Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][C:19]([C@@H:22]([NH2:24])[CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)[CH3:2].[CH2:25]1[CH2:35][CH2:34][N:33]2[C:28](=NCC[CH2:32]2)CC1.C1(NC)CC1.[O:41]1CCOCC1>>[CH:34]1([N:33]([CH3:28])[C:32]([NH:24][C@H:22]([C:19]2[CH:18]=[CH:17][C:16]([CH:13]3[CH2:12][CH2:11][N:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][CH:8]=4)[CH2:15][CH2:14]3)=[CH:21][CH:20]=2)[CH3:23])=[O:41])[CH2:25][CH2:35]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCOc1ccc(N2CCC(c3ccc([C@H](C)N)cc3)CC2)cc1
Reactant: C1COCCO1
Agent: CNC1CC1
Product: CCOc1ccc(N2CCC(c3ccc([C@H](C)NC(=O)N(C)C4CC4)cc3)CC2)cc1
Reaction time: 0.08 h

Procedure:
To 32.5 mg (0.10 mmol) (S)-1-{4-[1-(4-ethoxy-phenyl)-piperidin-4-yl]-phenyl}-ethylamine (XIII.1) in 1.5 mL dioxane, 30 μL (0.20 mmol) DBU and 33 mg (0.20 mmol) CDT are added at rt and the mixture is stirred for 5 min. Subsequently 8.5 mg (0.15 mmol cyclopropyl-methyl-amine are added and stirring is continued over night. The mixture is concentrated in vacuo. The residue is purified using reversed phase column chromatography (water+0.1% TFA:MeOH) and the corresponding fractions are concentrated to yield the desired product.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:23]([O:27][CH2:28][CH3:29])(=[O:26])[CH:24]=[CH2:25].Br[C:31]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:32]=1[CH2:33][C@H:34]([CH2:53][O:54][Si:55]([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56])[N:35]([C:42](=[O:52])[CH2:43][C:44]1[C:49]([Cl:50])=[CH:48][CH:47]=[CH:46][C:45]=1[Cl:51])[C@H:36]2[CH3:41].C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[Si:55]([O:54][CH2:53][C@H:34]1[CH2:33][C:32]2[C:37](=[CH:38][CH:39]=[CH:40][C:31]=2/[CH:25]=[CH:24]/[C:23]([O:27][CH2:28][CH3:29])=[O:26])[C@H:36]([CH3:41])[N:35]1[C:42](=[O:52])[CH2:43][C:44]1[C:49]([Cl:50])=[CH:48][CH:47]=[CH:46][C:45]=1[Cl:51])([C:58]([CH3:61])([CH3:59])[CH3:60])([CH3:57])[CH3:56]
Reactant: C[C@H]1c2cccc(Br)c2C[C@H](CO[Si](C)(C)C(C)(C)C)N1C(=O)Cc1c(Cl)cccc1Cl
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cccc2c1C[C@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)Cc1c(Cl)cccc1Cl)[C@H]2C
Temperature: 160 °C
Reaction time: 0.17 h
Yield: 96.9 %

Procedure:
Bubble nitrogen through acetonitrile. Place tri-o-tolylphosphine (72.3 mg, 0.23 mmol), palladium (II) acetate (11.8 mg, 0.052 mmol) and acetonitrile (0.96 mL) in a microwave vessel. Stir 10 min. Add ethyl acrylate (0.31 mL, 2.88 mmol). Add 1-[(1S,3R)-5-bromo-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-(2,6-dichlorophenyl)ethanone (0.54 g, 0.96 mmol). Add triethylamine (0.40 mL, 2.88 mmol) and stir vigorously. Blow nitrogen across the surface of the reaction. Seal the vessel and heat to 160° C. for 35 min in a microwave. Cool to room temperature and dilute with ethyl acetate. Filter the precipitate and wash with ethyl acetate. Concentrate the filtrate under reduced pressure to give a brown oil. Combine with the crude product from a substantially same reaction run with 0.27 mmol of 1-[(1S,3R)-5-bromo-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-(2,6-dichlorophenyl)ethanone. Purify the combined residues by silica gel chromatography, eluting with ethyl acetate: hexanes (gradient, 0-10%) to give the title compound (0.54 g, 0.93 mmol). MS (m/z): 576 (M+1). The following compound is prepared essentially by the method of Preparation 14.
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].O>CS(C)=O>[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: OCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cn1cnc2c1c(=O)n(CCCCCCO)c(=O)n2C
Reaction time: 0.83 h
Yield: 90.9 %

Procedure:
This example is a method of synthesis for inventive compound no. 3506 (see above for chemical name and structure). A mixture of theobromine (1.0 g, 5.5 mmol, available from Sigma) and 50% sodium hydride in oil (264 mg, 5.5 mmol) in dimethylsulfoxide (20 ml) was stirred for 50 minutes and then 6-bromo-1-hexanol (1.0 g, 5.5 mmol, available from Aldrich) was added. After stirring for 18 hours, the solution was treated with water (50 ml) and then extracted with two 25 ml aliquots of hexanes. The aqueous phase was extracted with three 35 ml aliquots of 25% ethanol-dichloromethane. The combined ethanol-dichloromethane extracts were dried over magnesium sulfate. The solvents were then evaporated under vacuum and remaining dimethylsulfoxide was removed by distillation under full pump vacuum, leaving 1.4 g of a white powder, 1-(6-hydroxyhexyl)-3,7-dimethylxanthine (5.0 mmol, 91% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:19])N(OC)C)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][Mg+].[Br-].OS([O-])(=O)=O.[Na+]>CCOCC>[C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:19])[CH3:21])[CH2:12][CH2:13]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C1CCC(NC(=O)OC(C)(C)C)CC1
Reactant: C[Mg+]
Agent: O=S(=O)([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)C1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.9 %

Procedure:
To a solution of [4-(methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester (11 g, 38.4 mmol) in ether (200 mL), cooled to 0° C., was added MeMgBr (3M in ether, 32 mL, 96 mmol). The mixture was stirred 4 h at rt. 10% aq. NaHSO4 (200 mL) was carefully added. The two layers were decanted and the aq. layer was extracted with EA (100 mL). The combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by CC (Hept-EA 2:1), affording the title methyl ketone as a white solid (7.4 g, 80% yield).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=2)=[CH:7][CH:6]=1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl.O1CCCC1>[CH2:21]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=2)=[CH:19][CH:20]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1ccccc1
Reactant: CNCCc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(CCc1ccc(Oc2ccc(C(N)=O)cn2)cc1)Cc1ccccc1
Yield: 58 %

Procedure:
Combine 6-[4-(2-Methylamino-ethyl)-phenoxy]-nicotinamide (135 mg, 0.5 mmol), benzaldehyde (53 μL, 0.52 mmol), sodium triacetoxyborohydride (0.21 g, 1.0 mmol), acetic acid (30 μL, 0.52 mmol), tetrahydrofuran (1 mL), and 1,2-dichloroethane (5 mL) then stir at room temperature for 18 hours. Dilute the reaction with saturated aqueous sodium bicarbonate solution and extract with ethyl acetate (3×50 mL). Dry the combined ethyl acetate extracts with sodium chloride/magnesium sulfate, filter, and concentrate on a rotary evaporator to yield 200 mg of the crude product. The crude product is purified by flash column chromatography on silica gel eluting with (0.5% conc. ammonium hydroxide/5% ethanol) to (1% conc. ammonium hydroxide/10% ethanol) in chloroform to yield 6-{4-[2-(benzyl-methyl-amino)-ethyl]-phenoxy}-nicotinamide (106 mg, 0.29 mmol): m/z=362.07 (M+1); 1H NMR (CDCl3, 300.00 MHz): 8.58 (s, 1H); 8.16 (dd, 3.0 Hz, 1H); 7.33-7.22 (m, 7H); 7.05 (d, 2H); 6.95 (d, 1H); 5.86 (br s, 2H); 3.63 (s, 2H), 2.89-2.72 (m, 4H); 2.34 (s, 3H), HPLC=100% (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax® SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[F:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH2:37].O.[OH-].[Li+]>O1CCCC1.CO.O>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:25]=[CH:26][C:27]([C:30](=[O:31])[NH:37][CH2:36][C:35]5[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=5[F:33])=[CH:28][CH:29]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: NCc1ccccc1F
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCc1ccccc1F)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
Using the conditions of General Procedure D for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 2-fluorobenzylamine (available from Aldrich Chemical Company, Inc.; 52 mg, 0.42 mmol) to give the crude amide product. The crude amide was hydrolyzed by adding THF (2 mL), water (0.05 mL), MeOH (1 mL), and lithium hydroxide monohydrate (12.3 mg, 0.29 mmol) and stirring the mixture overnight at room temperature. Tetrahydrofuran (2 mL) was added to dissolve the solid, and lithium hydroxide monohydrate (22 mg, 0.52 mmol) was added. The reaction mixture was stirred overnight, and then another portion of lithium hydroxide monohydrate (22 mg, 0.52 mmol) was added. The reaction mixture was stirred overnight. The reaction mixture was concentrated to dryness under vacuum at 40° C. 1 M HCl (3 mL) was added, and the mixture was stirred, concentrated to dryness, and purified and purified using HPLC Purification Conditions A to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(2-fluoro-benzylcarbamoyl)-biphenyl-2-carboxylic acid (75 mg, 63%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.18 (br s, 1H), 9.10 (t, J=5.8 Hz, 1H), 8.47 (s, 1H), 8.39 (d, J=1.8 Hz, 1H), 8.33 (d, J=2.0 Hz, 1H), 8.24 (dd, J=8.0, 1.8 Hz, 1H), 8.09 (dd, J=8.5, 2.0 Hz, 1H), 7.97 (d, J=8.3 Hz, 2H), 7.76 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.40 (t, J=7.7 Hz, 1H), 7.29-7.36 (m, 1H), 7.16-7.23 (m, 2H), 4.56 (d, J=5.8 Hz, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=1)[CH2:11][N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].[OH:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>COCCOC.O.C1(P([Pd](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:24][C:25]1[CH:30]=[CH:29][C:28]([C:8]2[CH:23]=[CH:22][CH:21]=[C:10]([CH2:11][N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=2)=[CH:27][CH:26]=1
Reactant: CN(Cc1cccc(Br)c1)C(=O)OC(C)(C)C
Reactant: OB(O)c1ccc(O)cc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CN(Cc1cccc(-c2ccc(O)cc2)c1)C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 67.7 %

Procedure:
41.6 ml (83.2 mmol) of aqueous 2M potassium carbonate solution are added dropwise to a solution of 10 g (33 mmol) of tert-butyl (3-bromobenzyl)-N-methylcarbamate and 8.3 g (60 mmol) of 4-hydroxybenzeneboronic acid in 100 ml of ethylene glycol dimethyl ether. The reaction medium is degassed and 1.9 g (1.7 mmol) of tetrakis(triphenylphosphino)palladium are added. After heating for 12 hours at 80° C., the reaction medium is cooled, diluted with water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on a column of silica eluted with an 80/20 heptane/ethyl acetate mixture. 7 g of tert-butyl (4′-hydroxybiphenyl-3-ylmethyl)methylcarbamate are obtained in the form of a beige-colored solid, in a yield of 68%.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:26][C:25]4[CH:28]=[CH:29][CH:30]=[C:23]([O:22][CH3:21])[CH:24]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: COc1cccc(CBr)c1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: COc1cccc(CN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)c1
Yield: 55 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 6) and 3-methoxy-benzyl bromide. Yield: 55%. 1H NMR (CDCl3, 400 MHz): δ2.19 (s, 3H), 2.42 (s, 3H), 3.81 (s, 3H), 3.85 (s, 2H), 4.58 (s, 2H), 5.06 (s, 2H), 6.81-6.88 (m, 3H), 7.26-7.31 (m, 1H), 7.92 (s, 1H), 8.08 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.07 μM.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[C:11]([C:14]([F:17])([F:16])[F:15])[NH:10][C:9]=2[C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:19])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36]Br.CCOCC>CC#N.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[C:11]([C:14]([F:15])([F:16])[F:17])[N:10]([CH2:36][C:35]3[CH:38]=[CH:39][CH:40]=[C:33]([Cl:32])[CH:34]=3)[C:9]=2[C:18]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[O:19])=[CH:4][CH:3]=1
Reactant: Clc1cccc(CBr)c1
Reactant: Cc1c(C(F)(F)F)[nH]c(C(=O)N2CCOCC2)c1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Solvent: O
Product: Cc1c(-c2ccc(Cl)cc2)c(C(=O)N2CCOCC2)n(Cc2cccc(Cl)c2)c1C(F)(F)F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(3-(4-Chlorophenyl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone (80 mg, 0.215 mmol) was dissolved in dry MeCN (5 mL). The solution was mixed with K2CO3 (59 mg, 0.429 mmol), followed by addition of 3-chlorobenzyl bromide (31 μL, 0.236 mmol). The reaction mixture was stirred vigorously at 80° C. overnight. The temperature was lowered to room temperature; the reaction mixture was combined with a few lumps of ice, Et2O (50 mL) and H2O (10 mL) to result in a clear two phase system. The phases were separated; the organic phase was washed with brine. Drying (Na2SO4) was followed by concentration in vacuo. The residue was dissolved in MeCN (30 mL), concentrated in vacuo and used for preparative TLC (silica, heptane/EtOAc, 5:1), providing 96 mg (90%) of SC-25 as a fluffy white solid.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:8][CH:7]=1)([OH:3])=O.[CH2:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH2:37]([NH:44][C:1]([CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:14][CH:13]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:10][CH:11]=1)=[O:3])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCC(=O)O)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCC(=O)NCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
(ee) Saponification of tert-butyl (3RS,4RS)-4-(4-ethoxycarbonylmethoxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 86(dd)] with 1N sodium hydroxide in methanol yielded tert-butyl (3RS,4RS)-4-(4-carboxymethoxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate, condensation of which with benzylamine in the presence of HBTU analogously to Example 36(b) gave tert-butyl (3RS,4RS)-4-[4-(benzylcarbamoyl-methoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a yellowish solid; MS: 598 (M+NH4)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:27][C:26](=O)[N:5]2[C:6]3[CH:25]=[CH:24][CH:23]=[CH:22][C:7]=3[CH2:8][N:9]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:11]([C:18]([O:20][CH3:21])=[O:19])=[C:10]3[CH:4]2[C:3]1=O.B#B.Cl>O1CCCC1.CO>[CH3:1][N:2]1[CH2:27][CH2:26][N:5]2[C:6]3[CH:25]=[CH:24][CH:23]=[CH:22][C:7]=3[CH2:8][N:9]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:11]([C:18]([O:20][CH3:21])=[O:19])=[C:10]3[CH:4]2[CH2:3]1
Reactant: COC(=O)c1c2n(c3ccccc13)Cc1ccccc1N1C(=O)CN(C)C(=O)C21
Agent: B#B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c2n(c3ccccc13)Cc1ccccc1N1CCN(C)CC21

Procedure:
A mixture of methyl 1,3,4,16b-tetrahydro-2-methyl-1,4-dioxo-2H,10H-indolo[2,1-c]pyrazino[1,2-a][1,4]benzodiazepine-16-carboxylate (1.48 kg) in tetrahydrofuran (52 L) is heated to reflux under an atmosphere of nitrogen and then a solution of diborane in tetrahydrofuran (1M, 9.47 L) is added over a period of one hour. The reaction mixture is maintained at reflux for 20 hours, at which time it is treated sequentially with methanol (4 L) (slow, cautious addition) and a solution of hydrogen chloride in methanol (7.5N, 1.6 L). The mixture is stirred, refluxed for 2 hours and evaporated in vacuo, and the solid residue obtained is triturated with acetone (4 L) for 1 hour, collected, washed with acetone (4×500 ml) and dried (18 hours, 50°/0.5 mm Hg) to yiled methyl 1,3,4,16b-tetrahydro-2-methyl-2H,10H-indolo[2,1-c]pyrazino[1,2-a][1,4]benzodiazepine-16-carboxylate hydrochloride, mp 272°-273° . This salt is suspended in dichloromethane and sufficient ammonium hydroxide (28%) in water is added to liberate the free base. The basic mixture is stirred for 45 minutes, the aqueous layer is removed and discarded and the organic layer is washed with water. The dichloromethane is evaporated in vacuo and the residual foam dissolved in boiling 2-propanol. The solution is filtered to remove a small amount of insolubles, then allowed to cool overnight for complete crystallization. The obtained solid is purified by recrystallization from 2-propanol. The solution is allowed to cool gradually while stirring overnight. The resulting crystals are collected by filtration, washed with 2-propanol and dried (16 hours, 80°/3 mm Hg) to yield methyl 1,3,4,16b-tetrahydro-2-methyl-2H,10H-indolo[2,1-c]pyrazino[1,2-a][1,4]benzodiazepine-16-carboxylate, mp 157°-159°, the compound of formula I wherein R1 is methyl, R2 and R3 are hydrogen and R4 is methoxycarbonyl.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[NH:13][CH:12]=2)=[C:6]([O:23][CH3:24])[CH:5]=1.C(N(CC)CC)C.[C:33](Cl)(Cl)=[O:34].C1(C)C=CC=CC=1.Cl.[NH2:45][CH:46]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]([C:33](=[O:34])[NH:45][CH:46]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH:12]=2)=[C:6]([O:23][CH3:24])[CH:5]=1
Reactant: O=C(Cl)Cl
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc([N+](=O)[O-])cc23)c(OC)c1
Reactant: NC(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cc2cn(C(=O)NC(c3ccccc3)c3ccccc3)c3ccc([N+](=O)[O-])cc23)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of 4-[5-nitro-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid methylester (0.50 grams, 1.47 mmol) and triethylamine (0.62 mL, 4.41 mmol) in methylene chloride (30 mL), at 0° C., was added a solution of phosgene in toluene (1.9 M in toluene, 1.5 mL, 2.9 mmol). The solution was warmed to room temperature and stirred for 1 hour. To this was added aminodiphenylmethane hydrochloride (0.65 grams, 2.94 mmol) and the resulting solution was stirred for 12 hours at room temperature. The solution was concentrated in vacuo and the crude triturated with methanol. The resulting pale yellow solid was collected via filtration to give 4-[1-(benzhydryl-carbamoyl)-5-nitro-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid methylester (0.672 grams, 83% yield).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:16])[NH:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([NH2:14])=[CH:9][C:8]=1[CH3:15])[CH2:2][CH3:3].[Cl:17][C:18]1[S:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1.C([BH3-])#N.[Na+].O.[Cl-].[Na+].O>CO>[CH2:1]([O:4][C:5](=[O:16])[NH:6][C:7]1[C:8]([CH3:15])=[CH:9][C:10]([NH:14][CH2:23][C:21]2[S:22][C:18]([Cl:17])=[CH:19][CH:20]=2)=[CH:11][C:12]=1[CH3:13])[CH2:2][CH3:3]
Reactant: CCCOC(=O)Nc1c(C)cc(N)cc1C
Reactant: O=Cc1ccc(Cl)s1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCOC(=O)Nc1c(C)cc(NCc2ccc(Cl)s2)cc1C
Temperature: 130 °C
Yield: 49 %

Procedure:
(4-Amino-2,6-dimethyl-phenyl)-carbamic acid propyl ester (84 mg) and 5-chloro-thiophene-2-carbaldehyde (48 uL) were dissolved in methanol (3 mL) and heated to 130° C. for 5 minutes in a sealed microwave process vial. Sodium cyanoborohydride (95 mg) was added and the reaction mixture was heated to 130° C. for 5 minutes in a sealed microwave process vial, followed by addition of water/brine (1:1, 3 mL). The product was extracted with ethyl acetate (3×3 mL) and the combined organic phases were washed with brine (5 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to furnish 66 mg (49% yield) of the title compound as an oil. LC-MS (m/z) 353 (MH+); tR=3.06, (UV, ELSD) 87%, 87%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH:5]([OH:10])[CH:6]1[CH2:9][O:8][CH2:7]1)[CH3:2].CC1C=CC=C([N+]([O-])=O)C=1C(OC(=O)C1C([N+]([O-])=O)=CC=CC=1C)=O.[CH3:37][C:38]([CH3:44])([CH:42]=[CH2:43])[C:39](O)=[O:40]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:3][C:4]([CH:5]([O:10][C:39](=[O:40])[C:38]([CH3:44])([CH3:37])[CH:42]=[CH2:43])[CH:6]1[CH2:7][O:8][CH2:9]1)=[O:11])[CH3:2]
Reactant: CCOC(=O)C(O)C1COC1
Reactant: C=CC(C)(C)C(=O)O
Agent: CN(C)c1ccncc1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Solvent: ClCCl
Product: C=CC(C)(C)C(=O)OC(C(=O)OCC)C1COC1
Reaction time: 4 h
Yield: 72.5 %

Procedure:
To a stirred solution of hydroxy-oxetan-3-yl-acetic acid ethyl ester (330 mg, 2.06 mmol), 2-methyl-6-nitrobenzoic anhydride (1.42 g, 4.12 mmol) and 4-dimethylamino pyridine (100 mg, 0.82 mmol) in dichloromethane (4 mL) was added a solution of 2,2-dimethyl-but-3-enoic acid (294 mg, 2.58 mmol) in dichloromethane (4 mL). The reaction mixture was stirred for 4 h and then evaporated. The residue was purified by silica gel chromatography using iso-hexanes/diethyl ether 4:1 to give the title compound (383 mg, 73%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.27 (t, J=7.1 Hz, 3H), 1.39 (s, 3H), 1.41 (s, 3H), 3.48-3.61 (m, 1H), 4.20 (q, J=7.1 Hz, 2H), 4.62-4.68 (m, 2H), 4.72-4.85 (m, 2H), 5.12-5.24 (m, 3H), 6.09 (dd, J=17.5, 10.6 Hz, 1H). LCMS (m/z) 257.1[M+H], Tr=2.31 min
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[C:10]([Cl:13])(=O)C.S(Cl)(Cl)=O>CO>[ClH:13].[OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: CC(=O)Cl
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1C[C@@H](O)CN1
Product: Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.2 %

Procedure:
To a suspension of trans-4-hydroxy-L-proline (200 g: 1.525 mole) in methanol (800 ml), acetylchloride (163 ml: 2.288 mole) is added dropwise under ice cooling in a nitrogen atmosphere. The mixture is warmed to room temperature, mixed with thionyl chloride (55.7 ml: 0.763 mole), and stirred for 4 hours at 40° C. to give (2S,4R)-4-hydroxy-2-methoxycarbonylpyrrolidine hydrochloride (244.27 g). Yield: 88%. Colorless crystals.