Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][NH:7][NH2:8])[CH3:2].C([O:14][C:15](=O)[CH:16]=[C:17]([NH2:21])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:21][C:17]1[NH:8][N:7]([CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([CH2:1][CH3:2])[CH:4]=2)[C:15](=[O:14])[CH:16]=1
Reactant: CCc1cccc(CNN)c1
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCc1cccc(Cn2[nH]c(N)cc2=O)c1
Reaction time: 8 h

Procedure:
14.2 g of 3-ethylbenzylhydrazine were added dropwise to a solution of 15.1 g of β-amino-β-ethoxyacrylic acid ethyl ester and a pinch of p-toluenesulphonic acid in 80 ml of ethanol, in the course of which the temperature rose from 22°to 30°. After stirring overnight, the solvent was distilled off in vacuo and the solid residue was recrystallised from ethanol. The product was the compound identified above. Melting point: 73°, 5 g (24%).
Reaction SMILES: S1C=CC=C1.O=[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH:8]1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C:26]1([CH2:32][NH2:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[H][H]>[Pd].CO.C(O)C>[C:20]1([CH2:19][O:18][C@H:8]2[C@@H:7]([NH:33][CH2:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: [H][H]
Reactant: CCOC(=O)N1CCC(=O)C(OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Solvent: c1ccsc1
Solvent: CCO
Product: CCOC(=O)N1CC[C@H](NCc2ccccc2)[C@H](OCc2ccccc2)C1

Procedure:
To 5 parts of a solution of 2 parts of thiophene in 40 parts of ethanol, were added 135 parts of ethyl 4-oxo-3-(phenylmethoxy)-1-piperidinecarboxylate, 55 parts of benzenemethanamine and 400 parts of, methanol. The whole was hydrogenated at normal pressure and at 50° C. with 8. parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 170 parts of ethyl cis-3-(phenylmethoxy)-4-[(phenylmethyl)amino]-1-piperidinecarboxylate as an oily residue (intermediate 48).
Reaction SMILES: [S:1]1[C:5](B(O)O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:20][N:21]2[CH:25]=[CH:24][N:23]=[C:22]2[CH3:26])[N:17]=[N:18][CH:19]=1>>[ClH:13].[S:1]1[C:5]([C:14]2[CH:15]=[C:16]([CH2:20][N:21]3[CH:25]=[CH:24][N:23]=[C:22]3[CH3:26])[N:17]=[N:18][CH:19]=2)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: Cc1nccn1Cc1cc(-c2cc3ccccc3s2)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e=307.3 (M+H+), was prepared from benzo[B]thiophene-2-boronic acid and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=2)[N:8]=[C:7]1[NH2:20].C(#N)C.NN.C(OC(=O)C)C>CO.[Fe](Cl)(Cl)Cl>[NH2:17][C:13]1[CH:12]=[C:11]([C:9]2[N:8]=[C:7]([NH2:20])[N:6]([CH2:5][C:4]3[CH:21]=[CH:22][CH:23]=[CH:24][C:3]=3[O:2][CH3:1])[CH:10]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccccc1Cn1cc(-c2cccc([N+](=O)[O-])c2)nc1N
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: CO
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccccc1Cn1cc(-c2cccc(N)c2)nc1N
Reaction time: 2 h

Procedure:
51.1 A mixture of 2.5 g 1-(2-methoxybenzyl)-4-(3-nitrophenyl)-1H-imidazole-2-ylamine (7.7 mmol, Example 45), 2.5 g activated carbon, 30 mg iron(III) chloride (in the form of the hexahydrate) in 100 mL methanol, and 20 mL acetonitrile was heated at reflux, slowly combined with 50 mL hydrazine, and then stirred for an additional 2 hr under reflux. The batch was filtered, concentrated, taken up in acetic ethyl ester, extracted with water, and the organic phase was dried (Na2SO4) and concentrated. The residue thus obtained was mixed with acetic ethyl ester, suctioned off, and dried (2 g target product).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([N:15]2[CH2:20][CH2:19][C@:18]([CH2:28][CH:29]=[CH2:30])([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[O:17][C:16]2=[O:31])[CH3:14])=[CH:9][CH:8]=1)(=O)[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:34]>C1(C)C=CC=CC=1.N1C=CC=CC=1.CCOC(C)=O>[CH2:28]([C@@:18]1([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[O:17][C:16](=[O:31])[N:15]([C@H:13]([C:10]2[CH:11]=[CH:12][C:7]([C:6]3[S:34][C:1]([CH3:2])=[N:4][N:5]=3)=[CH:8][CH:9]=2)[CH3:14])[CH2:20][CH2:19]1)[CH:29]=[CH2:30]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(C(=O)NNC(C)=O)cc2)C(=O)O1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3nnc(C)s3)cc2)C(=O)O1
Temperature: 130 °C
Yield: 61 %

Procedure:
N′-acetyl-4-((S)-1-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzohydrazide (4 mg, 0.009 mmol) was dissolved in 5:1 toluene/pyridine (1.5 mL). Phosphorus pentasulfide (8.1 mg, 2 equiv.) was added and the mixture was heated in Microwave Oven for 25 min at 130° C. LC-MS found reaction completed. The mixture was diluted with EtOAc (8 mL), washed with 5% HCl (2×5 mL), satd aq NaHCO3 solution (4 mL), brine (4 mL) and dried over Na2SO4. After filtration and concentration, the residue was purified by prep HPLC to afford 2.43 mg (61% yield). LC-MS Method 1 tR=1.7, min, m/z=438; 1H NMR (CDCl3) 7.66 (d, 2H), 7.26 (t, 2H), 7.02 (t, 2H), 6.97 (d, 2H), 5.69 (m, 2H), 5.07 (dd, 2H), 2.98 (m, 1H), 2.83 (s, 3H), 1.56 (d, 3H).
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:9])[CH2:3][C:2]2=[O:10].[Cl:11][C:12]1[CH:13]=[C:14](N=C=O)[CH:15]=[CH:16][C:17]=1[Cl:18].[H-].[Na+].Cl.C[N:26](C)[CH:27]=[O:28]>O>[Cl:11][C:12]1[CH:13]=[C:14]([C:1]23[CH2:8][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:9])[CH:3]([C:27]([NH2:26])=[O:28])[C:2]3=[O:10])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: CN(C)C=O
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: O=C1CC(=O)C2CCC1C2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: NC(=O)C1C(=O)C2CCC(c3ccc(Cl)c(Cl)c3)(C2)C1=O

Procedure:
A solution of bicyclo[3,2,1]octane-2,4-dione (0.34 g, 2.5 mmole), 3,4-dichlorophenyl isocyanate (0.94 g, 5 mmole), and 60% sodium hydride in mineral oil (0.11 g, 2.75 mmole) in dimethylformamide (100 mL) was stirred at 0° C. for 1 hour and heated at 45–50° C. under nitrogen for 24 hours. After cooling, the mixture was diluted with H2O and treated with 2N aqueous HCl until the mixture was clear. The clear solution was then extracted with dichloromethane. The organic layer was washed with H2O again, dried over anhydrous magnesium sulfate, and concentrated on a rotary evaporator. The residue was purified by chromatography on silica gel (40% dichloromethane/hexane) to give an oily solid as the expected product. The oily product was recrystallized from ethyl acetate/hexane to afford the title compound as a white solid, mp=146–148° C.; MS (−) ESI m/z=325 (M−H)−.
Reaction SMILES: CCN(CC)CC.[Si:8]([O:15]S(C(F)(F)F)(=O)=O)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[C:23]([C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:35]=1[N:34]=[C:33]([S:36][CH3:37])[N:32]([CH3:38])[C:31]2=[O:39])(=O)[CH3:24]>C(Cl)Cl>[Si:8]([O:15][C:23]([C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:35]=1[N:34]=[C:33]([S:36][CH3:37])[N:32]([CH3:38])[C:31]2=[O:39])=[CH2:24])([C:11]([CH3:12])([CH3:13])[CH3:14])([CH3:9])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CSc1nc2c(C(C)=O)cccc2c(=O)n1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(O[Si](C)(C)C(C)(C)C)c1cccc2c(=O)n(C)c(SC)nc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Et3N (0.094 mL, 0.674 mmol) and TBSOTf (0.131 mL, 0.570 mmol) were sequentially added to a yellow solution of 8-acetyl-3-methyl-2-(methylthio)quinazolin-4(3H)-one (128.7 mg, 0.518 mmol) in DCM (2.7 mL) at 0° C., and the resulting light-yellow solution was stirred at 0° C. for 30 min. The mixture was partitioned between DCM (50 mL) and saturated aq. NaHCO3 (20 mL). The organic layer was separated, and the aq. layer was extracted with DCM (30 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to provide crude 8-(1-((tert-butyldimethylsilyl)oxy)vinyl)-3-methyl-2-(methylthio)quinazolin-4(3H)-one as a peach-colored solid. This material was combined with 8-(1-ethoxyvinyl)-3-methyl-2-(methylthio)quinazolin-4(3H)-one (35.5 mg, 0.128 mmol), and the resulting mixture was taken up in THF (2.70 mL). Water (0.149 mL, 8.29 mmol) and NBS (115 mg, 0.648 mmol) were sequentially added at 25° C., and the resulting solution was stirred at 25° C. for 30 min. The mixture was partitioned between Et2O (50 mL) and water (30 mL). The organic layer was separated, sequentially washed with saturated aq. NaHCO3 (20 mL), water (20 mL), and brine (20 mL), then dried over Na2SO4, filtered, and concentrated in vacuo to provide crude 8-(2-bromoacetyl)-3-methyl-2-(methylthio)quinazolin-4(3H)-one as an off-white solid. NH4OAc (200 mg, 2.59 mmol) and piperidine-2,4-dione (88 mg, 0.777 mmol) were added to this solid, and the resulting mixture was taken up in EtOH (2.70 mL) and heated under argon in a sealed flask at 40° C. for 16 h. The reaction suspension was vacuum filtered, and the collected solid was washed with MeOH (20 mL) and dried in vacuo. The residue was triturated with DMSO (2.0 mL), and the resulting suspension was vacuum filtered. The collected solid was sequentially washed with MeOH (5 mL) and DCM (5 mL) and dried in vacuo to provide 3-methyl-2-(methylthio)-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinazolin-4(3H)-one (57.1 mg, 0.168 mmol, 26% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.67 (1H, br. s.), 8.05 (1H, dd, J=7.6, 1.2 Hz), 7.95 (1H, dd, J=7.8, 1.0 Hz), 7.44 (1H, t, J=7.8 Hz), 7.03 (1H, d, J=2.3 Hz), 6.96 (1H, br. s.), 3.56 (3H, s), 3.41 (2H, td, J=6.8, 2.2 Hz), 2.85 (2H, t, J=6.9 Hz), 2.74 (3H, s). m/z (ESI, +ve) 341.1 (M+H)+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:14]=1[CH2:15][S:16][C:17]1[CH2:21][C:20]([CH2:23][CH3:24])([CH3:22])[O:19][N:18]=1.O>C(Cl)(Cl)Cl>[F:12][C:13]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:14]=1[CH2:15][S:16]([C:17]1[CH2:21][C:20]([CH2:23][CH3:24])([CH3:22])[O:19][N:18]=1)=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC1(C)CC(SCc2c(F)cccc2F)=NO1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCC1(C)CC(S(=O)Cc2c(F)cccc2F)=NO1
Reaction time: 1 h
Yield: 34.8 %

Procedure:
4.6 g of m-chloroperbenzoic acid (purity: 70%, 18.8 mmoles) was added, with ice-cooling, to a solution of 4.1 g (15.0 mmoles) of 3-(2,6-difluorobenzylthio)-5-ethyl-5-methyl-2-isoxazoline dissolved in 50 ml of chloroform. The mixture was stirred for 1 hour and then at room temperature for 12 hours to give rise to a reaction. After the completion of the reaction the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution, water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 1.5 g (yield: 34.8%) of 3-(2,6-difluorobenzylsulfinyl)-5-ethyl-5-methyl-2-isoxazoline as a white powder (melting point: 30° C. or less).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:6]=[CH:7][N:8]2[C:12]([C:13]3[C@H:14]([CH3:27])[C@@H:15]4[C@@H:22]([C@H:23]([OH:25])[CH3:24])[C:21](=[O:26])[N:16]4[C:17]=3[C:18]([O-:20])=[O:19])=[CH:11][S:10][C:9]=12)=[O:4].[Na+].C(=O)([O-])O.[Na+].[C:35]([O:41][CH2:42]I)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C>[CH3:28][N:2]([CH3:1])[C:3]([C:5]1[N:6]=[CH:7][N:8]2[C:12]([C:13]3[C@H:14]([CH3:27])[C@@H:15]4[C@@H:22]([C@H:23]([OH:25])[CH3:24])[C:21](=[O:26])[N:16]4[C:17]=3[C:18]([O:20][CH2:42][O:41][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[O:19])=[CH:11][S:10][C:9]=12)=[O:4]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3csc4c(C(=O)N(C)C)ncn34)[C@H](C)[C@H]12
Reactant: CC(C)(C)C(=O)OCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(c3csc4c(C(=O)N(C)C)ncn34)[C@H](C)[C@H]12
Temperature: -30 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of 50 mg of sodium (1S,5R,6S)-2-[7-(N,N-dimethylcarbamoyl)imidazo[5,1-b]thiazol-3-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate in 0.7 ml of DMF was added 5.0 mg of sodium hydrogen carbonate, and the mixture was cooled to −30° C. under the atmosphere of argon. After addition of 43 mg of pivaloyloxymethyl iodide, the mixture was stirred for 1 hour, extracted with 20 ml of ethyl acetate, and the organic layer was washed with 12 ml of semi-saturated aqueous saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to a volume of about 1 ml. The residue thus obtained was purified by column chromatography on silica gel (dichloromethane:methanol=95:5) to give 48 mg of the title compound.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:24]1[O:26][CH2:25]1.[C:27](O)(=[O:29])[CH3:28]>>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([N:14]([CH2:25][CH2:24][OH:26])[CH2:28][CH2:27][OH:29])=[CH:15][CH:16]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C1CO1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: CC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Product: OCCN(CCO)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 84 %

Procedure:
4-Benzyloxyaniline hydrochloride 1A (9.32 g, 39.5 mmol) was dissolved in acetic acid (400 mL), triethylamine (6 mL, 43 mmol) was added followed by ethylene oxide (20 mL). The reaction mixture was stirred at room temperature for 72 h, the solvent was evaporated in a rotary evaporator under water pump then under oil pump at 50° C. for 1 h. The residue was then diluted with water (500 mL) and the precipitate recovered by filtration, washed with more water, then dried in dessicator over P2O5 to afford 2A (9.6 g, 84%) as a pale brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[C:29]([Cl:31])[C:28]([O:32][CH3:33])=[CH:27][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]3[CH:18]=[C:17]([O:19][CH2:20][CH2:21]Cl)[C:16]([O:23][CH3:24])=[CH:15][C:12]=3[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:25]#[N:26].[Cl:34][C:35]1[CH:63]=[C:62]([Cl:64])[C:61]([O:65][CH3:66])=[CH:60][C:36]=1[NH:37][C:38]1[C:47]2[C:42](=[CH:43][C:44]3[CH:51]=[C:50]([O:52][CH3:53])[C:49]([O:54][CH2:55][CH2:56]Cl)=[CH:48][C:45]=3[CH:46]=2)[N:41]=[CH:40][C:39]=1[C:58]#[N:59].[NH:67]1[CH2:72][CH2:71][O:70][CH2:69][CH2:68]1.[I-].[Na+]>COCCOC>[Cl:34][C:35]1[CH:63]=[C:62]([Cl:64])[C:61]([O:65][CH3:66])=[CH:60][C:36]=1[NH:37][C:38]1[C:47]2[C:42](=[CH:43][C:44]3[CH:51]=[C:50]([O:52][CH3:53])[C:49]([O:54][CH2:55][CH2:56][N:67]4[CH2:72][CH2:71][O:70][CH2:69][CH2:68]4)=[CH:48][C:45]=3[CH:46]=2)[N:41]=[CH:40][C:39]=1[C:58]#[N:59].[Cl:1][C:2]1[CH:30]=[C:29]([Cl:31])[C:28]([O:32][CH3:33])=[CH:27][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]3[CH:18]=[C:17]([O:19][CH2:20][CH2:21][N:67]4[CH2:72][CH2:71][O:70][CH2:69][CH2:68]4)[C:16]([O:23][CH3:24])=[CH:15][C:12]=3[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:25]#[N:26]
Reactant: COc1cc(Nc2c(C#N)cnc3cc4cc(OC)c(OCCCl)cc4cc23)c(Cl)cc1Cl
Reactant: C1COCCN1
Reactant: COc1cc(Nc2c(C#N)cnc3cc4cc(OCCCl)c(OC)cc4cc23)c(Cl)cc1Cl
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(Nc2c(C#N)cnc3cc4cc(OC)c(OCCN5CCOCC5)cc4cc23)c(Cl)cc1Cl
Product: COc1cc(Nc2c(C#N)cnc3cc4cc(OCCN5CCOCC5)c(OC)cc4cc23)c(Cl)cc1Cl
Temperature: 90 °C

Procedure:
A mixture of 0.436 g (0.87 mmol ) of 4-(2,4-dichloro-5-methoxyanilino)-7-methoxy-8-(chloroethoxy)benzo[g]quinoline-3-carbonitrile and 4-(2,4-dichloro-5-methoxyanilino)-8-methoxy-7-(chloroethoxy)benzo[g]quinoline-3-carbonitrile (1:1 mixture), 2.0 mL (23.0 mmol) of morpholine and 0.05 g of sodium iodide in 2.0 mL of ethylene glycol dimethyl ether is heated at 90° C. for 3.5 hours under nitrogen. The mixture is cooled, solvent is removed in vacuo and the resulting residue is stirred with a saturated solution of sodium bicarbonate. The crude solid is collected by filtration, washed with water, and dried in vacuo. Purification is carried out by silica gel chromatography, eluting with a gradient of 97:3 to 90:10 ethyl acetate/methanol to yield 0.241 g of 4-(2,4-dichloro-5-methoxyanilino)-8-methoxy-7-[2-(4-morpholinyl)ethoxy]benzo[g]quinoline-3-carbonitrile as a yellow solid, mp 210-212° C. and 0.203 g of 4-(2,4-dichloro-5-methoxyanilino)-7-methoxy-8-[2-(4-morpholinyl)ethoxy]benzo[g]quinoline-3-carbonitrile as a yellow solid, mp 207-214° C.
Reaction SMILES: [OH:1][C@H:2]([C:26]#[C:27][CH3:28])[CH2:3][C@:4]1([CH3:25])[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([CH3:24])[C:8]([CH3:23])=[C:9]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[CH3:14])[O:5]1.N1C2C(=CC=CC=2)C=CC=1>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(OCC)(=O)C.CCCCCC>[OH:1][C@H:2](/[CH:26]=[CH:27]\[CH3:28])[CH2:3][C@:4]1([CH3:25])[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([CH3:24])[C:8]([CH3:23])=[C:9]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:10]=2[CH3:14])[O:5]1
Reactant: CC#C[C@@H](O)C[C@]1(C)CCc2c(C)c(OCc3ccccc3)c(C)c(C)c2O1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Solvent: CCCCCC
Product: C/C=C\[C@@H](O)C[C@]1(C)CCc2c(C)c(OCc3ccccc3)c(C)c(C)c2O1

Procedure:
2.5 g. of 2(S)-[2(S)-hydroxy-3-pentynyl]-2,5,7,8-tetramethyl-6-benzyloxychroman and 0.25 g. of Lindlar catalyst in 15 ml. of ethyl acetate-hexane (2 = 1 parts by volume) containing 0.1 ml. of quinoline was hydrogenated at 25° C. and atmospheric pressure. The catalyst was filtered off and washed with ethyl acetate. The ethyl acetate solution was washed with 1.0 N aqueous HCl (3 × 50 ml.), dried over MgSO4 and concentrated in vacuo to give 2.508 g. of crude product. Crystallization of this material from pentane yield 2.053 g. of 2(S)-[2(S)-hydroxy-3(Z)-pentenyl]-2,5,7,8-tetramethyl-6-benzyloxychroman as white crystalls, m.p. 84°-86° C. [α]D25 - 30.57° (CHCl3).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=1)[O:12][CH2:13][CH:14]1[O:18][C:17](=[O:19])[N:16](C(OC(C)(C)C)=O)[CH2:15]1>O1CCCC1>[Cl:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=1)[O:12][CH2:13][CH:14]1[O:18][C:17](=[O:19])[NH:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC(COc2cccc(Cl)c2)OC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C1NCC(COc2cccc(Cl)c2)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
4 ml of trifluoroacetic acid were added, whilst ice-cooling, to a solution of 1.97 g of 5-(3-chlorophenoxymethyl)-3-t-butoxycarbonyloxazolidin-2-one (prepared as described in Preparation 2) in 4 ml of anhydrous tetrahydrofuran, and the mixture was stirred at room temperature for 1 hour. At the end of this time, the tetrahydrofuran and trifluoroacetic acid were removed from the reaction mixture by evaporation under reduced pressure, to give 1.23 g of the title compound having an Rf value of 0.43 (on silica gel thin layer chromatography, using ethyl acetate as the developing solvent).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([O:12][CH:13]([CH3:15])[CH3:14])[CH2:11][CH2:10]2)=[CH:5][C:4]=1CC)#[CH:2].[CH2:18]([O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1)[CH3:19].[CH2:30](N(CC)CC)[CH3:31]>[Cu]I.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>[CH:13]([O:12][C:9]1([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[C:2][C:25]3[CH:26]=[CH:27][C:22]([C:21]([O:20][CH2:18][CH3:19])=[O:29])=[CH:23][CH:24]=3)=[CH:8][C:7]=2[CH2:30][CH3:31])[CH2:10][CH2:11]1)([CH3:14])[CH3:15]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(C2(OC(C)C)CC2)cc1CC
Reactant: CCN(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OC(C)C)CC3)c(CC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
Using General Procedure F; 4-ethynyl-1-(1-isopropoxycyclopropyl)-3-ethyl-benzene (Intermediate 95, 108.0 mg, 0.47 mmol) and ethyl-4-iodo benzoate (Reagent A, 130.0 mg, 047 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (30.0 mg, 0.16 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (110 mg, 0.16 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc—hexanes) afforded 125.0 mg (71%) of the title compound as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:14])[CH2:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>CN(C)C=O.C(OCC)(=O)C>[CH2:23]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:14])[CH2:7][C:8]([CH3:12])([CH3:13])[O:9]2)=[CH:4][CH:3]=1)[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: CC1(C)CC(=O)c2ccc(O)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOc1ccc2c(c1)OC(C)(C)CC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
9.74 g of 7-hydroxy-2,2-dimethyl-4-oxochroman (CAS#: 17771-33-4) was dissolved in 150 ml of N,N-dimethylformamide. Thereafter, 10.5 g of potassium carbonate and 7.36 g of allyl bromide were added to the reaction solution, and the obtained mixture was stirred at room temperature overnight. Thereafter, the reaction solution was diluted with ethyl acetate, and then washed with water and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was then purified by silica gel column chromatography (hexane-ethyl acetate), so as to obtain 11.0 g of the subject compound.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C@@H:4]([OH:13])[CH2:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7].[CH3:21][C:22]([Si:25](Cl)([CH3:27])[CH3:26])([CH3:24])[CH3:23].N1C=CN=C1>CN(C=O)C.CCOC(C)=O>[NH2:2][C@@H:3]([CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[C@@H:4]([O:13][Si:25]([C:22]([CH3:24])([CH3:23])[CH3:21])([CH3:27])[CH3:26])[CH2:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCNC(=O)C[C@H](O)[C@@H](N)CC1CCCCC1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCNC(=O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](N)CC1CCCCC1
Yield: 78.5 %

Procedure:
A solution of the HCl salt of (3S,4S)-4-amino-N-butyl-5-cyclohexyl-3-hydroxypentanamide (279 mg, 1.03 mmol), TBSCl (311 mg, 2.06 mmol) and imidazole (281 mg, 4.12 mmol) in dry DMF (2 mL) was stirred at rt for 2 d. The mixture was diluted with EtOAc (90 mL), washed with 1:1 water/brine (3×20 mL), dried over Na2SO4 and concentrated to leave crude (3S,4S)-4-amino-N-butyl-3-(tertbutyldimethylsilyloxy)-5-cyclohexylpentanamide (311 mg, 78%) as a yellow syrup.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:19][NH2:20]>C(O)C>[C:1]1([C:7]2[NH:20][N:19]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: O=C(CC(=O)c1ccccn1)c1ccccc1
Solvent: O
Solvent: CCO
Product: c1ccc(-c2cc(-c3ccccn3)n[nH]2)cc1
Yield: 97.6 %

Procedure:
A 250 mL flask was charged with compound (1) (10 g 44 mmol), a magnetic follower and 150 mL of ethanol. Hydrazine monohydrate (2.15 mL, 44 mmol) was added and the mixture refluxed overnight. On cooling the ethanol was removed and the residue recrystallised from methanol to yield 2-(5-phenylpyrazol-3-yl)pyridine (2) as a pale yellow crystalline solid (9.5 g, 97%).