Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[NH:8][N:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][N:8]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=[N:7]1)[CH3:15]
Reactant: CC(C)c1ccn[nH]1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)Cn1nccc1C(C)C
Yield: 6 %

Procedure:
Prepared according to the method described for Preparation 75 using 5-isopropyl-1H-pyrazole and ethyl bromoacetate. The residue was purified using silica gel column chromatography eluting with 4:1 hexane:EtOAc. The title compound was isolated as the lower running minor product in 6% yield, and taken directly on to the next step.
Reaction SMILES: [CH2:1]([O:3][P:4]([O-:8])[O:5][CH2:6][CH3:7])[CH3:2].[H-].[Na+].[C:11]1([O:17][CH:18](Cl)Cl)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C)C=O.O>[O:17]([CH:18]([P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOP([O-])OCC
Reactant: ClC(Cl)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)C(Oc1ccccc1)P(=O)(OCC)OCC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Diethylphosphite (20.6 ml) was added dropwise at 20° C. to a stirred suspension of 55% sodium hydride (6.24 g) in dimethylformamide (90 ml). After stirring for a further 15 minutes, the mixture was cooled to 0° C., and dichloromethyl phenyl ether (9.27 g) was added dropwise. Stirring was continued overnight at 45° C., and the mixture was cooled in ice, diluted with water, neutralized and extracted with ethyl acetate. The organic phase was washed repeatedly with water, dried and evaporated in vacuo to yield an oil which was purified by chromatography on silica gel. Eluent: ether-acetone 85:15. The pure title compound was obtained as a colourless oil.
Reaction SMILES: [CH:1]([N:4]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=1)[CH2:5][C:6]1[N:7](COCC[Si](C)(C)C)[CH:8]=[N:9][CH:10]=1)([CH3:3])[CH3:2].[C:28](OC(=O)C)(=[O:30])[CH3:29]>C(O)C.[Pd].O1CCCC1>[N:9]1[CH:10]=[C:6]([CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[C:19]2[CH:20]=[C:21]([NH:25][C:28](=[O:30])[CH3:29])[CH:22]=[CH:23][CH:24]=2)[NH:7][CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)N(Cc1cncn1COCC[Si](C)(C)C)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(N(Cc2cnc[nH]2)C(C)C)c1
Reaction time: 8 h

Procedure:
Isopropyl-(3-nitro-phenyl)-[3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-ylmethyl]-amine (0.055 g, 0.14 mmol) was dissolved in ethanol, palladium on charcoal (20 mg, 10% Pd) was added and the mixture was hydrogenated overnight. The catalyst was filtered off and the solvent was evaporated. The residue was dissolved in ethyl acetate and filtered over silica gel. After evaporation the residue was dissolved in toluene (1.5 ml) and tetrahydrofuran (3 ml), acetic anhydride (0.015 mg, 0.14 mmol) was added and the mixture was stirred overnight. The solvents were evaporated and the residue was partitioned between sodium bicarbonate solution and ethyl acetate. The organic layer was dried over magnesium sulphate and evaporated. The residue was dissolved in tetrahydrofuran (5 ml) and tetrabutylammonium fluoride solution (0.3 ml, 1M) in tetrahydrofuran was added. After stirring the mixture at 65° C. overnight the solvent was evaporated and the residue was purified by flash chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: ethyl acetate/methanol=95:5) to yield a white gum, (0.005 g, 34%); MS (ISP): 273.2 ((M+H)+.).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:27]([NH:30][CH2:31][CH2:32][CH3:33])[CH2:28][CH3:29].Cl>C(#N)C>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][CH:13]([CH2:12][N:30]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:28][CH3:29])[O:18][C:17]=2[CH:19]=1)(=[O:24])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: CCCNCCC
Agent: Cl
Solvent: CC#N
Product: CCCN(CCC)CC1COc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 14 using [7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.175 g, 0.44 mmol), N-propylpropan-1-amine (1 ml) and ACN (3 ml). Yield: 0.11 g, 77%. The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 182° C. MS m/z (rel. intensity, 70 eV) 327 (M+, 1) 114 (100), 298 (17), 115 (8), 86 (6).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18]([C:20]2[C:21]([CH3:27])=[N:22][CH:23]=[N:24][C:25]=2[CH3:26])=[O:19])[CH2:10][CH2:9]1)#[N:2].CCN(CC)CC.[C:46](OC(=O)C)(=[O:48])[CH3:47]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]([CH:8]1[CH2:9][CH2:10][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18]([C:20]2[C:25]([CH3:26])=[N:24][CH:23]=[N:22][C:21]=2[CH3:27])=[O:19])[CH2:12][CH2:13]1)[C:29]1[CH:34]=[CH:33][C:32]([O:35][C:46](=[O:48])[CH3:47])=[CH:31][CH:30]=1)#[N:2]
Reactant: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(O)cc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCNC(=O)c3c(C)ncnc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a solution of the above phenol (45 mg, 0.087 mmol) in CH2Cl2 (2 mL) were added Et3N (0.04 mL, 0.29 mmol) followed by acetic anhydride (0.02 mL, 0.21 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 138 as a white solid (43 mg, 80%) following work-up and purification. 1H NMR (CDCl3) δ 0.82-1.12 (m, 5H), 1.54-1.58 (m, 1H), 1.76-1.79 (m, 3H), 2.18 (t, 1H, J=11.7 Hz), 2.25 (s, 3H), 2.51 (s, 6H), 2.57 (t, 1H, J=10.5 Hz), 2.74-2.86 (m, 3H), 3.30-3.36 (m, 1H), 3.56-3.62 (m, 1H), 3.82-3.87 (m, 1H), 3.89 (s, 2H), 6.53 (d, 2H, J=8.1 Hz), 6.87 (d, 2H, J=8.4 Hz), 7.41-7.46 (m, 1H), 7.52-7.55 (m, 3H), 8.60 (br s, 1H), 8.86 (s, 1H). 13C NMR (CDCl3) δ 12.37, 20.06, 20.93, 28.06, 29.26, 29.75, 38.92, 42.58, 47.57, 50.96, 55.43, 59.14, 111.59, 113.16, 117.91, 121.16, 128.32, 128.89, 129.64, 129.83, 129.94, 140.71, 141.26, 145.13, 156.53, 162.07, 165.32, 169.07. ES-MS m/z 555 (M+H). Anal. Calcd. for C32H38N6O3.0.8CH2Cl2: C, 63.27; H, 6.41; N, 13.50. Found. C; 63.46; H, 6.39; N, 13.29.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[N:15]1[CH:27]([CH2:28][CH:29]=O)[C:26]2[C:17](=[CH:18][C:19]([CH2:31][C:32]3[CH:33]=[N:34][C:35]([Cl:38])=[CH:36][CH:37]=3)=[C:20]3[C:25]=2[N:24]=[CH:23][CH:22]=[CH:21]3)[C:16]1=[O:39])(C(C)(C)C)(C)C.[CH3:40][NH:41][CH3:42].C(O)(=O)C.C([BH3-])#N.[Na+]>ClCCCl>[Cl:38][C:35]1[N:34]=[CH:33][C:32]([CH2:31][C:19]2[CH:18]=[C:17]3[C:16](=[O:39])[N:15]([C@H:10]4[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]4[OH:8])[CH:27]([CH2:28][CH2:29][N:41]([CH3:42])[CH3:40])[C:26]3=[C:25]3[C:20]=2[CH:21]=[CH:22][CH:23]=[N:24]3)=[CH:37][CH:36]=1
Reactant: CNC
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCCC[C@@H]1N1C(=O)c2cc(Cc3ccc(Cl)nc3)c3cccnc3c2C1CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(C)CCC1c2c(cc(Cc3ccc(Cl)nc3)c3cccnc23)C(=O)N1[C@H]1CCCC[C@@H]1O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of {8-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-5-[(6-chloropyridin-3-yl)methyl]-7-oxo-8,9-dihydro-7H-pyrrolo[3,4-h]quinolin-9-yl}acetaldehyde (see Example 22, 0.033 g, 0.058 mmol) in 1.2 mL of 1,2-dichloroethane was added dimethylamine (2 M in tetrahydrofuran, 0.059 mL, 0.12 mmol), acetic acid (0.0034 mL, 0.058 mmol), sodium cyanoborohydride (3.7 mg, 0.058 mmol), and 4 Å molecular sieves. The mixture was irradiated in a microwave reactor at 100° C. for 20 min, cooled to ambient temperature, and filtered. The filtrate was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in 2 mL of dichloromethane and treated with hydrochloric acid (6 M aqueous, 4 drops). After 14 hr, the mixture was diluted with dichloromethane, washed 2× with saturated aqueous sodium bicarbonate, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 479.2200 for [M+H]+ [calc'd for C27H32CN4O2, [M+H]+=479.2208]: 1H NMR (400 MHz, CDCl3) δ 8.97-8.96 (m, 1H), 8.34-8.28 (m, 2H), 7.78 (s, 1H), 7.54-7.50 (m, 1H), 7.44-7.40 (m, 1H), 7.24 (d, J=8.3 Hz, 1H), 5.21-5.19 (m, 1H), 4.69-4.51 (m, 1H), 4.47 (s, 2H), 3.42-3.33 (m, 1H), 3.29-3.15 (m, 2H), 2.76-2.63 (m, 1H), 2.49 (s, 6H), 2.29-2.17 (m, 2H), 1.81-1.68 (m, 2H), 1.48-1.00 (m, 5H) ppm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[CH2:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][C:35]1=[O:40]>CN(C=O)C>[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[CH2:33][N:34]1[CH2:39][CH2:38][N:37]([C:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:8][CH2:9]2)=[O:14])[CH2:36][C:35]1=[O:40]
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: O=C1CNCCN1Cc1ccc2ccccc2c1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1CN(C(=O)C2CCN(c3ccncc3)CC2)CCN1Cc1ccc2ccccc2c1
Yield: 18 %

Procedure:
Using an analogous procedure to that described in Example 1 except that DMF was used in place of methylene chloride as the reaction solvent, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with 1-(2-naphthylmethyl)-2-oxopiperazine trifluoroacetate salt to give 1-(2-naphthylmethyl)-2-oxo-4-[-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine in 18% yield;
Reaction SMILES: [CH:1]1([C:9]2[CH:14]=[C:13]([CH2:15]O)[CH:12]=[CH:11][C:10]=2[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[F:25])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:28])=O>C(Cl)Cl.CN(C=O)C>[Cl:28][CH2:15][C:13]1[CH:12]=[CH:11][C:10]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[F:25])=[C:9]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH:14]=1
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C2CCCCCCC2)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(CCl)cc2C2CCCCCCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a stirred solution of T11.6 (0.130 g, 0.4 mmol) in DCM (2.00 mL) and DMF (0.03 mL) at 0° C. was added thionyl chloride (0.06 mL, 0.8 mmol). The reaction was stirred at room temperature for 2 hours. After which, the reaction was concentrated in vacuo and the product was then purified on silica gel (0-10% EtOAc in hexanes) to yield T11 as a colorless oil (0.130 g, 95% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:17])[NH:12]2.[CH3:18][C@H:19]1[NH:24][C@@H:23]([CH3:25])[CH2:22][N:21]([C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH2:20]1>C(O)C.N1CCCCC1>[CH3:25][C@H:23]1[NH:24][C@@H:19]([CH3:18])[CH2:20][N:21]([C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[NH:12][C:11]2=[O:17])=[O:27])[CH2:22]1
Reactant: O=C1Cc2c(cccc2-c2ccccc2F)N1
Reactant: Cc1cc(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c(C=C2C(=O)Nc3cccc(-c4ccccc4F)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.3 %

Procedure:
To a solution of 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (62.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-{3-((cis)-3,5-dimethyl-piperazine-1-carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene}-4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (103.5 mg, 90%).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:17](=[O:19])=[O:18].CCOCC>O1CCCC1.CCCCCC>[C:1]1([C:7]2[S:8][C:9]([C:17]([OH:19])=[O:18])=[CH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cccs2)cc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)c1ccc(-c2ccccc2)s1
Reaction time: 1 h

Procedure:
A solution of 2-phenylthiophene (16.0 g, 0.1 mole) in 100 ml anhydrous tetrahydrofuran (THF) is treated dropwise with a solution of n-butyl lithium (0.11 mole) in hexane (2 M solution). Thereafter the mixture is stirred for 1 hr. The resulting black solution is poured onto 50 g of solid CO2 covered with ether. When all the CO2 is evaporated, the mixture is treated with 200 ml of water, acidified with 10% HCl and extracted with ether. The extract is washed with 5% NaOH. The latter washings are cooled and rendered acidic with 20% HCl. The resulting precipitate is collected and recrystallized from 100 ml CCl4 to give 5-phenyl 2-thiophenecarboxylic acid, mp 180° C, γmaxCHCl 3 1665 cm-1, as yellow green crystals.
Reaction SMILES: C1([C:7]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]=[N:8]2)C=CC=CC=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34]>CN(C)C=O.CCCCCC.C(OCC)C>[C:18]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[N:8]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C1=C(c2ccccc2)N=NC1(c1ccccc1)c1ccccc1
Reactant: COC(=O)CCCCCCCCBr
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOCC
Product: COC(=O)CCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 202.3 %

Procedure:
Sodium hydride (588 mg of a 60% dispersion in mineral oil, 13 mmol) was washed twice with hexane and covered with dimethylformamide (DMF), (45 mL). 3,3,5-Triphenyl-3H-pyrazole (3 g, 10 mmol) was added and the mixture stirred at 110° C. under a nitrogen atmosphere for 30 minutes before being cooled to room temperature. Methyl 9-bromononanoate (2.80 g, 11 mmol) in DMF (2 mL) was added dropwise, the mixture stirred at room temperature for 2 hours and then poured onto water (100 mL). The mixture was extracted with diethyl ether (3×100 mL), the extracts washed with water (3×100 mL), dried over sodium sulfate and concentrated to give an oil. Chromatography on a column of silica gel using a mixture of hexane and diethyl ether (2:1) as eluent afforded methyl 3,4,5-triphenyl-1H-pyrazol-1-nonanoate (4.72 g, 100%) as a viscous oil. (MS(CI): m/e=467 (MH+)
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]1[O:8][C:6](=[O:7])[C@H:5]([OH:9])[C@@H:4]([OH:10])[C@@H:3]1[OH:11].[CH3:13][NH2:14]>C(O)(C)C.CO>[CH3:13][NH:14][C:6]([C@@H:5]([C@H:4]([C@@H:3]([C@@H:2]([CH2:1][OH:12])[OH:8])[OH:11])[OH:10])[OH:9])=[O:7]
Reactant: CN
Reactant: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Solvent: CO
Solvent: CC(C)O
Product: CNC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
A suspension of 50 g gluconolactone in 500 ml of isopropanol/methanol (4/1) was treated with 23.8 ml of a 40% N-methylamine solution for 30 minutes. The N-methylgluconamide obtained in quantitative yields, was treated at 60° C. with 69 ml acetic anhydride and 35 ml acetic acid in the presence of 1% concentrated sulphuric acid.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=1.C(N(CC)CC)C.[OH-].[Na+]>C(Cl)Cl>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][N:25]([C:6](=[O:7])[C:5]3[CH:9]=[CH:10][CH:11]=[C:3]([N:2]([CH3:12])[CH3:1])[CH:4]=3)[CH2:26][CH2:27]2)=[CH:16][CH:15]=1
Reactant: CN(C)c1cccc(C(=O)Cl)c1
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1cccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6.51 g of 3-dimethylaminobenzoyl chloride in 130 ml of methylene chloride is added dropwise, over a period of 10 minutes, to a solution, stirred at room temperature, of 7.97 g of 1-[2-(4-chlorophenyl)-ethyl]-piperazine and 3.6 g of triethylamine in 150 ml of methylene chloride. The reaction mixture is stirred overnight at room temperature, diluted with methylene chloride, rendered alkaline with 2N NaOH and washed with water, dried over sodium sulphate and concentrated to dryness by evaporation. The residue is recrystallised from ethanol. 1-[2-(4-chlorophenyl)-ethyl]-4-(3-dimethylaminobenzoyl)-piperazine having a melting point of 110°-112° is thus obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[NH:7][C@@H:8]1[C:22](=[O:23])[N:21]2[CH2:24][C@H:25]([OH:27])[CH2:26][C@H:20]2[C:19](=[O:28])[NH:18][C@:17]2([C:30](=[O:39])[NH:31][S:32]([C:35]3([CH3:38])[CH2:37][CH2:36]3)(=[O:34])=[O:33])[CH2:29][C@H:16]2[CH:15]=[CH:14][CH2:13][CH2:12][CH:11]([CH3:40])[CH2:10][C@H:9]1[CH2:41][CH3:42])([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:49]([N:51]2[CH:55]=N[CH:53]=[CH:52]2)=[O:50])C=1.[F:56][C:57]1[CH:65]=CC=[C:62]2[C:58]=1CN[CH2:61]2>>[F:56][C:57]1[CH:58]=[CH:62][CH:61]=[C:53]2[C:65]=1[CH2:55][N:51]([C:49]([O:27][C@H:25]1[CH2:24][N:21]3[C:22](=[O:23])[C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:43])[C@H:9]([CH2:41][CH3:42])[CH2:10][CH:11]([CH3:40])[CH2:12][CH2:13][CH:14]=[CH:15][C@@H:16]4[CH2:29][C@@:17]4([C:30](=[O:39])[NH:31][S:32]([C:35]4([CH3:38])[CH2:36][CH2:37]4)(=[O:33])=[O:34])[NH:18][C:19](=[O:28])[C@@H:20]3[CH2:26]1)=[O:50])[CH2:52]2
Reactant: Fc1cccc2c1CNC2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC[C@@H]1CC(C)CCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@H]1NC(=O)OC(C)(C)C
Agent: CC[C@@H]1CC(C)CC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@H]1NC(=O)OC(C)(C)C
Agent: CC[C@@H]1CC(C)CC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C(=O)[C@H]1NC(=O)OC(C)(C)C
Product: CC[C@@H]1CC(C)CCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C(=O)[C@H]1NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
A solution of tert-butyl((2R,6S,7R,13aS,14aR,16aS,Z)-7-ethyl-2-hydroxy-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate (0.062 g, 0.1 mmol) and CDI (0.019 g, 0.120 mmol) was stirred for 6 h. To the solution was added 4-fluoroisoindoline (0.018 g, 0.130 mmol), and then stirred overnight. Concentration gave 80 mg of a crude mixtures (2R,6S,7R,13aS,14aR,16aS,Z)-6-((tert-butoxycarbonyl)amino)-7-ethyl-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate, which was used as it was.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([Cl:9])=[CH:6][C:7]=1[F:8].[CH3:11][C:12]([OH:16])([C:14]#[CH:15])[CH3:13]>>[Cl:9][C:5]1[C:4]([CH3:10])=[CH:3][C:2]([C:15]#[C:14][C:12]([CH3:13])([OH:16])[CH3:11])=[C:7]([F:8])[CH:6]=1
Reactant: C#CC(C)(C)O
Reactant: Cc1cc(Br)c(F)cc1Cl
Product: Cc1cc(C#CC(C)(C)O)c(F)cc1Cl

Procedure:
By the method of Example (IV-1), 100 mmol of 3-bromo-6-chloro-4-fluoro-toluene are reacted with 2-methyl-3-butin-2-ol to give 1-(4-chloro-2-fluoro-5-methyl-phenyl)-3-methyl-1-butin-3-ol, except that the mixture is only filtered after the reaction and not concentrated. The filtrate is then admixed with 1.5 g of sodium hydroxide (powder) and the mixture is heated to the boil in a distillation apparatus (with Vigreux column). Distillate is continuously removed, until the boiling point of triethylamine (89° C.) is reached. The mixture is then allowed to cool, filtered and flashed with some ml of triethylamine. The filtrate is subsequently subjected to fractional distillation.
Reaction SMILES: [C:1]([C@@H:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([OH:17])=O)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[CH2:20][NH:21][C:22](=[O:30])[O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27].[CH:38](N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CCOCC.CN(C=O)C>[C:1]([CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([NH:18][C@@H:19]([CH2:31][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:20][N:21]([CH3:38])[C:22](=[O:30])[O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:29])[CH3:27])=[O:17])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: C[Si](C)(C)CCOC(=O)NC[C@@H](N)CC1CCCCC1
Reactant: O=C(O)[C@H]1CCC[C@@H](C(=O)c2ccccc2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C[C@H](CC1CCCCC1)NC(=O)C1CCCC(C(=O)c2ccccc2)C1)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a stirred solution of cis-3-benzoylcyclohexane-1-carboxylic acid (78 mg, 0.34 mmol), 2-(trimethylsilyl)ethyl (S)-2-amino-3-cyclohexylpropylcarbamate (116 mg, 0.37 mmol) and diisopropylethylamine (0.13 mL, 0.70 mmol) in CH2Cl2 (2 mL) were added solid 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 200 mg, 0.53 mmol) and DMF (0.5 mL). The mixture was stirred at rt for 3 h, diluted with ether (90 mL), washed with 5% aqueous HCl (25 mL), sat'd aqueous NaHCO3 (25 mL), and brine (25 mL) and dried over Na2SO4. Removal of the solvent under reduced pressure left an oil (260 mg) which was applied to a 2-g silica SPE cartridge and eluted sequentially with 0, 10, 25, 50, 75, and 100% EtOAc in hexanes (15 mL of each) to give six fractions. Fractions 2-4 were pooled and evaporated to afford 2-(trimethylsilyl)ethyl (S)-2-(3-benzoylcyclohexane-carboxamido)-3-cyclohexylpropylmethylcarbamate (170 mg, 91%) as an oil. MS ESI +ve m/z 528 (M+1).