Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][C:18]([OH:26])([CH2:19]3)[CH2:17]1)[CH2:23]2)[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@H:27]12[CH2:32][C@H:31]1[CH2:30][C@@H:29]([C:33]([NH2:35])=[O:34])[NH:28]2.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:33]([C@@H:29]1[CH2:30][C@H:31]2[C@H:27]([CH2:32]2)[N:28]1[C:13](=[O:14])[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][C:18]([OH:26])([CH2:19]3)[CH2:17]1)[CH2:23]2)(=[O:34])[NH2:35]
Reactant: NC(=O)[C@@H]1C[C@@H]2C[C@@H]2N1
Reactant: O=C(N[C@H](C(=O)O)C12CC3CC(CC(O)(C3)C1)C2)OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)[C@@H](NC(=O)OCc1ccccc1)C12CC3CC(CC(O)(C3)C1)C2
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
(2S)-2-{[(Benzyloxy)carbonyl]amino}-2-(3-hydroxyadamantan-1-yl)acetic acid of Formula-XIV (20 gm), 1-ethyl-3-(3-dimethyl aminoporpyl)carbodiimide (13.8 gm), (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide of formula-III (14.8 gm) and 1-hydroxy benzotriazole (10.2 gm) were dissolved in N,N-dimethyl formamide (80 ml). The reaction mixture was cooled to about 20° C. Addition of N,N-diisopropylethylamine (15.8 gm) was then carried out for 15 min. The reaction mixture was stirred for 4 hrs and the solvent was distilled off. To the residue 2N HCl solution was added. Aqueous phase was extracted with ethyl acetate. Organic phase was washed with NaHCO3 solution, dried and evaporated to yield 23.3 gms (90%) of title product. MP: 105-106° C., H1NMR (300 MHz, CDCl3): 0.81 (dd, 1H), 0.96 (m, 1H), 1.46-1.82 (m, 12H), 1.93 (s, 1H), 2.2 (m, 3H), 2.45 (dd, 1H), 3.6 (m, 1H), 4.5-4.61 (dd, 1H), 4.76-4.86 (dd, 1H), 5.0 (s, 2H), 5.34 (d, 1H), 5.69 (s, 1H), 5.82-5.85 (dd, 1H), 6.83-6.89 (s, 1H), 7.31-7.35 (m, 5H).
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]#[CH:29])=[CH:24][C:23]=3[F:30])[C:15]3=[CH:16][N:17]=[CH:18][CH:19]=[C:14]3[CH:13]=2)=[O:11])[CH2:4][O:3]1.Cl>>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[CH:29])=[CH:24][C:23]=2[F:30])[C:15]2=[CH:16][N:17]=[CH:18][CH:19]=[C:14]2[CH:13]=1)=[O:11]
Reactant: C#Cc1ccc(Cn2c(C(=O)NOC[C@H]3COC(C)(C)O3)cc3ccncc32)c(F)c1
Agent: Cl
Product: C#Cc1ccc(Cn2c(C(=O)NOC[C@H](O)CO)cc3ccncc32)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 18.6 %

Procedure:
1-(4-Ethynyl-2-fluoro-benzyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide (30 mg, 0.07 mmol) was dissolved in 0.067 M methanolic HCl solution (3 ml, 0.20 mmol) and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo then azeotroped with toluene (2×15 ml) to give a solid residue. Purification of the solid residue by flash chromatography (NH2-SPE, dichloromethane, ethyl acetate, 20:80 methanol:dichloromethane, 5:35:60 triethylamine:methanol: dichloromethane) followed by trituration in acetonitrile afforded the product as a cream solid (5 mg, 18%). LCMS (Method A): RT=4.03 min, (M−H)−=382, M+H+=384. 1H NMR (CD3OD): 3.58 (1H, s), 3.60 (2H, m), 3.85 (1H, m), 3.91 (1H, dd, J=10.2, 6.8 Hz), 4.03 (1H, dd, J=10.2, 3.8 Hz), 5.97 (2H, s), 6.84 (1H, t, J=7.9 Hz), 7.11 (1H, s), 7.16 (1H, dd, J=7.9, 1.5 Hz), 7.21 (1H, dd, J=10.8, 1.5 Hz), 7.76 (1H, d, J=5.6 Hz), 8.22 (1H, d, br, J=5.6 Hz), 8.93 (1H, s).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:11]([N+:25]([O-])=O)[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[H][H]>CO.[Pd]>[NH2:25][C:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)CCCCCOc1ccc(-c2ccc(C#N)cc2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCCOc1ccc(-c2ccc(C#N)cc2)cc1N

Procedure:
Prepared from 4-cyano-4'-(5-methoxycarbonyl-pentyloxy)-3'-nitro-biphenyl by hydrogenating with hydrogen under 5 bars of pressure in methanol in the presence of 10% palladium/charcoal at ambient temperature.
Reaction SMILES: [CH2:1](OS(C)(=O)=O)[CH2:2][CH2:3][CH3:4].[N:10]1([C:16]2[C:17](=[O:34])[N:18]([CH2:22][CH2:23][O:24][C:25]3[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:26]=3[F:33])[CH:19]=[CH:20][N:21]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Cl.N1(C2C(=O)N(CCOC3C=C(F)C(F)=CC=3F)C=CN=2)CCNCC1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CCOC(C)=O.O>[F:33][C:26]1[CH:27]=[C:28]([F:32])[C:29]([F:31])=[CH:30][C:25]=1[O:24][CH2:23][CH2:22][N:18]1[CH:19]=[CH:20][N:21]=[C:16]([N:10]2[CH2:15][CH2:14][N:13]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:12][CH2:11]2)[C:17]1=[O:34]
Reactant: O=c1c(N2CCNCC2)nccn1CCOc1cc(F)c(F)cc1F
Reactant: CCCCOS(C)(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCCCN1CCN(c2nccn(CCOc3cc(F)c(F)cc3F)c2=O)CC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Methanesulfonic acid butyl ester (0.30 g, 1.97 mmol; from Step 1) was added to a mixture of 3-(1-piperazinyl)-1-[2-(2,4,5-trifluorophenoxy)ethyl]-2(1H)-pyrazinone (0.50 g, 1.4 mmol; from the free base of Example 3) and potassium carbonate (0.10 g, 2.89 mmol) in DMSO (3 g). After being stirred for 3 h at 60° C., water (50 g) and EtOAc (100 g) were added to the reaction mixture. The layers were separated and the organic layer was concentrated in vacuo. The residue was purified by chromatography on a MPLC column using a continuous gradient (0-100% EtOAc in heptane) as eluent. This furnished 33 mg (8%) of the title compound as an oil. 1H NMR analysis supports the stated structure. HPLC purity: 100%. HRMS m/z calcd for C20H25F3N4O2 (M)+ 410.1930, found 410.1920.
Reaction SMILES: CN(CN(C)C)C.C(Cl)(=O)C.[F:12][C:13]([F:31])([F:30])[C:14]1[CH:15]=[C:16]([CH:27]=[CH:28][CH:29]=1)[O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2.C[N:33]([CH2:35][C:36]1C2C(=CC=C(OC3C=CC=C(C(F)(F)F)C=3)C=2)NC=1)C.[C-]#N.[K+].CI>C(Cl)Cl.CN(C=O)C>[C:35]([CH2:36][C:21]1[C:20]2[C:24](=[CH:25][CH:26]=[C:18]([O:17][C:16]3[CH:27]=[CH:28][CH:29]=[C:14]([C:13]([F:12])([F:30])[F:31])[CH:15]=3)[CH:19]=2)[NH:23][CH:22]=1)#[N:33]
Reactant: FC(F)(F)c1cccc(Oc2ccc3[nH]ccc3c2)c1
Reactant: CN(C)Cc1c[nH]c2ccc(Oc3cccc(C(F)(F)F)c3)cc12
Agent: CN(C)CN(C)C
Agent: [C-]#N
Agent: [K+]
Solvent: CC(=O)Cl
Solvent: CI
Solvent: ClCCl
Product: N#CCc1c[nH]c2ccc(Oc3cccc(C(F)(F)F)c3)cc12
Yield: 0 %

Procedure:
Treatment of a cooled solution of N,N,N',N'-tetramethyldiaminomethane (0.26 g, 0.34 mL, 2.50 mmol) in CH2Cl2 (7.3 mL) with acetyl chloride (0.20 g, 0.18 mL, 2.53 mmol) followed by a solution of 5-(3-trifluoromethylphenoxy) indole (0.50 g, 1.79 mmol) in CH2Cl2 (6.2 mL), gave after work-up: 3-(N,N-dimethylaminomethyl)-5-(3-trifluoromethylphenoxy)indole as a gum. This was treated with finely ground potassium cyanide (0.45 g, 6.9 mmol) and methyl iodide (1.03 g, 0.45 mL, 7.26 mmol) in DMF (9 mL) for 16 hr, and after appropriate work-up and chromatography (silica gel; hexane/Et2O; 0-45%) 3-cyanomethyl-5-(3-trifluoromethylphenoxy)indole was obtained as an almost colourless gum, 0.415 g (73%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1.[H-].[Na+].Cl[CH2:25][C:26]1[O:27][CH:28]=[CH:29][CH:30]=1.C(OCC)(=O)C>O1CCCC1.CN(C)C=O>[O:27]1[CH:28]=[CH:29][CH:30]=[C:26]1[CH2:25][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1
Reactant: ClCc1ccco1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccco2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Combine (1H-benzimidazol-2-yl)-(1-ethoxycarbonyl-piperidin-4-yl)amine (1.5 g, 5.2 mmol) in tetrahydrofuran (45 mL) and dimethylformamide (5 mL). Cool in an ice-bath. Add sodium hydride (0.25 g, 60% n in oil, 6.24 mmol). After 90 minutes, add 2-(chloromethyl)furan (0.90 g, 7.8 mmol). Warm to ambient temperature. After 60 hours, quench by the addition of ice and then a saturated aqueous ammonium chloride solution. Evaporate to remove most of the tetrahydrofuran, dilute with ethyl acetate, and extract with a saturated aqueous sodium bicarbonate solution, water, and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give (1-(fur-2-ylmethyl)-1H-benzimidazol-2-yl)(1-(ethoxycarbonyl)piperidin-4-yl)amine: Rf=0.29 (silica gel, ethyl acetate).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10](I)=[CH:9][CH:8]=1)[CH3:6])=[O:4].[CH2:16]([OH:21])[CH2:17][CH2:18][C:19]#[CH:20]>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.[Cu]I>[F:1][C:2]([F:15])([F:14])[C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([C:20]#[C:19][CH2:18][CH2:17][CH2:16][OH:21])=[CH:9][CH:8]=1)[CH3:6])=[O:4]
Reactant: CN(C(=O)C(F)(F)F)c1ccc(I)cc1
Reactant: C#CCCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CN(C(=O)C(F)(F)F)c1ccc(C#CCCCO)cc1

Procedure:
Intermediate 33 (0.377 g, 1.147 mmol) in 10 mL of TEA was combined with PdCl2(PPh3)2 (0.02294 mmol, 0.016 g) the mixture was then degassed using N2 for 5 minutes. Then CuI (0.01147 mmol, 0.002 g) and Pent-4-yn-1-ol (1.147 mmol, 0.115 g) then reacted at 50° C. for 4 hours. The reaction was worked up quenching the reaction with 1× saturated NaHCO3, extracted 4×25 ml EtOAc then washed 1× water, 1× saturated NaCl, dried over Na2SO4, then concentrated. The product was purified 0-75% EtOAc in Hexanes over 20 min on silica. ES/MS calcd. for C14H14F3NO2 285.1. Found m/z=286 (M+H)+.
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:9]=[CH:10][C:11]([O:14]C)=[N:12][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CI.[C:18](=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:1][C:2]1([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[N:12]([CH3:18])[CH:13]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COc1ccc(C2(O)CCCCC2)cn1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: Cn1cc(C2(O)CCCCC2)ccc1=O
Yield: 81.9 %

Procedure:
A mixture of 5-(1-hydroxycyclohexyl)-2-methoxypyridine (17.1 g), methyl iodide (11.7 g) and potassium carbonate (22.8 g) was heated in 330 mL of refluxing acetonitrile for 18 hours. The mixture was cooled and filtered, and the solids were washed with methanol. The filtrate was concentrated to yield 14.0 g of powder, which was used in subsequent reactions without further purification.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[C:9]([O:11][CH:12](Cl)[CH3:13])=[O:10].[OH:15][C@@H:16]([C@H:18]1[C:38](=[O:39])[N:20]2[C:21]([C:35]([O-:37])=[O:36])=[C:22]([S:25]/[CH:26]=[CH:27]\[C:28]3[S:32][CH:31]=[N:30][C:29]=3[CH2:33][OH:34])[C@H:23]([CH3:24])[C@H:19]12)[CH3:17].[Na+]>>[OH:15][C@@H:16]([C@H:18]1[C:38](=[O:39])[N:20]2[C:21]([C:35]([O:37][CH:12]([O:11][C:9]([N:3]3[C@H:2]([CH3:1])[CH2:7][CH2:6][CH2:5][C@@H:4]3[CH3:8])=[O:10])[CH3:13])=[O:36])=[C:22]([S:25]/[CH:26]=[CH:27]\[C:28]3[S:32][CH:31]=[N:30][C:29]=3[CH2:33][OH:34])[C@H:23]([CH3:24])[C@H:19]12)[CH3:17]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: CC(Cl)OC(=O)N1[C@H](C)CCC[C@@H]1C
Agent: [Na+]
Product: CC(OC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12)OC(=O)N1[C@H](C)CCC[C@@H]1C
Yield: 17.3 %

Procedure:
In the same manner as in step b) in Example 125, 98 mg of the title compound was prepared from 283 mg of 1-[(cis-2,6-dimethylpiperidin-1-yl)carbonyloxy]ethyl chloride and 404 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.O.O[N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30]C=2N=N1.CN(C)CCCN=C=NCC.C1(CCN)CC1>ClCCl>[CH:28]1([CH2:27][CH2:26][NH:22][C:8]([C:5]2[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:10])[CH2:29][CH2:30]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc(Cl)nn1
Agent: CCN=C=NCCCN(C)C
Agent: NCCC1CC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCC1CC1)c1ccc(Cl)nn1
Reaction time: 0.25 h
Yield: 55.1 %

Procedure:
To a solution of 6-chloropyridazine-3-carboxylic acid (15.8 mmol) in dichloromethane (95 mL) was added diisopropylethylamine (46.7 mmol), 1-hydroxybenzotriazole monohydrate (23.7 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (23.7 mmol) under nitrogen atmosphere at ambient temperature. The resulting mixture was stirred for 15 minutes and 2-cyclopropylethylamine (20.2 mmol) was added. After stirring for 36 hours at ambient temperature, the reaction mixture was diluted with dichloromethane (100 mL), then washed with water and dried over anhydrous Na2SO4. The solvent was removed in vacuo. Purification via column chromatography (30% ethyl acetate in hexanes) afforded the title compound (8.70 mmol). Yield 55%.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:14]([O:16][CH3:17])=[O:15])[NH:9]2.[CH3:18]I>CCCCCC.CN(C=O)C>[CH3:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:14]([O:16][CH3:17])=[O:15])[N:9]2[CH3:18]
Reactant: COC(=O)c1cc2c(OC)cccc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(OC)cccc2n1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
NaH (60% dispersion in mineral oil, 0.3 g, 7.3 mmole) was washed with hexane then suspended in anhydrous DMF (16 mL). The mixture was cooled to 0° C. and methyl 4-methoxy-1H-indol-2-carboxylate (1.0 g, 4.87 mmole) was added. The mixture was stirred under argon for 10 min, then MeI (1.3 mL, 20 mmole) was added, and the thick slurry was stirred at RT for 2.5 hr. The reaction was quenched with 10% NH4Cl (2 mL) and concentrated. The residue was partitioned between H2O and Et2O, and the organic layer was dried over MgSO4 and concentrated to yield the title compound (1.03 g, 96%) as a white solid: MS (ES) m/e 220.2 (M+H)+.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:31]=[CH:30][C:11]2[C:12]([OH:29])=[CH:13][C:14]3[CH2:15][C:16]4[CH:17]=[C:18]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:19]=[CH:20][C:21]=4[C:22]=3[C:10]=2[CH:9]=1.[C:32](=[O:34])=[O:33].Cl>CCCCCC.C(OCC)C.C(OCC)(=O)C>[OH:29][C:12]1[C:11]2[CH:30]=[CH:31][C:8]([O:7][CH3:6])=[CH:9][C:10]=2[C:22]2[C:21]3[CH:20]=[CH:19][C:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:17][C:16]=3[CH:15]([C:32]([OH:34])=[O:33])[C:14]=2[CH:13]=1
Reactant: COc1ccc2c(O)cc3c(c2c1)-c1ccc(-c2ccccc2)cc1C3
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc2c(O)cc3c(c2c1)-c1ccc(-c2ccccc2)cc1C3C(=O)O
Temperature: 25 °C

Procedure:
A solution of n-butyl lithium (n-BuLi) (2.5M, 47.2 mL) in hexane was added into 500 mL two neck flask which contained 10.0 g of the product of Step 4 in diethyl ether (200 mL). The mixture was refluxed for five hours, cooled to room temperature, and poured rapidly onto crushed dry-ice. When the temperature of reaction mixture reached room temperature, ethyl acetate (150 mL) was added and the resulting mixture was acidified by concentrated hydrochloric acid. The organic layer was recovered and dried over sodium sulfate. After removing the solvent, 9.4 g of 5-hydroxy-2-methoxy-9-phenyl-7H-benzo[c]fluorene-7-carboxylic acid was obtained as a white solid. This step was repeated to produce additional product for the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6](O)=[O:7].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH2:6][OH:7]
Reactant: Cc1ccccc1OCC(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1ccccc1OCCO
Yield: 89 %

Procedure:
The title compound was prepared by the procedure of Preparation 2 in 89% yield from 2-(methylphenoxy) acetic acid and lithium aluminum hydride.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[CH2:15][C@@H:14]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][C@@:12]([O:39]C)([C@@H:24]2[CH2:28][S:27][C:26](=[O:29])[N:25]2CC2C=CC(OC)=CC=2)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C@]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@H]2C[C@@H](CCCC=CCCC(C)=CC(=O)O2)O1>>[C:1]([O:9][C@@H:10]1[CH2:15][C@@H:14]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:13][C@@:12]([OH:39])([C@@H:24]2[CH2:28][S:27][C:26](=[O:29])[NH:25]2)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H](OC(=O)c3ccccc3)C[C@@H](CCc3ccccc3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C\CC/C(C)=C\C(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCC(C)=CC(=O)O3)O2)cc1
Product: O=C1N[C@H]([C@@]2(O)C[C@H](OC(=O)c3ccccc3)C[C@@H](CCc3ccccc3)O2)CS1

Procedure:
Application of the method shown in Example 46, with the modification that (2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-phenethyl-tetrahydro-2H-pyran-4-yl benzoate is substituted for (R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, affords the title compound.
Reaction SMILES: [Na+].[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:16])[C:13]([O-:15])=[O:14])=[CH:8][CH:7]=1)[CH:3]([CH3:5])[CH3:4].[CH3:17][N:18]([CH2:20][CH2:21]Cl)[CH3:19]>C1C=CC=CC=1>[CH3:17][N:18]([CH2:20][CH2:21][O:14][C:13](=[O:15])[CH:12]([C:9]1[CH:8]=[CH:7][C:6]([CH2:2][CH:3]([CH3:5])[CH3:4])=[CH:11][CH:10]=1)[CH3:16])[CH3:19]
Reactant: CC(C)Cc1ccc(C(C)C(=O)[O-])cc1
Reactant: CN(C)CCCl
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C)Cc1ccc(C(C)C(=O)OCCN(C)C)cc1
Yield: 87.3 %

Procedure:
A mixture of 3.3 g of 2-(p-isobutylphenyl)propionic acid sodium salt, 2.3 g of dimethylaminoethyl chloride and 30 ml of benzene was refluxed for 12 hours. A solid mass produced was filtered off, and the benzene was distilled away from the filtrate under reduced pressure to leave an oily residue. This redidue was distilled under reduced pressure to give 3.5 g of 2-(p-isobutylphenyl)propionic acid dimethylaminoethyl ester as a colorless oil, boiling at 133°-136° C./1 mmHg. Analysis-Calculated for C17H27NO2 : C, 73.61; H, 9.81; N, 5.05. Found: C, 73.50; H, 9.72; N, 5.02. The infrared spectrum showed strong C=O absorption at 1730 cm-1 characteristic for ester. Mass spectrum: parent ion 277 m/e.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:15]=1[NH2:16]>>[OH:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=1[C:7]([NH:16][C:15]1[CH:17]=[C:18]([C:21]([F:23])([F:24])[F:22])[CH:19]=[CH:20][C:14]=1[O:13][CH3:12])=[O:9]
Reactant: COc1ccc(C(F)(F)F)cc1N
Reactant: Cc1ccc(O)c(C(=O)O)c1
Product: COc1ccc(C(F)(F)F)cc1NC(=O)c1cc(C)ccc1O
Yield: 77.9 %

Procedure:
Using 5-methylsalicylic acid and 2-methoxy-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][C:15]([CH:24]=O)=[CH:14]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CO.[CH3:28][NH2:29].[BH4-].[Na+].[ClH:32].C(=O)([O-])O.[Na+]>CO>[ClH:32].[CH3:28][NH:29][CH2:24][C:15]1[CH:16]=[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:13]([S:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)(=[O:12])=[O:11])[CH:14]=1
Reactant: CN
Reactant: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Reaction time: 0.5 h

Procedure:
1-[(3-Nitrophenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde (750 mg) was dissolved in methanol (50 mL), 40% methylamine methanol solution (1.64 g) was added at room temperature, and the mixture was stirred for 30 min. Sodium borohydride (240 mg) was added at room temperature, and the mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (100 mL) was added, and the mixture was stirred for 5 min. The reaction mixture was alkalized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to give a free base of the title compound as a crude product. A part (50 mg) of the obtained crude free base was dissolved in methanol (10 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound as colorless crystals (yield 43 mg, 5%).
Reaction SMILES: [C:1](Cl)(=O)C.[CH3:5][O:6][C:7](=[O:33])/[CH:8]=[CH:9]/[C:10]1[CH:11]=[C:12]2[C:29](=[CH:30][CH:31]=1)[O:28][C:15]1([CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23]C(C)(C)C)=O)[CH2:16]1)[CH2:14][C:13]2=[O:32]>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:33])/[CH:8]=[CH:9]/[C:10]1[CH:11]=[C:12]2[C:29](=[CH:30][CH:31]=1)[O:28][C:15]1([CH2:20][CH2:19][CH2:18][N:17]([C:21](=[O:23])[CH3:1])[CH2:16]1)[CH2:14][C:13]2=[O:32]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(=O)OC(C)(C)C)C1)O2
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(C)=O)C1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
Acetyl chloride (168 mg, 2.14 mmol) was added dropwise to a stirred solution of (±)-(E)-3-[4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester (Intermediate 2, 600 mg, 1.78 mmol) and TEA (0.742 ml, 5.33 mmol) in DCM (30 ml). The resulting mixture was stirred overnight at RT, then washed with 5% NaHCO3, brine and dried over Na2SO4. The crude mixture was purified by column chromatography (eluent: DCM/MeOH 99:1) to give (±)-(E)-3-[1′-acetyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester (609 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.C[C:23]1[CH:30]=[C:29](O)[CH:28]=[CH:27][C:24]=1[CH:25]=[O:26]>>[CH:25]([C:24]1[CH:27]=[CH:28][C:29]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)=[CH:30][CH:23]=1)=[O:26]
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: Cc1cc(O)ccc1C=O
Product: N#Cc1ccc(N(CCOc2ccc(C=O)cc2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1C from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and methyl 4-hydroxybenzaldehyde: 1H NMR (300 MHz, CDC3) δ 9.89 (s, 1H), 7.88-7.80 (m, 2H), 7.68 (d, J=8.9 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H), 7.02 (dd, J=8.8, 2.7 Hz, 1H, partially overlapped with 6.99-6.93), 6.99-6.93 (m, 2H), 4.31 (t, J=5.2 Hz, 2H), 4.20 (q, J=8.5 Hz, 2H), 4.05 (t, J=5.2 Hz, 2H).
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH:4][C:5]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]>CCOCC.C1COCC1>[OH:4][C:5]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH3:3])=[O:8]
Reactant: C=[N+]=[N-]
Reactant: Cc1ccc(C(=O)O)c(O)n1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)nc1O
Reaction time: 2 h

Procedure:
Excess diazomethane in ether was added portionwise over 15 mins to 9.58 g (~60 mmoles) of 2-hydroxy-6-methyl nicotinic acid in 900 mL of THF at 0°. After stirring 2 hours, excess diazomethane was removed in vacuo. The resulting white solid was filtered and washed with hexane and dried. This fluffy solid was the required methyl ester. The filtrate was concentrated. The resulting solid was redissolved in a minimum amount of THF and hexane was added until no further precipitation was observed. Solid was filtered and washed with hexane and dried to provide more of the desired compound.