Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH:5][C:6](=[O:13])[C@H:7]([CH2:9][C:10](=[O:12])[OH:11])[NH2:8].N[C@H]([C:31](O)=[O:32])CC1C=CC=CC=1.[NH2:34][C@H:35]([C:40]([OH:42])=[O:41])[CH2:36][C:37]([OH:39])=O>>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH:5][C:6](=[O:13])[C@H:7]([CH2:9][C:10](=[O:11])[OH:12])[NH2:8].[CH:31]([NH:34][C@@H:35]1[C:40](=[O:41])[O:42][C:37](=[O:39])[CH2:36]1)=[O:32].[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH2:5]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Product: COC(=O)[C@@H](N)Cc1ccccc1
Product: O=CN[C@H]1CC(=O)OC1=O

Procedure:
A method according to claim 1 wherein α-L-aspartyl-L-phenylalanine methyl ester, L-phenylalanine and L-aspartic acid are recovered from solutions formed in the preparation of α-L-aspartyl-L-phenylalanine methyl ester using, as raw materials, N-formyl-L-aspartic anhydride and L-phenylalanine methyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6](Br)[CH:7]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([C:2]2[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:7]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)/C=C/c1cc(Br)cc(Br)c1
Product: CCOC(=O)/C=C/c1cc(-c2ccccc2)cc(-c2ccccc2)c1

Procedure:
The colourless solid, (E)-ethyl 3-[1,1′;3′,1″]terphenyl-5′-yl-acrylate was prepared from (E)-ethyl 3-(3,5-dibromophenyl)-acrylate and phenylboronic acid by a procedure analogous to that described in example 52a.
Reaction SMILES: [Na].[C:2]1([CH:8]([OH:11])[CH2:9][SH:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:12]([CH:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH2:13]>C1(C=CC(O)=CC=1)O.C(O)C>[C:2]1([CH:8]([OH:11])[CH2:9][S:10][CH:14]([CH:12]=[CH2:13])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(Cl)c1ccccc1
Reactant: OC(CS)c1ccccc1
Agent: Oc1ccc(O)cc1
Agent: [Na]
Solvent: CCO
Product: C=CC(SCC(O)c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 104.8 %

Procedure:
To 125 ml of absolute ethanol was added 5.7 g (0.247 moles) of sodium metal. After the sodium had dissolved, the solution was cooled to 0° to 5° C. and 38 g (0.247 moles) of 1-phenyl-2-mercaptoethanol was added dropwise. After addition, the reaction was stirred at 0° to 5° C. for 1 hour and then 37.7 g (0.247 moles) of vinylbenzyl chloride was added dropwise. After the addition was complete, 0.5 g of hydroquinone was added and the mixture was refluxed for 2 hours. The mixture was cooled and the sodium chloride was removed by filtration. The solvent was evaporated and the residue was added to 100 ml of water. The aqueous mixture was extracted with three 100 ml portions of ether and the combined ethereal extracts were dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated to leave 70 g of the product as a crude oil. Due to its high boiling point, the product was used without further purification in the synthesis of the following sulfone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:19])[C:5]([CH:8](C(OCC)=O)C(OCC)=O)=[N:6][CH:7]=1.Cl>>[Br:1][C:2]1[CH:3]=[C:4]([Cl:19])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ncc(Br)cc1Cl
Agent: Cl
Product: Cc1ncc(Br)cc1Cl
Yield: 48.4 %

Procedure:
A solution of impure diethyl 2-(5-bromo-3-chloropyridin-2-yl)malonate (Intermediate 42, 0.41 g, 1.2 mmol) and conc. aq. HCl (3 mL) was heated at reflux for 3 h. The volatiles were removed in vacuo, and the residue was co-evaporated with acetonitrile. The residual solid (mono-decarboxylated acid) was dissolved in dioxane (4.5 mL) and heated at reflux overnight. The volatiles were removed in vacuo. The residue was purified by flash chromatography (4 g SiO2, heptane/EtOAc gradient) affording the title compound (0.12 g, 51% yield): 1H NMR (500 MHz, CDCl3) δ ppm 2.60 (s, 3H), 7.82 (d, 1H), 8.46 (d, 1H); MS (CI) m/z 206 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[NH:4][N:3]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:40][C:41]1[CH:42]=[C:43]([C:48]2[CH:52]=[CH:51][N:50]([CH2:53][CH2:54][NH2:55])[N:49]=2)[CH:44]=[CH:45][C:46]=1[Cl:47]>C(Cl)Cl>[Cl:40][C:41]1[CH:42]=[C:43]([C:48]2[CH:52]=[CH:51][N:50]([CH2:53][CH2:54][NH:55][C:7]([C:5]3[NH:4][N:3]=[C:2]([CH3:1])[CH:6]=3)=[O:9])[N:49]=2)[CH:44]=[CH:45][C:46]=1[Cl:47]
Reactant: NCCn1ccc(-c2ccc(Cl)c(Cl)c2)n1
Reactant: Cc1cc(C(=O)O)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NCCn2ccc(-c3ccc(Cl)c(Cl)c3)n2)[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
To a stirred solution of 3-methyl-1H-pyrazole-5-carboxylic acid (104 mg, 0.83 mmol) in DCM (2.0 ml) was added DIPEA (0.144 mL 0.81 mmol). EDCI (159 mg, 0.83 mmol) and HOBt (112 mg, 0.83 mmol). After 10 min 2-(3-(3,4-dichloro-phenyl)-1H-pyrazol-1-yl)ethanamine (102 mg, 0.40 mmol) was added to the reaction mixture as a solution in DCM (2.0 ml). The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO3 solution and water. The organic phase was dried over Na2SO4, evaporated and purified by chromatography (CombiFlash, 1st column silica, eluent: 0-10% MeOH/DCM; 2nd column C-18 RP, eluent: 0-100% MeCN/water) to obtain 65 mg (45%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 2.24 (s, 3H), 3.64 (q, 2H), 4.31 (t, 2H), 6.36 (s, 1H), 6.81 (d, 1H), 7.65 (d, 1H), 7.77 (d, 1H), 7.80 (dd, 1H), 8.00 (d, 1H), 8.23 (s, 1H), 12.88 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]=1.C=O.Cl.[CH:15]12[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH:16]1[NH2:25])[CH2:22]2.[C:26](O)(=O)[CH3:27]>>[CH:15]12[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH:16]1[N:25]1[CH2:5][CH2:6][CH:11]3[CH:2]([CH2:3][CH2:4][C:26]4[CH:27]=[CH:7][CH:8]=[CH:9][C:10]=43)[CH2:1]1)[CH2:22]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: CC(=O)O
Reactant: CC1=CCCc2ccccc21
Agent: C=O
Agent: Cl
Product: c1ccc2c(c1)CCC1CN(C3C4CC5CC(C4)CC3C5)CCC21

Procedure:
Following the procedure of Example 1, step 3, 5.00 g (34.7 mmol) of 1-methyl-3,4-dihydronaphthalene in 35 ml of acetic acid was reacted with 11.3 ml of 37% formaldehyde solution and 14.96 g of 2-adamantanamine hydrochloride. Work up gave 14.47 g of crude 3-(2-adamantyl)-1,2,3,4,4a,5,6,10b-octahydrobenz[f]isoquinoline. Following the procedure of Example 2, this was reacted with 2.09 g of lithium wire in 500 ml of liquid ammonia, 200 ml of anhydrous THF and 5 ml of aniline. Chromatography on flash silica, eluting with 2-10% methanol/dichloromethane, then on alumina, eluting with 0-4% ethyl acetate/petroleum ether, gave 2.73 g (24%) of the title product as a white solid. The hydrochloride salt was made using ethereal hydrogen chloride. Upon evaporation of the solvent and recrystallisation from ethanol/ethyl acetate/petroleum ether, the title product hydrochloride was obtained as a white solid, m.p. 247°-252° C. NMR δ(D2O/CD3CN) 1.52 (1H, m), 1.69-1.98 (15H, m), 2.48 (2H, s), 2.59-2.75 (3H, m), 2.91-3.09 (3H, m), 3.29-3.34 (1H, m), 3.79 (1H, m), 3.95 (1H, m), 7.18-7.24 (3H, m), 7.30-7.33 (1H, m). m/z (CI+, NH3) 322 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([O:7][CH2:8][CH3:9])[NH:4][C:3]=1[CH:10]=[O:11].[C:12]([O:16][C:17]([C:19]1[C:20]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31]Br)=[C:27]([F:33])[CH:26]=2)=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>>[C:12]([O:16][C:17]([C:19]1[C:20]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][N:4]3[C:3]([CH:10]=[O:11])=[C:2]([Br:1])[N:6]=[C:5]3[O:7][CH2:8][CH3:9])=[C:27]([F:33])[CH:26]=2)=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)c(F)c1
Reactant: CCOc1nc(Br)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1nc(Br)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
5-Bromo-2-ethoxy-3H-imidazole-4-carbaldehyde (6.0 g, 27.4 mmol), 4′-bromomethyl-3′-fluorobiphenyl-2-carboxylic acid t-butyl ester (10.0 g, 27.4 mmol), and potassium carbonate (3.8 g, 27.4 mmol) were dissolved in DMF (383 mL, 4950 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with water, and the mixture was extracted with EtOAc, washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated. The resulting material was purified by silica gel chromatography (0-30% EtOAc:hexanes) to yield intermediate (16a) (9.5 g). MS m/z: [M+H+] calcd for C24H24BrFN2O4, 503.3. found 503.2. 1H-NMR (CDCl3): 9.57 (1H, s), 7.80 (1H, d), 7.48 (2H, m), 7.27 (1H, s), 7.11 (1H, t), 7.01 (2H, d), 5.47 (2H, s), 4.33 (2H, q), 1.41 (3H, t), 1.24 (9H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7](/[CH:8]=[N:9]/[C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:22](=[O:26])[CH:23]([CH3:25])[CH3:24]>O1CCCC1.FC(F)(F)S([O-])(=O)=O.[Y+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[OH:26][CH:22]1[C:19]2[C:10](=[CH:11][CH:12]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:18]=2)[NH:9][CH:8]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:21][CH:20]=2)[C:23]1([CH3:25])[CH3:24]
Reactant: CC(C)C=O
Reactant: COC(=O)c1ccc(/N=C/c2ccc([N+](=O)[O-])cc2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Y+3]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1ccc([N+](=O)[O-])cc1)N2
Yield: 19.6 %

Procedure:
To a solution of (E)-methyl 4-(4-nitrobenzylideneamino)benzoate (284 mg 1 mmol) and yttrium(III) trifluoromethanesulfonate (62 mg, 0.1 mmol) in tetrahydrofuran (5 mL) was added isobutyraldehyde (72 mg, 1.5 mmol). The resultant mixture was stirred at room temperature for 16 h. Thin layer chromatography showed the starting material was completely consumed. The reaction mixture was quenched with water and separated. The aqueous solution was extracted with dichloromethane and the combined organic layers were dried over anhydrous sodium sulfate. Solvent was removed in vacuo to give the crude product, which was purified by column chromatography (petroleum ether/ethyl acetate=3:1) to afford 70 mg of methyl 4-hydroxy-3,3-dimethyl-2-(4-nitrophenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow solid. Yield: 20%.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:12])[CH:8]=2)[N:3]=1.[Se](=O)=[O:14]>C(OCC)(=O)C>[F:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH:1]=[O:14])[CH:11]=[N:10]2
Reactant: Cc1cnc2cc(F)ccc2n1
Reactant: O=[Se]=O
Solvent: CCOC(C)=O
Product: O=Cc1cnc2cc(F)ccc2n1
Yield: 29 %

Procedure:
Using the method of Kepez (Monatahefte fur Chemie, 1989, 120, 127–130), a solution of 2-methyl-6-fluoroquinoxaline (225 mg 1.39 mmol) in ethyl acetate (30 mL) was treated with selenium dioxide (2.5 g) and the reaction mixture heated at reflux for 36 hours. The reaction was filtered hot and concentrated. Chromatography through a Biotage silica cartridge (8×4 cm i.d.) using a gradient of hexane to 10% ethyl acetate (in hexane) afforded 71 mg (29%) of 6-fluoroquinoxaline-2-carboxaldehyde.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH:10]=[N:11]O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[C:10]#[N:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C=NO)cc1OC1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C#N)cc1OC1CCCC1
Yield: 71.4 %

Procedure:
3-cyclopentyloxy-4-methoxybenzaldehyde (13.00 g, 59.02 mM) and hydroxylamine hydrochloride (8.46 g, 118.04 mM) were dissolved in pyridine (120 ml) and the resultant mixture was heated to reflux for 23 hours. The solution obtained was cooled to room temperature, water (100 ml) was added, then the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was removed in vacuo to obtain a green oily residue. The residue was purified by flash chromatography (SiO2: eluted by 20% ethyl acetate/hexane). The solvent was removed in vacuo and the resultant product was dried to obtain 3-cyclopentyloxy-4-methoxybenzaldehyde oxime 14.57 g as a colorless oil. The 3-cyclopentyloxy-4-methoxybenzaldehyde oxime (14.57 g) thus obtained was dissolved in acetic acid (130 ml) and the resultant mixture was heated to reflux for 22 hours. The solution obtained was ice cooled, then a saturated sodium hydrogencarbonate solution was added to neutralize it. The solution was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo to obtain a red solid residue. The residue was purified by flash chromatography (SiO2: eluted by 25% ethyl acetate/hexane). The solvent was removed in vacuo and the result dried to obtain 3-cyclopentyloxy-4-methoxybenzonitrile 9.60 g (yield 75.2%) as a yellow-green oil.
Reaction SMILES: Br[C:2]1(Br)[CH2:4][CH:3]1[O:5][N:6]=[C:7]([C:13]1([O:18][CH2:17][CH2:16][O:15]1)[CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[CH:3]1([O:5][N:6]=[C:7]([C:13]2([O:15][CH2:16][CH2:17][O:18]2)[CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:2]1
Reactant: CCOC(=O)C(=NOC1CC1(Br)Br)C1(C)OCCO1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: CCOC(=O)C(=NOC1CC1)C1(C)OCCO1
Yield: 104.1 %

Procedure:
To a solution of ethyl 2-(2,2-dibromocyclopropyloxyimino)-3,3-ethylenedioxybutyrate (syn isomer)(16.4 g) in benzene (300 ml) was dropwise added tri-n-butyltin hydride (33 ml). To the mixture was added 2,2'-azobisisobutyronitrile (0.5 g) and the resulting mixture was refluxed for 2 hours under nitrogen atmosphere. The mixture was concentrated in vacuo and the residue was subjected to column chromatography on silica gel using a mixture of chloroform and ethyl acetate (4:1 V/V) as an eluent to give ethyl 2-cyclopropyloxyimino-3,3-ethylenedioxybutyrate (syn isomer)(10.36 g) as an oil.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14])[CH:2]=[CH2:3]>C1COCC1.O.[Pd]>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[C:13]([F:14])([F:15])[F:16])[CH2:2][CH3:3]
Reactant: C=CCc1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1ccc(N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.8 %

Procedure:
To a solution of 1-allyl-4-nitro-2-(trifluoromethyl)benzene (750 mg, 3.24 mmol) in 18 mL of THF and 3.6 mL of H2O was added 10% Pd/C (250 mg, 3.24 mmol). The reaction was stirred at room temperature under an H2 balloon for 24 hr. After filtering to remove Pd/C, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, 100% Heptane-10% Ethyl Acetate/90% Heptane, to give 4-propyl-3-(trifluoromethyl)aniline (440 mg). LCMS retention time=1.53 minutes (LC method 3); MS (m+1)=203.8. 1H NMR (400 MHz, DMSO-d6) δ 0.93 (t, J=7.4 Hz, 3H), 1.54 (sxt, J=7.6 Hz, 2H), 2.51-2.56 (m, 2H), 5.66 (s, 2H), 6.44 (dd, J=8.5, 1.9 Hz, 1H), 6.52 (d, J=2.1 Hz, 1H), 7.24 (d, J=8.6 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:30][CH2:29][C:7]2([O:11][CH2:10][C:9]([C:12]3[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([N:20]4[C:24]([C:25]([F:28])([F:27])[F:26])=[N:23][N:22]=[N:21]4)[N:13]=3)=[CH:8]2)[CH:6]1[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)=[O:4]>CO.[OH-].[Pd+2].[OH-]>[CH3:1][O:2][C:3]([C@H:5]1[CH2:30][CH2:29][C@:7]2([O:11][CH2:10][C@H:9]([C:12]3[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([N:20]4[C:24]([C:25]([F:28])([F:26])[F:27])=[N:23][N:22]=[N:21]4)[N:13]=3)[CH2:8]2)[C@@H:6]1[C:31]1[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=1)=[O:4]
Reactant: COC(=O)C1CCC2(C=C(c3nc(-n4nnnc4C(F)(F)F)ccc3OC)CO2)C1c1ccc(F)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@H]1CC[C@@]2(C[C@@H](c3nc(-n4nnnc4C(F)(F)F)ccc3OC)CO2)[C@@H]1c1ccc(F)cc1

Procedure:
This material was made by hydrogenation with H2 in methanol over 20% palladium hydroxide of 6-(4-fluorophenyl)-3-[3-methoxy-6-(5-trifluoromethyl-tetrazol-1-yl)-pyridin-2-yl]-1-oxaspiro[4.4]non-3-ene-7-carboxylic acid methyl ester by the method given in Example 6, Step G. NMR (400 MHz, CDCl3): δ 7.66(d, J=7Hz,1H); 7.29(m, 3H); 6.90(t, J=9 Hz, 2H); 4.1(t, J=7Hz, 1H); 3.88 (s over multiplet, 3H+1H); 3.54(s,3H); 3.2-3.35(m, 3H); 2.25-2.33(m, 1H); 2.1-2.22(m, 3H); 1.90-2.0(m, 2H); Mass spectrum: 522 (M+1).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=O)(C)(C)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16].NC[C@@H]1CCCN1CC.C(=O)C>>[CH3:14][S:15]([N:11]1[CH2:12][CH2:13][C@@H:9]([NH2:8])[CH2:10]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: CC=O
Agent: CCN1CCC[C@H]1CN
Product: CS(=O)(=O)N1CC[C@@H](N)C1

Procedure:
By using (R)-(+)-3-(t-butoxycarbonylamino)pyrrolidine (2.0 g) and methanesulfonyl chloride (1 ml) as starting materials, the title compound (0.98 g) was obtained in the same manners as those of Reference Example 58, (1) and Reference Example 39, (2).
Reaction SMILES: C(OC(=O)[N:7]([O:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[C:37]=1[Cl:46])[CH2:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:46][C:37]1[C:38]([C:42]([F:43])([F:44])[F:45])=[CH:39][CH:40]=[CH:41][C:36]=1[CH2:35][N:20]([CH2:21][CH:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:19][CH2:18][CH2:17][O:16][NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1
Reactant: COc1ccc(N(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(NOCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)cc1
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a solution of {3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-methoxy-phenyl carbamic acid tert-butyl ester (0.05 g, 0.075 mmol) and CH2Cl2 (2 mL), TFA (0.20 mL, 1.2 mmol) was added and the reaction mixture was stirred for 1 h. The mixture was then poured into NaHCO3, extracted with CH2Cl2, dried over Na2SO4, filtered, and concentrated to yield the product as a yellow oil (0.03 g, 70%): MS(ES) m/e 569.4 [M+H]+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:18])([CH3:17])[CH3:16])[O:11][C:10]([CH3:30])([CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=1)[CH:9]=[CH:8]2)(=[O:3])[CH3:2].[H][H]>C1C=CC=CC=1.C(O)(=O)C.[Pd]>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:18])([CH3:16])[CH3:17])[O:11][C:10]([CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([NH2:27])=[CH:25][CH:26]=1)([CH3:30])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc2c(cc1C(C)(C)C)OC(C)(COc1ccc([N+](=O)[O-])cc1)C=C2
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CC(=O)Oc1cc2c(cc1C(C)(C)C)OC(C)(COc1ccc(N)cc1)CC2

Procedure:
2.1 g of 6-acetoxy-7-t-butyl-2-methyl-2-(4-nitrophenoxymethyl)-2H-chromene (prepared as described in Preparation 57) were dissolved in a mixture of 20 ml of benzene and 2 ml of acetic acid, and the compound was reduced for 10 hours at room temperature, in the presence of 0.1 g of 10% w/w palladium-on-carbon, and under about 1 atmosphere (about 1 bar) pressure of hydrogen. The catalyst was filtered off, and the reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and then with water, after which it was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography, eluted with benzene, to give the title compound as a slightly brown oil.
Reaction SMILES: [C:1]([O:4][C@H:5]([C@H:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH2:20][N:19]([CH3:24])[C:18]3=[O:25])[C:10]1=[O:26])[C:6]([OH:8])=O)(=[O:3])[CH3:2].[NH2:27][C:28]1[CH:42]=[CH:41][C:31]([CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:30][CH:29]=1>>[C:1]([O:4][C@H:5]([C@H:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH2:20][N:19]([CH3:24])[C:18]3=[O:25])[C:10]1=[O:26])[C:6]([NH:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][NH:33][C:34]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:40])=[CH:41][CH:42]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H](C(=O)O)[C@H]1OCCN(c2ccc3c(c2)C(=O)N(C)C3)C1=O
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Product: CC(=O)O[C@@H](C(=O)Nc1ccc(CNC(=O)OC(C)(C)C)cc1)[C@H]1OCCN(c2ccc3c(c2)C(=O)N(C)C3)C1=O
Yield: 74.2 %

Procedure:
According to the Step 70-5 in the synthetic method for EXAMPLE 70, compound 70-4 (50 mg) was treated with tert-butyl 4-aminobenzylcarbamate (37 mg) to afford compound 71-1 (58 mg) as white solid after preparative LC purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:24][CH3:25])[C:9]3[C:14]([CH2:15]NC4CCNCC4)=[CH:13][N:12]=[CH:11][C:10]=3[N:23]=2)=[N:4][O:5][N:6]=1.[CH3:26][N:27]1[CH:32]2[CH2:33][CH2:34][CH:28]1[CH2:29][CH:30]([NH2:35])[CH2:31]2.[BH4-].[Na+].[Cl:38]CCl>C(O)(=O)C>[ClH:38].[ClH:38].[NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:24][CH3:25])[C:9]3[C:14]([CH2:15][NH:35][CH:30]4[CH2:29][CH:28]5[N:27]([CH3:26])[CH:32]([CH2:33][CH2:34]5)[CH2:31]4)=[CH:13][N:12]=[CH:11][C:10]=3[N:23]=2)=[N:4][O:5][N:6]=1
Reactant: CCn1c(-c2nonc2N)nc2cncc(CNC3CCNCC3)c21
Reactant: CN1C2CCC1CC(N)C2
Reactant: ClCCl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCn1c(-c2nonc2N)nc2cncc(CNC3CC4CCC(C3)N4C)c21
Product: Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The product of Example 191 Step 1 (150 mg, 0.58 mmole) in 5% acetic acid and dichloromethane (5 ml) was treated with 8-Methyl-8-aza-bicyclo[3.2.1]oct-3-ylamine (179 mg, 1.2 mmole) and stirred at ambient temperature for 20 minutes. Sodium borohydride (13 mg, 0.34 mmol) was added and the reaction mixture stirred at ambient temperature for 20 hours. The product was diluted with dichloromethane, washed water followed by saturated brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 20% ammonia in methanol/dichloromethane. to afford the title compound as a free base; (34 mg, 15%) MS (ES+) m/e 396 [M+H]+. A solution of the resulting free base (34 mg, 0.08 mmol) in anhydrous methanol (1 ml) was treated with 1M hydrochloric acid in ether and stirred for 30 minutes. The resulting white precipitate was filtered and dried in vacuo to afford the title compound as a colourless hydrochloride salt; (34 mg, 92%) MS (ES+) m/e 396 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[C:4]([CH3:8])=[N:3]1.Cl[C:10]1[CH:15]=[C:14]([NH:16][C:17]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:18]=2[C:19]([NH:21][CH3:22])=[O:20])[C:13]([Cl:28])=[CH:12][N:11]=1>>[Cl:28][C:13]1[C:14]([NH:16][C:17]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:18]=2[C:19]([NH:21][CH3:22])=[O:20])=[CH:15][C:10]([NH:7][C:5]2[C:4]([CH3:8])=[N:3][N:2]([CH3:1])[CH:6]=2)=[N:11][CH:12]=1
Reactant: Cc1nn(C)cc1N
Reactant: CNC(=O)c1ccc(F)cc1Nc1cc(Cl)ncc1Cl
Product: CNC(=O)c1ccc(F)cc1Nc1cc(Nc2cn(C)nc2C)ncc1Cl

Procedure:
1,3-Dimethylpyrazol-4-amine and 2-(2,5-dichloropyridin-4-ylamino)-4-fluoro-N-methylbenzamide were reacted according to the procedure of example 3.40 to afford 2-(5-chloro-2-(1,3-dimethyl-1H-pyrazol-4-ylamino)pyridin-4-ylamino)-4-fluoro-N-methylbenzamide (23 mg) as a beige solid. 1H NMR spectrum: (300 MHz, DMSO) δ 2.02 (3H, s), 2.71 (3H, d), 3.64 (3H, s), 6.72 (1H, d), 6.86 (1H, td), 7.27 (1H, dd), 7.71 (1H, dd), 7.79 (1H, s), 7.92 (1H, s), 8.04 (1H, s), 8.63 (1H, m), 10.43 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+ =389