dihydrate. 1H NMR (300 MHz, CD3OD) δ ppm 8.27 (s, 1H), 7.95 (d, J=8.5 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 3.96-3.83 (m, 1H), 3.81-3.68 (m, 1H), 3.62-3.36 (m, 3H), 2.94-2.69 (m, 4H), 2.51-2.36 (m, 1H), 2.23-2.06 (m, 1H), 1.83-1.68 (m, 4H), 1.66-1.50 (m, 2H); MS (DCI/NH3) m/z 332 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[CH:6]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:7]3[N:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][N:10]([CH3:11])[C:4]=2[CH:3]=1.[CH3:24][C:25]([CH3:40])([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][C:37](O)=[O:38])[CH2:32][CH2:31]1)=[O:29])[CH3:26].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[CH:6]([N:16]3[CH2:21][CH2:20][N:19]([C:37](=[O:38])[CH2:36][CH:33]4[CH2:34][CH2:35][N:30]([C:28]([O:27][C:25]([CH3:26])([CH3:24])[CH3:40])=[O:29])[CH2:31][CH2:32]4)[CH2:18][CH2:17]3)[C:7]3[N:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][N:10]([CH3:11])[C:4]=2[CH:3]=1
Reactant: CN1Cc2cccnc2C(N2CCNCC2)c2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2cccnc2C(N2CCN(C(=O)CC3CCN(C(=O)OC(C)(C)C)CC3)CC2)c2ccc(Cl)cc21
Temperature: 20 °C
Reaction time: 20 h
Yield: 30.1 %

Procedure:
(8-Chloro-6,11-dihydro-6-methyl-5H-pyrido[3,2-c][1]benzazepin-11-yl)-piperazine (531 mg, 1.14 mmol), 1-(1,1-dimethylethoxycarbonyl)-4-piperidine-acetic acid (570 mg, 2.3 mmol), EDCl (439 mg) and HOBT (311mg) were dissolved in DMF (8 ml), and NMM (4 ml) was added. The reaction mixture was stirred at 20° C. for 20 hours and then water (100 ml) was added, and the resulting tan suspension was extracted with EtOAc (2×30 ml). The EtOAc phase was then washed with Na2CO3 (30 ml), dried over Na2SO4, filtered, and evaporated. The product was chromatographed over silica gel in CH2Cl2, and the column was eluted with CH2Cl2 and with CH2Cl2 /MeOH (95:5). The resulting purer material (0.75 g) was rechromatographed over silica gel in hexane/acetone (85:15) and eluted with increasing amounts of acetone (finally 30%). The product was rechromatographed on silica gel to afford the title compound (0.19 g), m.p. 86-98° C.; found: C, 64.64; H, 7.39; N, 12.12; calcd. for C30H40ClN5O3 : C, 65.03; H, 7.28; N, 12.64; HRMS: calcd. 554.2898; found 554.2891.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]P(=O)(OC)OC)=[CH:4][C:3]=1[C:15]([NH:17][CH2:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2)=[O:16].C([N-]C(C)C)(C)C.[Li+].[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][C:47](=O)[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38]>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:47]2[CH2:48][CH2:49][N:44]([C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:43])[CH2:45][CH2:46]2)=[CH:4][C:3]=1[C:15]([NH:17][CH2:18][C:19]12[CH2:20][CH:21]3[CH2:27][CH:25]([CH2:24][CH:23]([CH2:22]3)[CH2:28]1)[CH2:26]2)=[O:16]
Reactant: COP(=O)(Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1)OC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=Cc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of the crude [[4-chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]phenyl]methyl]phosphonic acid, dimethyl ester (2.50 g, Example 50a) in tetrahydrofuran (50 ml) at −78 ° C. was added a solution of lithium diisopropylamide (7.30 ml, 2M in tetrahydrofuran). The reaction was allowed to warm to room temperature and stirred for 15 min. N-t-butoxycarbonylpiperidin-4-one (1.52 g) in tetrahydrofuran (5 ml) was then added and the mixture stirred for 24 h. The reaction was diluted with water and extracted with ethylacetate. The organic layer was washed with brine and dried over magnesium sulfate. The crude material was purified on a silica gel (0 to 5% methanol in dichloromethane) to afford the subtitle compound as a white foam.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I/[C:10](/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:11]\[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[C:17]1(/[C:10](/[C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C#Cc1ccccc1
Reactant: CCOC(=O)/C=C(\I)c1ccccc1
Product: CCOC(=O)/C=C(\C#Cc1ccccc1)c1ccccc1

Procedure:
The general procedure was used to convert phenylacetylene and (Z)-ethyl 3-iodo-3-phenylacrylate to the title product. Purification by flash chromatography (5% ethyl acetate in hexanes as the eluent) gave the analytically pure product as a light yellow oil (530 mg, 96% yield). 1H NMR (400 MHz, CDCl3) δ 7.78 (m, 2H), 7.63 (m, 2H), 7.38 (m, 6H), 6.59 (s, 1H), 2.06 (q, 2H), 1.35 (t, 3H). 13C NMR (100 MHz, CDCl3) δ 165.12, 136.92, 136.08, 131.85, 129.66, 128.99, 128.42, 128.18, 126.96, 122.54, 122.48, 101.88, 86.68, 60.16, 14.17. Anal. Calc'd. for C19H16O2: C, 82.58; H, 5.84; Found C,
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([NH2:13])[CH:7]=1)[CH3:2].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O.CO>CS(C)=O>[CH2:1]([O:3][C:4](=[O:14])[NH:5][C:6]1[CH:11]=[CH:10][C:9]2[N:12]=[C:18]([C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[Cl:15])[NH:13][C:8]=2[CH:7]=1)[CH3:2]
Reactant: O=Cc1ccccc1Cl
Reactant: CCOC(=O)Nc1ccc(N)c(N)c1
Solvent: CO
Solvent: CS(C)=O
Product: CCOC(=O)Nc1ccc2nc(-c3ccccc3Cl)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A freshly prepared solution of (3,4-diamino-phenyl)-carbamic acid ethyl ester in DMSO (0.2 M, 0.10 mL) was placed in a vial. To it was added 2-chloro-benzaldehyde (0.2 M in toluene, 0.12 mL), followed by FeCl3 (0.02 M in THF, 0.050 mL). The mixture was stirred in open air at ambient temperature overnight. The mixture was then diluted by MeOH and the whole was loaded onto a solid phase extraction (SPE) cartridge that contained strong cation exchange (SCX) (1 g media in 6 mL cartridge, United Chemical Technology). Wash-to-waste (5 mL MeOH) was followed by elute-to-collect (5 mL 20:2:1 ethyl acetate-MeOH-Et3N) and, after evaporation of volatiles, the crude was further purified by silica gel column chromatography to give [2-(2-chloro-phenyl)-3H-benzoimidazol-5-yl]-carbamic acid ethyl ester: MS (m/z) 315.97 (M+1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])#[CH:15]>>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]#[C:15][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)CCc1ccc(I)cc1
Reactant: C#Cc1ccccc1OC
Product: COC(=O)CCc1ccc(C#Cc2ccccc2OC)cc1

Procedure:
The title compound was prepared from methyl 3-(4-iodophenyl)propanoate (90 mg, 0.31 mmol) and 1-ethynyl-2-methoxybenzen (40 μL, 0.31 mmol) according to the general procedure IC to give 86 mg (94%) of a pure orange-brown oil. Rf=0.44 (EtOAc:PE; 1:2); 1H NMR (CDCl3): δ 7.48 (d, J=8.1 Hz, 3H) 7.29-7.22 (m, 1H) 7.16 (d, J=8.2, 2H) 6.95-6.88 (m, 2H) 3.90 (s, 3H) 3.66 (s, 3H) 2.95 (t, J=7.6 Hz, 2H) 2.63 (t, J=7.6 Hz, 2H); 13C NMR (CDCl3): δ 173.3, 160.1, 140.8, 133.7, 132.0, 129.8, 128.4, 121.7, 120.6, 112.7, 110.9, 93.5, 85.6, 56.0, 51.8, 35.6, 31.0; ESI-MS m/z 317.0 (M+Na+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:17][OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:17][O:18][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:28])=[O:27])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(N[C@@H]1CCCC[C@H]1CO)OCc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCC[C@H]2NC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
A solution of (1R,2R)-(2-hydroxymethylcyclohexyl)-carbamic acid benzyl ester (6.0 g, 22.8 mmol) in pyridine (35 mL) was stirred on an ice-acetone bath and treated with toluene-4-sulfonyl chloride (4.78 g, 25.1 mmol). The reaction was stirred on an ice-water bath for 3 hours, then ice-cold water (35 mL) was added slowly. The mixture was diluted further with ice water and the resulting slurry was stirred at room temperature for 1 hour. The solid was collected by filtration, washed with water, and dried under vacuum to provide a white powdery solid (9.1 g, 96%).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][NH:12][CH2:11][CH2:10][N:9]1C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:21]=[C:22]1[C:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][N:23]1[CH2:39][C:40](O)=[O:41].C(N(C(C)C)CC)(C)C.Cl>ClCCl>[CH2:1]([CH:8]1[NH:9][CH2:10][CH2:11][N:12]([C:40](=[O:41])[CH2:39][N:23]2[CH2:24][CH2:25][C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:22]2=[O:21])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1Cc1ccccc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCNC(Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
To tert-butyl 2-benzylpiperazine-1-carboxylate (0.052 g, 0.190 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.051 g, 0.173 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.069 g, 0.181 mmol) in dichloromethane (0.5 mL) was added diisopropylethylamine (0.045 mL, 0.259 mmol), and the reaction was stirred a room temperature. After stirring overnight, the reaction was concentrated, loaded onto a silica gel column (Analogix® SF15-12, Burlington, Wis.) and eluted with a gradient of 5% to 100% ethyl acetate/hexanes. To the resulting product was added HCl (2.0 Min diethyl ether, 3.57 μl, 0.117 mmol), and the reaction was stirred at room temperature overnight. The reaction was centrifuged, and the solvent was decanted away from the solid. Diethyl ether (1 mL) was added, and the suspension was sonicated to give a fine suspension. The reaction was centrifuged, the solvent was decanted and the resulting solid dried to give the title compound as the hydrochloride salt. 1H NMR (300 MHz, pyridine-d5) δ ppm 7.05-7.50 (m, 15H), 4.65-4.80 (m, 2H), 4.25-4.55 (m, 2H), 3.95-4.15 (m, 2H), 3.40-3.75 (m, 5H), 2.95-3.27 (m, 2H), 2.75-2.85 (m, 2H); MS (DCI+) m/z 454.2 (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][CH:11]([CH3:15])[C:12](Cl)=[O:13]>C(N(CC)CC)C>[CH3:10][CH:11]([CH3:15])[C:12]([NH:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:13]
Reactant: CC(C)C(=O)Cl
Reactant: NCCN1CCCCC1
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NCCN1CCCCC1

Procedure:
(2-Piperidin-1-ylethyl)amine was treated with 2-methylpropanoyl chloride in the presence of triethylamine to obtain 2-methyl-N-(2-piperidin-1-ylethyl)propanamide.