Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:33]2[C:28](=[CH:29][C:30]([C:43](O)=[O:44])=[CH:31][CH:32]=2)[N:27]=1.C(N(CC)C(C)C)(C)C.[CH:55]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:58]=[CH:57][C:56]=1[C@H:65]([NH2:67])[CH3:66]>CN(C)C=O>[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:33]2[C:28](=[CH:29][C:30]([C:43]([NH:67][C@@H:65]([C:56]3[CH:57]=[CH:58][C:59]4[C:64](=[CH:63][CH:62]=[CH:61][CH:60]=4)[CH:55]=3)[CH3:66])=[O:44])=[CH:31][CH:32]=2)[N:27]=1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Reactant: C[C@@H](N)c1ccc2ccccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1ccc2c(N3CCN(C)CC3)nc(N)nc2c1)c1ccc2ccccc2c1
Reaction time: 0.17 h
Yield: 48.6 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (40 mg, 0.1 mmol) was added to a solution of 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (20 mg, 0.07 mmol) in N,N-dimethylformamide (1 mL) and N,N-diisopropylethylamine (24 μL, 0.14 mmol). The reaction mixture was stirred for 10 minutes, and then (1R)-1-(2-naphthyl)ethanamine (24 mg, 0.14 mmol) was added. The crude reaction mixture stirred for 18 h. at r.t. and then was purified on RP-HPLC (pH=2) to afford the title product (15 mg, 27%) as a TFA salt as an off white amorphous solid. 1H NMR (300 MHz, DMSO): δ 1.52 (d, 3H), 2.82 (s, 3H), 3.22 (m, 2H), 3.65 (m, 4H), 4.65 (m, 2H), 5.32 (m, 1H), 7.44 (m, 2H), 7.54 (dd, 1H), 7.76-7.86 (m, 5H), 7.92 (d, 1H), 8.02 (d, 1H); Analytic LCMS (M+H)+: m/z=441.2.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[OH:15])[CH:7]=[CH:8][C:9]([OH:11])=[O:10])[CH:2]=[CH2:3].[C:16](OC(=O)C)(=[O:18])[CH3:17]>[OH-].[Na+]>[CH2:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[CH:7]=[CH:8][C:9]([OH:11])=[O:10])[CH:2]=[CH2:3]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCc1cc(C=CC(=O)O)ccc1O
Agent: [Na+]
Agent: [OH-]
Product: C=CCc1cc(C=CC(=O)O)ccc1OC(C)=O
Temperature: 0 °C

Procedure:
118 g (0.058 mol) of 3-allyl-4-hydroxy-cinnamic acid are dissolved in 580 ml of 2 N sodium hydroxide solution, 800 g of ice are added and 120 g (1.16 mols) of acetic anhydride are introduced dropwise over the course of 15 minutes at 0°-5°C, whilst stirring. The crystals which have precipitated are then separated off, suction-dried and recrystallised from ethyl acetate. 3-Allyl-4-acetoxy-cinnamic acid of melting point 143°-144°C is thus obtained.
Reaction SMILES: [CH:1]([N:4]([CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:6])([CH3:3])[CH3:2].Br[CH2:22]CCCC=C>>[CH2:16]([N:4]([CH:1]([CH3:2])[CH3:3])[C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:6])[CH2:17][CH2:18][CH2:19][CH:20]=[CH2:22]
Reactant: C=CCCCN(C(=O)N[C@H](C(=O)O)C(C)(C)C)C(C)C
Reactant: C=CCCCCBr
Product: C=CCCCCN(C(=O)N[C@H](C(=O)O)C(C)(C)C)C(C)C

Procedure:
N-{[Hex-5-en-1-yl(isopropyl)amino]carbonyl}-3-methyl-L-valine was prepared according to the procedure described for N-{[isopropyl(pent-4-en-1-yl)amino]carbonyl}-3-methyl-L-valine by using 6-bromo-1-hexene in Step 1. LRMS (ESI) m/z 299 [(M+H)+; calcd for C16H31N2O3: 299.2].
Reaction SMILES: [CH3:1][N:2]1[C@@H:7]2[CH2:8][C:9]([CH2:11][C@H:3]1[CH2:4][CH2:5][CH2:6]2)=O.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[CH3:1][N:2]1[CH:3]2[CH2:4][CH2:5][CH2:6][CH:7]1[CH2:8][C:9]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[CH:11]2
Reactant: C1CCNC1
Reactant: CN1[C@@H]2CCC[C@H]1CC(=O)C2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CN1C2C=C(N3CCCC3)CC1CCC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.9 %

Procedure:
To pseudo-pelletierine (1.5 g, 9.8 mmol) in toluene (75 mL) was added pyrrolidine (4.9 mL, 58.75 mmol). TiCl4 (0.66 mL, 6.0 mmol) in toluene (10 mL) was then added to the mixture at −5° C. The reaction mixture was left to warm up to rt and stirred for 2 days. The mixture was filtered and the filtrate was concentrated to a residue and toluene (100 mL) was added and the mixture was filtered again. The filtrate was concentrated to a residue to afford the product (2.0 g, 100%) as yellow oil.
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH:9][C:10]1([C:16]([NH:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH:20]2[OH:25])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:8].[CH3:26][S:27]([C:30]1(F)[CH:35]=[CH:34][CH:33]=[CH:32][CH2:31]1)(=[O:29])=[O:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH:9][C:10]1([C:16]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[S:27]([CH3:26])(=[O:29])=[O:28])[CH2:21][CH:20]2[OH:25])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:8]
Reactant: O=C(NC1(C(=O)NC2CCNCC2O)CCCCC1)c1ccco1
Reactant: CS(=O)(=O)C1(F)C=CC=CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccccc1N1CCC(NC(=O)C2(NC(=O)c3ccco3)CCCCC2)C(O)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
To the solution of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride (600 mg, 1.55 mmol) obtained in Step 4 and 1-flourophenyl methyl sulfone (272 g, 1.55 mmol) in 30 ml of dimethylformamide, was added potassium carbonate (500 mg). The reaction mixture was stirred overnight at about 100° C. and cooled to room temperature. The reaction mixture was diluted with 200 ml of ethyl acetate and washed with brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 390 mg of the titled compound as white solid.
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:9]=[CH:8][NH:7][N:6]=1)[CH2:2][CH3:3].[H-].[Na+].[CH2:12]([N:15]([CH2:19][CH2:20][CH3:21])[C:16](Cl)=[O:17])[CH2:13][CH3:14]>O1CCCC1>[CH2:12]([N:15]([CH2:19][CH2:20][CH3:21])[C:16]([N:7]1[CH:8]=[N:9][C:5]([S:4][CH2:1][CH2:2][CH3:3])=[N:6]1)=[O:17])[CH2:13][CH3:14]
Reactant: CCCSc1nc[nH]n1
Reactant: CCCN(CCC)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCSc1ncn(C(=O)N(CCC)CCC)n1
Reaction time: 1 h

Procedure:
A solution of 35.75 g. 3-propylthio-1,2,4-triazole in 150 ml. dry tetrahydrofuran was added dropwise to a stirred suspension of sodium hydride in mineral oil (14.4 g. of 50% suspension; 7.2 g. sodium hydride). The resulting mixture was refluxed with stirring for 1 hour. Heating was discontinued, and 40.9 g. dipropylcarbamoyl chloride was added dropwise to the stirred mixture, causing the evolution of heat with consequent refluxing. The reaction mixture was refluxed with stirring overnight, cooled, and filtered to remove sodium chloride formed in the reaction. The filtrate was distilled under reduced pressure to remove solvent, and the residual oil was dissolved in methylene dichloride. The resulting solution was washed successively with 0.5N sodium hydroxide solution, water, and finally 0.5N hydrochloric acid. The washed solution was distilled under reduced pressure to give 1-dipropylcarbamoyl-3-propylthio-1,2,4-triazole, b.p. 128° - 120° C./0.1 mm. Elemental analysis satisfactory.
Reaction SMILES: [OH:1][C@H:2]1[C@H:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])[C:10]2[CH:9]=[CH:8][N:7]3[C:17]([CH3:21])=[C:18]([CH3:20])[N:19]=[C:6]3[C:5]=2[NH:4][C@@H:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[H-].[Na+].[CH3:30][O:31][C:32](Cl)=[O:33].Cl>O1CCCC1>[CH3:30][O:31][C:32]([O:1][C@H:2]1[C@H:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])[C:10]2[CH:9]=[CH:8][N:7]3[C:17]([CH3:21])=[C:18]([CH3:20])[N:19]=[C:6]3[C:5]=2[NH:4][C@@H:3]1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:33]
Reactant: COC(=O)Cl
Reactant: COCCO[C@@H]1c2ccn3c(C)c(C)nc3c2N[C@H](c2ccccc2)[C@H]1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCO[C@@H]1c2ccn3c(C)c(C)nc3c2N[C@H](c2ccccc2)[C@H]1OC(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
A suspension of 2 g of (7R,8R,9R)-8-hydroxy-7-(2-methoxyethoxy)-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine in 30 ml of dry tetrahydrofuran is treated in small portions with 0.34 g of sodium hydride suspension (80% strength in paraffin) and stirred at room temperature for 30 minutes, then 0.66 g of methylchloroformate is added dropwise and the mixture is stirred for 3 h. It is then poured onto ice water, neutralized with semiconcentrated aqueous hydrochloric acid and extracted three times with a little ethyl acetate, and the collected organic phases are washed with a little water and dried over potassium carbonate. The volatile components are stripped off in vacuo and the solid residue is purified on silica gel (eluent: diethyl ether). 1.2 g of the title compound of melting point 176–77° C. (diethyl ether) are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]2[N:11]([CH:12]=[C:13]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:22][CH:21]=3)[C:14]=2[CH2:18][CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][C:35](=[O:38])[C:36]#[CH:37].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[C:35]([C:36]1[CH:37]=[C:12]2[N:11]3[C:15](=[CH:16][CH:17]=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:10]=13)[C:14]([CH2:18][CH3:19])=[C:13]2[C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:25]=1)(=[O:38])[CH3:34]
Reactant: C#CC(C)=O
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)cn2cc(OCc3ccccc3)ccc12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2cc(C(C)=O)c3c(OCc4ccccc4)ccc1n23
Yield: 38 %

Procedure:
6-Benzyloxy-2-(4-benzyloxyphenyl)-1-ehtylindolizine, prepared in example 23, step 5, (2.17 g, 5.0 mmol) was dissolved in 100 ml of dry toluene under a nitrogen atmosphere, and the mixture was stirred in an ice bath, while 3-butyn-2-one (0.34 ml, 5.75 mmol) was added dropwise. The cooling source was removed and stirring was continued for twenty hours. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (0.57 g, 0.25 mmol) was added in portions and stirring was continued for 11/2 hour. The solvent was evaporated and the crude product was purified by column chromatography over silica gel 60, using 20% of ethyl acetate in petroleum ether as the eluent. Fractions containing the product were colleted and the solvent was evaporated. The crude product was and crystallized from diethyl ether to afford 0.955 g (38%) of 4-acetyl-5-benzyloxy-2-(4-benzyloxyphenyl)-1-ethylpyrrolo[2,1,5-cd]indolizine as crystals. MS(SP): m/z 499 (M+). 1H-NMR (CDCl3, 400 MHz) δ: 1.44 (t, 3H); 2.79 (s, 3H); 3.15 (q, 2H); 5.15 (s, 2H); 5.44 (s, 2H); 7.15 (d, 2H); 7.32-7.46 (m, 7H); 7.50 (d, 2H); 7.60 (d, 2H); 7.67-7.74 (m, 3H); 7.94 (s, 1H).
Reaction SMILES: Br[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH2:13][CH3:14])[CH:5]=1)=[CH2:3].[Li]C(C)(C)C.[CH:20]([CH:22]=[CH2:23])=[O:21]>>[CH2:13]([O:12][C:6]1[CH:5]=[C:4]([CH:2]=[CH:3][CH:20]([OH:21])[CH:22]=[CH2:23])[CH:9]=[CH:8][C:7]=1[O:10][CH3:11])[CH3:14]
Reactant: C=C(Br)c1ccc(OC)c(OCC)c1
Reactant: C=CC=O
Agent: [Li]C(C)(C)C
Product: C=CC(O)C=Cc1ccc(OC)c(OCC)c1
Yield: 86.2 %

Procedure:
According to the General Procedure C, 1-Bromo-1-(3-ethoxy-4-methoxyphenyl)ethene (1.40 g, 5.44 mmol), t-BuLi (8.00 ml, 13.60 mmol) and acrolein (914 mg, 16.32 mmol) are converted to give after workup and chromatography [SiO2, PE/EE gradient from 5:1 to 2:1, Rf (PE/EE=2:1)=0.31] the title compound (1.10 g, 4.69 mmol) as a colorless oil;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br[CH:25]([CH2:29]Br)[C:26]([NH2:28])=[O:27]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:10][CH2:11][N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=3)[CH:25]([C:26]([NH2:28])=[O:27])[CH2:29]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NC(=O)C(Br)CBr
Reactant: COc1ccc(CNCCNc2cc(Cl)cc(Cl)c2)cc1OC
Product: COc1ccc(CN2CCN(c3cc(Cl)cc(Cl)c3)CC2C(N)=O)cc1OC

Procedure:
In a manner similar to Preparation 1, react N-(3,5-dichlorophenyl)-N'-[(3,4-dimethoxyphenyl)methyl]-1,2-ethanediamine with 2,3-dibromopropanamide to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[N:4]=[C:3]1[NH2:12].C([O-])(O)=O.[Na+].[Cl:18][C:19]1[N:24]=[C:23](Cl)[CH:22]=[CH:21][N:20]=1>C1COCC1.C(O)C>[Cl:18][C:19]1[N:24]=[C:23]([NH:11][C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH2:12])=[N:4][C:5]=3[CH:10]=2)[CH:22]=[CH:21][N:20]=1
Reactant: Cn1c(N)nc2cc(N)ccc21
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1c(N)nc2cc(Nc3ccnc(Cl)n3)ccc21
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of 1-Methyl-1H-benzoimidazole-2,5-diamine (0.63 g, 3.89 mmol) in THF (4 ml) and ethanol (12 ml) was added NaHCO3 (0.98 g, 11.67 mmol) and 2,4-dichloropyrimidine (1.45 g, 9.7 mmol) and the reaction was heated to 80° C. After 5 h, the reaction was filtered hot and concentrated to a gray foam. Ether was added and the solid was filtered and dried to give N5-(2-Chloro-pyrimidin-4-yl)-1-methyl-1H-benzoimidazole-2,5-diamine as an red solid. MS (ESI) m/z=275 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].Br[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1>C(O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: Oc1cccc(I)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Ic1cccc(OCc2ccc3ccccc3c2)c1

Procedure:
To a solution of 3-iodophenol (4.0 g, 18 mmol) in ethanol (40 mL) is added potassium hydroxide (1.0 g, 18 mmol) and 2-(bromomethyl) naphthalene (4.0 g, 18 mmol) and this mixture is refluxed overnight. The hot reaction is filtered and the filtrate is chilled in ice. The ensuing precipitate is collected by filtration to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.84-7.89 (m, 4H), 7.48-7.53 (m, 3H), 7.40 (d, 1H), 7.29-7.32 (m, 1H), 6.95-7.04 (m, 2H), 5.20 (s, 2H); MS (EI) 360 (M)+.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[C:6]1([CH2:12][N:13]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:15]([O:26][CH3:27])[CH2:14]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl.[OH-].[Na+]>[C:20]1([N:19]([C@H:16]2[CH2:17][CH2:18][N:13]([CH2:12][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:14][C@H:15]2[O:26][CH3:27])[C:1](=[O:4])[CH2:2][CH3:3])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCC(=O)Cl
Reactant: CO[C@@H]1CN(Cc2ccccc2)CC[C@@H]1Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCC(=O)N(c1ccccc1)[C@H]1CCN(Cc2ccccc2)C[C@H]1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
Propionyl chloride (0.77g, 8.3 mmol) was added to cis-1-phenylmethyl-3-methoxy-4-phenylaminopiperidine (7b, 1.6g, 5.3 mmol) from Example 4 in 30ml of dichloromethane. The reaction solution was stirred at room temperature overnight and subsequently diluted with 20ml of 10% sodium hydroxide solution. The organic layer was separated and the aqueous layer was extracted with 2×50ml of dichloromethane. The combined organic layers were dried and concentrated under vacuum to yield 1.84g (99%) of crude cis-N-phenyl-N-(1-phenylmethyl-3-methoxy-4-piperidinyl) propanamide (I).
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][N:9]=[CH:10]2.[OH-].[Na+]>C(O)(=O)C>[CH:10]1[C:11]2[C:6](=[C:5]([CH2:4][C:3]([OH:15])=[O:2])[CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:8][N:9]=1
Reactant: COC(=O)Cc1cccc2cnccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C(O)Cc1cccc2cnccc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
Isoquinolin-5-yl-acetic acid methyl ester (Preparation 6, Step 3; 90 mg, 0.448 mmol) was treated with aqueous sodium hydroxide (4N, 3 mL) and the solution was heated at 50° C. for 4 h. The solution was cooled to 0° C. and acetic acid (2 mL) was added dropwise, which resulted in the formation of a precipitate. The mixture was kept at 0° C. overnight (ca. 15 h) and the precipitate was removed via filtration and was washed with water. The solid was dried in air to afford 35 mg (47% yield) of isoquinolin-5-yl-acetic acid; 1H NMR (400 MHz, CD3OD) δ9.24 (s, 1H), 8.47 (d, J=6.2 Hz, 1H), 8.04 (d, J=7.9 Hz, 1H), 7.96 (d, J=6.2 Hz, 1H), 7.74 (d, J=6.6 Hz, 1H), 7.66 (t, J=7.6 Hz, 1H), 4.11 (s, 2H); MS (AP/Cl): 188.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22].Cl>CN(C)C=O.C(OCC)(=O)C>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]([O:1][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: CC(C)=CCBr
Reactant: COc1ccc(O)c(C=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(OCC=C(C)C)c(C=O)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2-hydroxy-5-methoxybenzaldehyde (7.6 g, 50 mmol) in dry N,N-dimethylformamide (100 mL) was added potassium carbonate (10.4 g), followed by 1-bromo-3-methylbut-2-ene (10.0 g, 67 mmol). The mixture was stirred at room temperature for 48 hours and ethyl acetate added. Sufficient 1M hydrochloric acid was cautiously added to neutralize the base, and the organic layer washed with water three times, followed by brine, and dried over magnesium sulfate. The mixture was filtered, and solvent removed from the filtrate under reduced pressure, to provide 5-methoxy-2-(3-methylbut-2-enyloxy)benzaldehyde.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C([O:23][C:24]1[C:25](=[O:56])[C:26](=O)[C:27]=1[NH:28][C:29]1[CH:30]=[N:31][N:32]([CH3:54])[C:33]=1[NH:34][C:35]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)C.C(N(CC)CC)C>C(O)C>[CH3:54][N:32]1[C:33]([NH:34][C:35]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:29]([NH:28][C:27]2[C:24](=[O:23])[C:25](=[O:56])[C:26]=2[NH:1][CH:2]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:30]=[N:31]1
Reactant: CCOc1c(Nc2cnn(C)c2NC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)c1=O
Reactant: CC(C)(C)OC(=O)NCC(N)CNC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cn1ncc(Nc2c(NC(CNC(=O)OC(C)(C)C)CNC(=O)OC(C)(C)C)c(=O)c2=O)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 84.5 %

Procedure:
To a suspension of di-tert-butyl (2-amino-1,3-propanediyl)biscarbamate (810 mg) and 3-ethoxy-4-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-3-cyclobutene-1,2-dione (957 mg) in ethanol (10 ml) was added triethylamine (0.279 ml), and the mixture was stirred under reflux for 1 day. The reaction mixture was concentrated to about 5 ml in vacuo. To the concentrate was added diisopropyl ether. The precipitated crystals were collected by filtration and dried in vacuo to give di-tert-butyl {2-[(2-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-3,4-dioxocyclobut-1-en-1-yl)amino]-1,3-propanediyl}biscarbamate (1.22 g) as a solid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([Mg]Cl)(C)C.[CH2:26]([O:28][C:29]1[C:36]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:35][CH:34]=[CH:33][C:30]=1[CH:31]=[O:32])[CH3:27].O>O1CCCC1>[CH2:38]([O:37][C:36]1[C:29]([O:28][CH2:26][CH3:27])=[C:30]([CH:31]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=2)[OH:32])[CH:33]=[CH:34][CH:35]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Reactant: CCOc1c(C=O)cccc1OCc1ccccc1
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: CCOc1c(OCc2ccccc2)cccc1C(O)c1cn([Si](C(C)C)(C(C)C)C(C)C)c2ncccc12
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 13.9 %

Procedure:
To a solution of 3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (635, 1.306 g, 3.26 mmol) in tetrahydrofuran (42 mL) at −20° C. under nitrogen was added isopropylmagnesium chloride (1.70 mL, 2.0 M solution in tetrahydrofuran, 3.40 mmol). The reaction mixture was stirred at −20° C. for 1.5 hours. It was allowed to warm to 5° C. and then kept at 5° C. for 1 hour. The reaction mixture was then cooled down to −20° C. To this solution was slowly added a solution of 2-ethoxy-3-benzyloxybenzaldehyde (663, 0.698 g, 2.72 mmol, prepared by protocol of Example 43, Steps 1-3 of Scheme 71, using benzyl bromide in place of 4-chloro-benzyl bromide in Step 1) in tetrahydrofuran (42 mL). The reaction mixture was stirred at −20° C. for 2.5 hrs, and was allowed to warm to 5° C. for 2.5 hours. The reaction mixture was poured into iced water, extracted with ethyl acetate, washed with saturated ammonium chloride and brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as light-yellow oil (664, 200 mg, 13.9%).
Reaction SMILES: S(O[CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.BrCC1CCCCO1.[F:34][C:35]1[C:36]([F:53])=[CH:37][C:38]2[O:52][CH2:51][C:41]3([C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[NH:43][C:42]3=[O:50])[C:39]=2[CH:40]=1>>[F:34][C:35]1[C:36]([F:53])=[CH:37][C:38]2[O:52][CH2:51][C:41]3([C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[N:43]([CH2:12][CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:17][CH2:18]4)[C:42]3=[O:50])[C:39]=2[CH:40]=1
Reactant: O=C1Nc2ccccc2C12COc1cc(F)c(F)cc12
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: BrCC1CCCCO1
Product: CC(C)(C)OC(=O)N1CCC(CN2C(=O)C3(COc4cc(F)c(F)cc43)c3ccccc32)CC1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using tert-butyl 4-(tosyloxymethyl)piperidine-1-carboxylate to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3-indol]-2″(1H)-one, tert-butyl 4-[(5,6-difluoro-2′-oxospiro[1-benzofuran-3,3-indol]-1′(2′H)-yl)methyl]piperidine-1-carboxylate was obtained (57%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.34 (ddd, J=9.0, 7.6, 1.5 Hz, 1H), 7.16-7.06 (m, 2H), 6.92 (d, J=7.8 Hz, 1H), 6.78 (dd, J=10.3, 6.3 Hz, 1H), 6.49 (dd, J=10.3, 6.3 Hz, 1H), 4.95 (d, J=9.0 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 4.13 (br s, 2H), 3.74-3.56 (m, 2H), 2.69 (t, J=12.4 Hz, 2H), 2.07-1.96 (m, 1H), 1.68-1.63 (m, 2H), 1.45 (s, 9H), 1.32-1.26 (m, 2H); MS (ES+) m/z 493.3 (M+23).
Reaction SMILES: CC1(C)O[O:3]1.[CH2:6]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CC(C)=O>[CH2:14]([N:13]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:3])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CC1(C)OO1
Solvent: CC(C)=O
Product: ON(Cc1ccccc1)Cc1ccccc1
Yield: 98 %

Procedure:
A solution of 0.051 M dimethyldioxirane in acetone (32.9 ml, 1.67 mmol) was added to a cold stirred solution of N,N-dibenzylamine (Aldrich; 0.331 g, 1.67 mmol) in acetone (5 ml). The mixture was stirred for fifteen minutes in an ice bath. Evaporation of the solvent on the rotary evaporator gave a white crystalline solid. The solid was dissolved in acetone and the solution dried with anhydrous Na2SO4. The solvent was removed to give a chromatographically homogeneous white solid (0.352 g, 98% yield). Measured mp was 121-122; reported mp is 122-123 (DeLaMare et al 1963).