Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26](Br)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].[CH3:37][C:38]1([CH3:45])[C:42]([CH3:44])([CH3:43])[O:41][BH:40][O:39]1>O1CCCC1.C(N(CC)CC)C.CC#N.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([B:40]3[O:41][C:42]([CH3:44])([CH3:43])[C:38]([CH3:45])([CH3:37])[O:39]3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1Br
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1B1OC(C)(C)C(C)(C)O1

Procedure:
A mixture of EXAMPLE 1D (1.2 g), 1.0 M 4,4,5,5-tetramethyl-1,3,2-dioxaborolane in tetrahydrofuran (4.24 mL), triethylamine (0.92 mL), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane (0.087 g) in CH3CN (15 mL) was heated at 100° C. in a Biotage Initiator microwave reactor for 30 minutes. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel to provide the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:17]([CH3:22])([CH3:21])[CH2:16][CH2:15][C:14]([CH3:24])([CH3:23])[C:13]=3[CH:12]=2)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[C:27](OC(=O)C)(=[O:29])[CH3:28].C(N(CC)CC)C.O>ClCCl>[C:27]([N:10]([C:11]1[CH:20]=[CH:19][C:18]2[C:17]([CH3:21])([CH3:22])[CH2:16][CH2:15][C:14]([CH3:24])([CH3:23])[C:13]=2[CH:12]=1)[CH2:9][C:8]1[CH:25]=[CH:26][C:5]([C:1]([O:3][CH3:4])=[O:2])=[CH:6][CH:7]=1)(=[O:29])[CH3:28]
Reactant: COC(=O)c1ccc(CNc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(CN(C(C)=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
4.2 g (12 mmol) of N-(4-carbomethoxybenzyl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine (from Example 11) and 1.6 ml (16 mmol) of acetic anhydride and 2.3 ml (17 mmol) of triethylamine in 100 ml of dichloromethane were stirred at room temperature. After the reaction was complete, the solution was poured into water and extracted with ethyl acetate, and the organic phase was separated off and evaporated; the residue was recrystallized from ethanol and yielded N-acetyl-N-(4-carbomethoxybenzyl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine. 2.5 g of this product and 5.0 g of potassium hydroxide in 90 ml of 5:3:1 ethanol/water/dimethyl sulfoxide were then refluxed for 1 hour and, after cooling, three times the volume of ice-water was added and the pH was adjusted to 4 with 2N hydrochloric acid. The precipitate was filtered off and dried, yielding 1.5 g of the title compound of melting point 219°-223° C.
Reaction SMILES: C(OC([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]([N:21]([C:25](=[O:27])[CH3:26])[CH:22]2[CH2:24][CH2:23]2)[CH2:13][CH:12]1[CH3:28])=O)C1C=CC=CC=1>CO.[Pd]>[CH:22]1([N:21]([CH:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:11][CH:12]([CH3:28])[CH2:13]2)[C:25](=[O:27])[CH3:26])[CH2:23][CH2:24]1
Reactant: CC(=O)N(C1CC1)C1CC(C)N(C(=O)OCc2ccccc2)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CC(=O)N(C1CC1)C1CC(C)Nc2ccccc21
Reaction time: 8 h

Procedure:
Benzyl-4-[acetyl(cyclopropyl)amino]-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate was dissolved in MeOH and a catalytic amount of Palladium on Carbon (10%) was added. The round bottom flask in which resided the resulting solution was evacuated and backfilled with hydrogen. The reaction was stirred under the hydrogen atmosphere overnight. The mixture was carefully filtered through a Celite® plug and concentrated to afford crude product. The crude residue was purified by silica gel chromatography (hexanes-ethyl acetate system) to afford N-cyclopropyl-N-(2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)acetamide.
Reaction SMILES: [CH:1]([C:3]1[C:7](Br)=[CH:6][S:5][CH:4]=1)=[O:2].C(N(CC)CC)C.[CH3:16][O:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[CH:27])=[CH:22][CH:21]=1>CN(C=O)C.[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>[CH3:16][O:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][C:7]2[C:3]([CH:1]=[O:2])=[CH:4][S:5][CH:6]=2)=[CH:22][CH:21]=1
Reactant: O=Cc1cscc1Br
Reactant: C#Cc1ccc(OCOC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCOc1ccc(C#Cc2cscc2C=O)cc1
Yield: 66.9 %

Procedure:
3-Formyl-4-bromothiophene (14.7 g) was dissolved in DMF (100 ml), followed by the addition of triethylamine (100 ml), CuI (0.25 g), Pd(PPh3)2Cl2 (0.5 g) and 4-methoxymethoxy-1-ethynylbenzene (11.4 g), and the mixture was reacted at 70° C. overnight. The reaction solution was filtered through Celite, poured into 1N hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate and brine, dried and evaporated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate system), to give 3-{[4-(methoxymethoxy)phenyl]ethynyl}-4-formylthiophene as a colorless oil (12.8 g, yield; 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:24]([C:28]1[N:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:31]=[C:30]([CH:39]=O)[CH:29]=1)[CH:25]([CH3:27])[CH3:26]>>[CH2:24]([C:28]1[N:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:31]=[C:30]([CH2:39][NH:21][CH2:20][CH2:19][N:16]2[CH2:15][CH2:14][N:13]([CH:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:23][CH:22]=3)[CH2:18][CH2:17]2)[CH:29]=1)[CH:25]([CH3:27])[CH3:26]
Reactant: NCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Reactant: CC(C)Cc1cc(C=O)nn1-c1ccccc1
Product: CC(C)Cc1cc(CNCCN2CCN(C(c3ccccc3)c3ccc(Cl)cc3)CC2)nn1-c1ccccc1
Yield: 95 %

Procedure:
Compound 96 was prepared using the same method as that of Example 1 except that 4-(4-chlorobenzhydryl)piperazin-1-ylethylamine and 5-iso-butyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(C)([O-])C.[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:9]1([NH:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Brc1ccccn1
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: c1ccc(Nc2ccccn2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
2-bromopyridine (3.0 g) and aniline (5.3 g) were dissolved in toluene (40 mL), tris(dibenzylideneacetone)dipalladium (0) (350 mg), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (480 mg) and sodium tert-butoxide (2.6 g) were added, then stirred at 80° C. for three hours. Ethyl acetate (100 mL) was added to the reaction solution, and then washed with water (100 mL). The organic layer was extracted with 2N hydrochloric acid (100 mL), and washed with ethyl acetate (100 mL). The water layer was made alkaline with 2N sodium hydroxide aqueous solution (150 mL) and then extracted with ethyl acetate (200 mL). The organic layer was washed with a saturated sodium chloride solution (50 mL). After drying on anhydrous sodium sulfate, filtration and vacuum concentration, the residue was washed with diethyl ether to give the above-identified compound (2.1 g, yield 72%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[CH:3]=1.[C:16]([C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH:13][C:27]([NH:26][C:23]3[CH:24]=[CH:25][C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:21][CH:22]=3)=[O:28])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: Nc1ccc(Oc2cc(Cl)ncn2)cc1
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(NC(=O)Nc2ccc(Oc3cc(Cl)ncn3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(6-chloro-pyrimidin-4-yl-oxy)-aniline (Stage 21.1; 3.77 g, 15 mmol) in THF (55 ml) under N2-atmosphere, 4-tertbutylphenyl isocyanate (5.26 g, 30 mmol) dissolved in THF (5 ml) is added. During stirring for 1 h at rt a suspension is formed. The mixture is then re-dissolved in AcOEt and a solution of NaHCO3 in water, the aqueous layer separated off and extracted twice with AcOEt. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated in vacuo. Stirring of the resulting solid in Et2O finally yields the title compound: m.p.: 111-112° C.; 1H-NMR (DMSO-d6): 8.75 (s, HN), 8.65 (s, 1H), 8.62 (s, HN), 7.51 (d, 2H), 7.36 (d, 2H), 7.33 (s, 1H), 7.31 (d, 2H), 7.17 (d, 2H), 1.27 (Me3C).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17])[NH:7]2.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:29][C:30]([NH2:32])=[O:31]>C(#N)C>[C:12]([C:11]1[C:3]([C:2]([F:1])([F:20])[F:21])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:29][C:30]([NH2:32])=[O:31])[C:6]([CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:5]2)#[N:13]
Reactant: NC(=O)CBr
Reactant: N#Cc1ccc2[nH]c(CCC(F)(F)F)cc2c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: N#Cc1ccc2c(cc(CCC(F)(F)F)n2CC(N)=O)c1C(F)(F)F
Yield: 51 %

Procedure:
To a solution of 4-(trifluoromethyl)-2-(3,3,3-trifluoropropyl)-1H-indole-5-carbonitrile (Example 302A) (0.200 g, 0.653 mmol) in anhydrous acetonitrile (50 mL) was added Cs2CO3 (0.851 g, 0.2.612 mmol) and 2-bromoacetamide (0.300 g, 1.37 mmol). The mixture was heated under N2, for 2 h. Upon cooling, the mixture was partitioned between EtOAc and water. The organic phase was separated, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-20% EtOAc-hexanes gradient) to afford a pure product (0.121 g, 51% yield): MS (ES) m/z 363 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:27]4[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[C:29]([O:30][CH3:31])[CH:28]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Reactant: COc1ccc(B(O)O)cc1OC
Product: COc1ccc(-c2ccc3oc(-c4ccc(OC)c([N+](=O)[O-])c4)nc3c2)cc1OC

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 3,4-dimethoxyphenylboronic acid (157 mg, 0.85 mmol) the subtitle compound was obtained (180 mg, 78%). 1H NMR (CDCl3) δ 8.74(d, 1H), 8.44(dd, 1H), 7.91(d, 1H), 7.62(d, 1H), 7.57(dd, 1H), 7.25(d, 1H), 7.19–7.14(m, 2H), 6.98(d, 1H), 4.07(s, 3H), 3.97(s, 3H), 3.94(s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH2:6][C:5](=[O:7])[N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C[O:42][C:43](=[O:56])[C@H:44]([OH:55])[C@H:45]([NH2:54])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[Cl:53].CCN(C(C)C)C(C)C.[OH-].[Na+]>CN(C=O)C.C1COCC1>[Cl:53][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[CH2:46][C@@H:45]([NH:54][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([N:4]2[C:5](=[O:7])[CH2:6][C:2]([CH3:1])=[N:3]2)=[CH:16][CH:15]=1)[C@@H:44]([OH:55])[C:43]([OH:56])=[O:42]
Reactant: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1
Reactant: COC(=O)[C@H](O)[C@H](N)Cc1ccccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1=NN(c2ccc(C(=O)N[C@H](Cc3ccccc3Cl)[C@@H](O)C(=O)O)cc2)C(=O)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.8 %

Procedure:
4-(3-Methyl-5-oxo-2-pyrazolin-1-yl)benzoic acid (42 mg, 0.2 mmol, 1.0 eq.) was combined with DMF (500 μL) and HATU (88 mg, 0.2 mmol, 1.2 eq.) and stirred at room temperature for 15 minutes. (2R,3R)-3-Amino-4-(2-chloro-phenyl)-2-hydroxy-butyric acid methyl ester (47 mg, 0.2 mmol, 1.0 eq.) in DIPEA (70 μL, 2.0 eq.) and DMF (500 μL) was then added and the resulting mixture was stirred overnight at room temperature. THF (500 μL) and 2 M aqueous NaOH (600 μL, 1 mmol) was added and the mixture was heated at 50° C. overnight. The solvent was removed and the product was dissolved in AcOH/H2O (50%) and purified by preparative HPLC to yield the title compound (58.3 mg, 56% purity). MS m/z [M+H]+ calc'd for C21H20ClN3O5, 430.11. found 430.0.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].N([O-])=O.[Na+].[I-:19].[K+]>Cl.O>[I:19][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: Nc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc(I)c(C(F)(F)F)c1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
4-Amino-3-trifluoromethyl benzoic acid (1.8 g, 8.8 mmol) is suspended in conc. HCl (30 mL). A solution of sodium nitrite (0.76 g, 11.0 mmol) in water (15 mL) is added dropwise at 0° C. The mixture is stirred at 0-10° C. for 30 min. A solution of potassium iodide (14.6 g, 88 mmol) in water (25 mL) is added dropwise. The mixture is stirred at room temperature for 1 h. The product is extracted with EtOAc (80 mL), washed with brine (80 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography using a gradient (EtOAc/Hexane) to afford the title compound (2.4 g, 86%) as a solid. LC-ES/MS m/e 339.3 (M+23), 315.0 (M−1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][NH:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=[CH:4][N:3]=1.[CH:28](=O)[CH3:29]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][N:12]([CH2:28][CH3:29])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(NCCCNCc1cccc(-c2ccnc(Cl)n2)c1)c1ccccc1
Reactant: CC=O
Product: CCN(CCCNC(=O)c1ccccc1)Cc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 43 was coupled with acetaldehyde following procedure E. LC-MS showed the product had the expected M+H+ of 409.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:11][CH2:12][CH:13]=O)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[F:15][C:16]1[CH:21]=[C:20]([N:22]2[CH2:26][CH2:25][C@H:24]([N:27]3[CH2:31][CH2:30][CH2:29][C@@H:28]3[CH3:32])[CH2:23]2)[CH:19]=[CH:18][C:17]=1[NH2:33].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH3:1][O:2][C:3]([C:5]1([CH2:11][CH2:12][CH2:13][NH:33][C:17]2[CH:18]=[CH:19][C:20]([N:22]3[CH2:26][CH2:25][C@H:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH3:32])[CH2:23]3)=[CH:21][C:16]=2[F:15])[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1(CCC=O)CCOCC1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc(N)c(F)c2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)C1(CCCNc2ccc(N3CC[C@H](N4CCC[C@@H]4C)C3)cc2F)CCOCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4-(3-Oxo-propyl)tetrahydro-pyran-4-carboxylic acid methyl ester (135 mg, 0.515 mmol, 1 eq) was dissolved in 2.4 mL of 1,2-dichloroethane. To this was added 2-Fluoro-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine (103 mg, 0.515 mmol, 1 eq) in 6.2 mL of 1,2-dichloroethane. To the combined mixture was added glacial acetic acid (96 mg, 1.6 mmol, 3.1 eq) followed by NaBH(OAc)3 (330 mg, 1.55 mmol, 3 eq). The reaction mixture was stirred at rt for 15 h. The reaction mixture was quenched with water, transferred to a separatory funnel and extracted with CH-2Cl2 (2×100 mL). The combined organics were dried over Na2SO4, concentrated under vacuum and purified by column chromatography on silica gel (40 g column, 6% MeOH in CH2Cl2; 35 mL/min). This gave 130 mg (61%) of the title compound as a beige semi-solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][CH:10]=O.[Cl-].[CH2:13]([O:20][C:21]1[CH:46]=[CH:45][CH:44]=[CH:43][C:22]=1[CH2:23][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N12CCCN=C1CCCCC2>>[CH2:13]([O:20][C:21]1[CH:46]=[CH:45][CH:44]=[CH:43][C:22]=1[CH:23]=[CH:10][CH:9]=[CH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=CC=Cc1ccccc1Cl
Reactant: c1ccc(COc2ccccc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Product: Clc1ccccc1C=CC=Cc1ccccc1OCc1ccccc1
Yield: 90 %

Procedure:
Then, following a procedure similar to that described in the first part of Preparation 3, the whole of this 3-(2-chlorophenyl)-2-propenal was reacted with 7.97 g of 2-benzyloxybenzyltriphenylphosphonium chloride (prepared as described in Preparation 1) and 3.35 g of 1,8-diazabicyclo[5,4,0]undec-7-ene. The resulting crude product was purified as described in the first part of Preparation 3, to give 4.57 g (yield 90%) of 1-(2-benzyloxyphenyl)-4-(2-chlorophenyl)butadiene as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[O:12][C:13]1[S:17][C:16]([CH2:18][NH2:19])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:23]1[C:32]2[C:27](=[CH:28][C:29]([C:33](O)=[O:34])=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>O1CCCC1.O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[O:12][C:13]1[S:17][C:16]([CH2:18][NH:19][C:33]([C:29]2[CH:28]=[C:27]3[C:32](=[CH:31][CH:30]=2)[N:23]=[CH:24][CH:25]=[CH:26]3)=[O:34])=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccc(Oc2cccc(OCc3ccccc3)c2)s1
Reactant: O=C(O)c1ccc2ncccc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Oc2cccc(OCc3ccccc3)c2)s1)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
To a solution of C-(5-(3-benzyloxy-phenoxy)-thiophen-2-yl)-methylamine described in Preparation Example 18 (180 mg, 0.578 mmol) and 6-quinolinecarboxylic acid (100 mg, 0.578 mmol) in tetrahydrofuran (5 mL) were added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (307 mg, 0.694 mmol) and triethylamine (0.16 mL, 1.16 mmol), and the solution was stirred overnight at room temperature. Ethyl acetate and water were added to the reaction solution, which was then partitioned, the organic layer was washed with water, and then, dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by NH silica gel column chromatography (hexane: ethyl acetate), and quinoline-6-carboxylic acid (5-(3-benzyloxy-phenoxy)-thiophen-2-ylmethyl)-amide (73 mg, 27%) was obtained as a pale yellow solid.
Reaction SMILES: [C:1]([CH:4]([CH2:10][C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].C([O-])(=O)C.[NH4+:23]>C(O)(=O)C>[CH3:2][C:1]1[NH:23][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2ccccc2)[nH]c1C
Temperature: 80 °C
Reaction time: 18 h
Yield: 45.1 %

Procedure:
Ethyl 2-acetyl-4-oxo-4-phenylbutanoate (3.0 g) and ammonium acetate (1.39 g) were added to acetic acid (20 mL), and the mixture was stirred at 80° C. for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→1:1) to give the title compound as a brown solid (yield 1.25 g, 45%).
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].[OH:7][C@@H:8]1[C@@:33]2([CH3:34])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:32]2[CH2:31][CH2:30][C@@:29]2([CH3:35])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:28])[CH2:21][CH2:22][C@@H:23]([OH:27])[CH:24]([CH3:26])[CH3:25])[CH2:11][C@@H:10]([OH:36])[CH2:9]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:3]([O:2][C:1]([O:7][C@@H:8]1[C@@:33]2([CH3:34])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:32]2[CH2:31][CH2:30][C@@:29]2([CH3:35])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:28])[CH2:21][CH2:22][C@@H:23]([O:27][C:1]([O:2][CH2:3][CH3:4])=[O:5])[CH:24]([CH3:26])[CH3:25])[CH2:11][C@@H:10]([O:36][C:1]([O:2][CH2:3][CH3:4])=[O:5])[CH2:9]1)=[O:5])[CH3:4]
Reactant: CCOC(=O)Cl
Reactant: CC(C)[C@H](O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CC[C@@H](OC(=O)OCC)C(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OCC)C1
Temperature: 0 °C

Procedure:
A ethyl chlorocarbonate (24.75 ml) was added dropwise to a solution of 1α,3β,24(R)-trihydroxycholest-5-ene (3.63 g), 4-dimethylaminopyridine (6.25 g) and methylenechloride (40 ml) with stirring at 0° C. After stirring for 27 hours at 60° C., the reaction mixture was poured into ice water and extracted with methylenechloride. The extracts were washed with 2 N hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to give 4.98 g of residual product. The residue was recrystallized from methanol (10 ml) to afford 3.64 g of 1α,3β,24(R)-triethoxycarbonyoxycholest-5-ene as crystals.
Reaction SMILES: [O:1]=[C:2]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH:10]([CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[O:9][CH2:8][CH2:7]3)[CH2:4][O:3]1.[F:27][C:28]1[C:29]([CH2:38][C:39](=[O:46])[N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:30][C:31]([O:36][CH3:37])=[C:32]([CH:35]=1)[C:33]#[N:34].N1(C2C=CC(CC(N3CCN(CC4C5C(=C6COC(=O)C6=CC=5)CCO4)CC3)=O)=CC=2)C=NN=N1>>[F:27][C:28]1[C:29]([CH2:38][C:39](=[O:46])[N:40]2[CH2:41][CH2:42][N:43]([CH2:15][CH:10]3[C:11]4[C:6](=[C:5]5[CH2:4][O:3][C:2](=[O:1])[C:14]5=[CH:13][CH:12]=4)[CH2:7][CH2:8][O:9]3)[CH2:44][CH2:45]2)=[CH:30][C:31]([O:36][CH3:37])=[C:32]([CH:35]=1)[C:33]#[N:34]
Reactant: Cc1ccc(S(=O)(=O)OCC2OCCc3c2ccc2c3COC2=O)cc1
Reactant: COc1cc(CC(=O)N2CCNCC2)c(F)cc1C#N
Agent: O=C1OCc2c1ccc1c2CCOC1CN1CCN(C(=O)Cc2ccc(-n3cnnn3)cc2)CC1
Product: COc1cc(CC(=O)N2CCN(CC3OCCc4c3ccc3c4COC3=O)CC2)c(F)cc1C#N

Procedure:
5-Fluoro-2-methoxy-4-(2-oxo-2-{4[(3-oxo-3,6,8,9-tetrahydro-1H-furo[3,4-f]isochromen-6-yl)methyl]piperazin-1-yl}ethyl)benzonitrile was prepared from (3-oxo-3,6,8,9-tetrahydro-1H-furo[3,4-f]isochromen-6-yl)methyl4-methylbenzenesulfonate and 5-fluoro-2-methoxy-4-[2-oxo-2-(piperazin-1-yl)ethyl]benzonitrile in an analogous fashion to that described above for the synthesis of 6-[(4-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazin-1-yl)methyl]-8,9-dihydro-1H-furo[3,4-f]isochromen-3(6H)-one. MS m/e 480 (M+1)+.