Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[C:7]([C:15]1[N:16]=[C:17]([NH2:20])[S:18][CH:19]=1)=[N:8][O:9][CH2:10][C:11](=[O:14])[NH:12][NH2:13])([CH3:4])([CH3:3])[CH3:2].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[C:34]([O:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][C:46]=1[O:47][C:48](=[O:50])[CH3:49])[C:41]([Cl:43])=[O:42])(=[O:36])[CH3:35].CCOCC>C(Cl)Cl.CO>[ClH:43].[C:1]([O:5][C:6](=[O:21])[C:7]([C:15]1[N:16]=[C:17]([NH2:20])[S:18][CH:19]=1)=[N:8][O:9][CH2:10][C:11](=[O:14])[NH:12][NH:13][C:41](=[O:42])[C:40]1[CH:44]=[CH:45][C:46]([O:47][C:48](=[O:50])[CH3:49])=[C:38]([O:37][C:34](=[O:36])[CH3:35])[CH:39]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(=NOCC(=O)NN)c1csc(N)n1
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1OC(C)=O
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(=O)NNC(=O)CON=C(C(=O)OC(C)(C)C)c2csc(N)n2)cc1OC(C)=O
Product: Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
In 50 ml of methylene chloride was suspended 6.12 g (19.4 mmole) of 2-(2-amino-1,3-thiazol-4-yl)-2-carbazoylmethoxyiminoacetic acid tert-butyl ester, and to the suspension was added 20.8 g (102.3 mmole) of N,O-bis(trimethylsilyl)acetamide to form a solution. To the ice-cooled solution was added 5.467 g (21.3 mmole) of 3,4-diacetoxybenzoic acid chloride and the mixture was stirred for 2 hours under ice-cooling. The resulting mixture was poured into 800 ml of ether and to the mixture was added a small amount of methanol while stirring. Resulting precipitates were collected by filtration, washed with ether and then dried to obtain 10.2 g of 2-(2-amino-1,3-thiazol-4-yl)-2-[3-(3,4-diacetoxybenzoyl)carbazoyl]methoxyiminoacetic acid tert-butyl ester hydrochloride. (Yield: 98.2%)
Reaction SMILES: C(O[C@@H:5]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]1OC(=O)C)(=O)C.[C:17]([O:20][C:21]1([C:37](=[O:39])[CH3:38])[CH2:30][C:29]2[C:28](=[O:31])[CH:27]=[CH:26][C:25](=[O:32])[C:24]=2[C:23]2([S:36][CH2:35][CH2:34][S:33]2)[CH2:22]1)(=[O:19])[CH3:18]>C1(C)C(C)=CC=CC=1>[C:17]([O:20][C:21]1([C:37](=[O:39])[CH3:38])[CH2:30][C:29]2[C:28](=[O:31])[C:27]3[C:26](=[CH:6][C:7]4[C:8]([CH:5]=3)=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:25](=[O:32])[C:24]=2[C:23]2([S:36][CH2:35][CH2:34][S:33]2)[CH2:22]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC1(C(C)=O)CC2=C(C(=O)C=CC2=O)C2(C1)SCCS2
Reactant: CC(=O)O[C@@H]1c2ccccc2[C@H]1OC(C)=O
Solvent: Cc1ccccc1C
Product: CC(=O)OC1(C(C)=O)CC2=C(C(=O)c3cc4ccccc4cc3C2=O)C2(C1)SCCS2
Yield: 81.8 %

Procedure:
A mixture of 0.825 g (0.00375 mol) of trans-1,2-diacetoxy-1,2-dihydrobenzocyclobutene and 1.20 g (0.0034 mol) of rac-3'-acetoxy-3'-acetyl-1',2',3',4',5',8'-hexahydro-5',8'-dioxospiro[1,3-dithiolane-2,1'-naphthalene] [prepared as described in Example 5(A)] in 65 ml of xylene was stirred and heated under reflux under an atmosphere of nitrogen for 16 hours. The solution was evaporated to dryness and the residue was stirred with 20 ml of diethyl ether and filtered to give 1.259 g (82%) of rac-3'-acetoxy-3'-acetyl-1',2',3',4',5',12'-hexahydro-5',12'-dioxospiro[1,3-dithiolane-2,1'-naphthacene] in the form of a bright yellow solid of melting point 239°-241° C.
Reaction SMILES: CN(CCN(C)C)C.[Li][CH:10]([CH2:12]C)[CH3:11].[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[F:24])[C:18]([OH:20])=[O:19].CSC.BrCC=C>C1COCC1>[CH2:12]([C:16]1[C:15]([F:14])=[C:23]([F:24])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19])[CH:10]=[CH2:11]
Reactant: [Li]C(C)CC
Reactant: O=C(O)c1ccc(F)c(F)c1
Agent: CN(C)CCN(C)C
Solvent: CSC
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCc1c(C(=O)O)ccc(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To a solution of TMEDA (32.2 g, 0.278 mol) in dry THF (150 mL) was added s-BuLi (1.3 M, 0.278 mol, 214 mL) at −78° C. The mixture was stirred at this temperature for 0.5 hour, and then a solution of 3,4-difluorobenzoic acid (20 g, 0.127 mol) in THF (100 mL) was added dropwise. After stirring for 1 hour, CuBr.DMS (3.9 g, 0.019 mol, 15% mol) was added, followed by 3-bromoprop-1-ene (46 g, 0.38 mol) in 50 mL of THF. The reaction mixture was allowed to warm to room temperature and was quenched with water. The aqueous layer was washed with Et2O, and acidified with 4 N HCl. The mixture was extracted with Et2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give 2-allyl-3,4-difluorobenzoic acid (22 g, 55%). 1H NMR (CDCl3): 3.91 (d, 2H), 5.06 (m, 2H), 6.01 (m, 1H), 7.12 (m, 1H), 7.90 (m, 1H).
Reaction SMILES: [C:1]([N:5]1[C:9]([Cl:10])=[C:8]([CH2:11]O)[C:7]([C:13]([F:16])([F:15])[F:14])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].P(Br)(Br)[Br:18].O>C(OCC)C>[Br:18][CH2:11][C:8]1[C:7]([C:13]([F:16])([F:15])[F:14])=[N:6][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:9]=1[Cl:10]
Reactant: CC(C)(C)n1nc(C(F)(F)F)c(CO)c1Cl
Reactant: BrP(Br)Br
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)n1nc(C(F)(F)F)c(CBr)c1Cl
Temperature: -10 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
A solution of 9.2 g (35.7 mmoles) of (1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol dissolved in 100 ml of diethyl ether was cooled to −10° C. Thereto was added 11.6 g (42.9 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature overnight to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with diethyl ether. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 10.0 g (yield: 87.3%) of 4-bromomethyl-1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8](Cl)=[CH:7][C:3]=1[NH:4][CH2:5][CH3:6].[OH:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH2:21]>>[Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[N:4]([NH:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][OH:15])[CH2:5][CH3:6]
Reactant: NCCOCCO
Reactant: CCNc1cc(Cl)c([N+](=O)[O-])cc1Cl
Product: CCN(NCCOCCO)c1ccc([N+](=O)[O-])cc1Cl

Procedure:
0.01 mole (2.35 g) of 2,5-dichloro-4-nitro-N-ethylaniline is heated in 10 ml of β-(β'-hydroxyethoxy)ethylamine for 30 minutes on a steam bath.
Reaction SMILES: Cl.C([NH:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([F:17])=[C:12]([NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])[N:11]=1)C1C=CC=CC=1>[Pd].CO>[NH2:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([F:17])=[C:12]([NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])[N:11]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:17])=[C:12]([NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])[N:11]=1
Reactant: CC(C)(C)Nc1nc(NCc2ccccc2)c(Cl)cc1F
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)Nc1nc(N)c(Cl)cc1F
Product: CC(C)(C)Nc1nc(N)ccc1F
Reaction time: 1 h

Procedure:
To a mixed solution of 18 ml methanol and 1.4 g concentrated hydrochloric acid were added 3.1 g of 20 2-benzylamino-6-(t-butylamino)-3-chloro-5-fluoropyridine together with 0.33 g of 10% palladium on carbon, and the mixture was hydrogenated at 30° C. for 1 hour. The catalyst was separated by filtration, and the solvent and the like were distilled off under reduced pressure. To the residue was added 50 ml of chloroform, and the mixture was washed with 10 ml of 6% aqueous solution of sodium hydroxide, and the chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel, 40 g; eluent: chloroform:n-hexane, 3:1 and then 1:1) to obtain 1.35 g of 2-amino-6-(t-butylamino)-3-chloro-5-fluoropyridine as a pale brown oil, and 0.32 g of 2-amino-6-(t-butylamino)-5-fluoropyridine as a brown oil.
Reaction SMILES: C(Cl)Cl.C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]([C:21]2[CH:22]=[C:23]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:30][CH:29]=3)[C:24]([Cl:27])=[CH:25][CH:26]=2)=[O:20])[CH2:13][CH2:12]1)=O)(C)(C)C.FC(F)(F)C(O)=O>O>[NH:11]1[CH2:12][CH2:13][CH:14]([CH2:17][NH:18][C:19]([C:21]2[CH:22]=[C:23]([C:28]3[CH:29]=[CH:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][CH:33]=3)[C:24]([Cl:27])=[CH:25][CH:26]=2)=[O:20])[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)c2ccc(Cl)c(-c3ccc(-c4ccccc4)cc3)c2)CC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCC1CCNCC1)c1ccc(Cl)c(-c2ccc(-c3ccccc3)cc2)c1
Reaction time: 1 h
Yield: 98.8 %

Procedure:
To an oven dried 10 mL round bottom flask was added 5 mL of DCM, 20 mg (0.04 mmol) of 331, 1.5 mL trifluoroacetic acid (TFA), and 50 μL H2O. The reaction solution was stirred for 1 hour and quenched with 1 mL of saturated NaHCO3. The product was taken up in 20 mL of DCM and the organic solution further washed with water (3×15 mL) and dried over Na2SO4. The organic solution was rotary evaporated to provide 16.0 mg of the product as a pale tan oil (99.0% yield). 1H NMR 400 MHz DMSO-d6: δH 8.71 (1H, dd, J=2.7, 3.1 Hz), 8.48 (1H, br s), 8.07 (1H, br s), 7.90 (1H, s), 7.83-7.30 (10H, m); 3.28-1.16 (11H, m); MS (ES+) m/z 405 (M+H); HPLC (214 nm), rt 4.94 min, 99.8%.
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[NH2:11][C:12]1[C:17]([O:18][CH2:19][C@@H:20]([C:29](O)=[O:30])[NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:16][CH:15]=[CH:14][C:13]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CN(C=O)C>CCOC(C)=O>[O:30]=[C:29]1[NH:11][C:12]2[C:13]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:14][CH:15]=[CH:16][C:17]=2[O:18][CH2:19][C@@H:20]1[NH:21][C:22](=[O:23])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1cccc(-c2ccccc2)c1N)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1COc2cccc(-c3ccccc3)c2NC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 34.3 %

Procedure:
0.143 ml of diethyl cyanophosphonate (156 mg, 0.96 mmol) is introduced, at 0° C., into a 25 mL three-necked flask containing 260 mg of 42 (0.70 mmol) and 6.5 mL of DMF, followed 10 minutes later by 0.109 ml of TEA (0.77 mmol). The reaction medium is stirred at 0° C. for 2 h. 25 ml of AcOEt are added and then the mixture is washed with twice 25 mL of distilled water. The organic phase is dried over MgSO4, filtered and then evaporated to dryness. The crude product is chromatographed on a silica cartridge (24 g, eluent heptane/AcOEt, in an AcOEt gradient: 25 to 75%). 85 mg of expected product 43 are obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)#[N:24]>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)=[CH:3][C:2]=1[C:28]1[CH:29]=[CH:30][C:25]([C:23]#[N:24])=[CH:26][CH:27]=1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: N#Cc1ccc(B(O)O)cc1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccc(C#N)cc4)c3)cnc2c1F
Yield: 10 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 4-cyanobenzeneboronic acid were coupled in the same way as in Example 30 to give 2′-fluoro-5′-[8-fluoro-7-(1-hydroxy-1-methylethyl)-imidazo[1,2-α]pyridin-3-yl]biphenyl-4-carbonitrile as an off-white solid (12 mg, 10%): m/z (ES+) 390 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[OH:15])[CH:5]=[CH:4][N:3]=1.[NH2:16][C:17](=[O:31])[C@@H:18]([NH:20][C:21]1[N:26]=[C:25](Cl)[N:24]=[C:23]([C:28]([NH2:30])=[O:29])[CH:22]=1)[CH3:19].C([O-])([O-])=O.[Cs+].[Cs+].ClCCl>CN(C=O)C.[Cu]I.C(Cl)Cl.CO>[NH2:16][C:17](=[O:31])[C@@H:18]([NH:20][C:21]1[N:26]=[C:25]([O:15][C:9]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=2)[N:24]=[C:23]([C:28]([NH2:30])=[O:29])[CH:22]=1)[CH3:19]
Reactant: Nc1cc(-c2cc(Cl)ccc2O)ccn1
Reactant: C[C@H](Nc1cc(C(N)=O)nc(Cl)n1)C(N)=O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: C[C@H](Nc1cc(C(N)=O)nc(Oc2ccc(Cl)cc2-c2ccnc(N)c2)n1)C(N)=O
Temperature: 120 °C
Reaction time: 4 h
Yield: 88.3 %

Procedure:
A mixture of 2-(2-aminopyridin-4-yl)-4-chlorophenol (110 mg, 0.5 mmol), (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-chloropyrimidine-4-carboxamide (122 mg, 0.5 mmol), CuI (10 mg, 0.05 mmol) and Cs2CO3 (191 mg, 0.5 mmol) in DMF (3 mL) was stirred at 120° C. for 4 hrs. The reaction mixture was cooled to room temperature, worked up with dichloromethane and subjected to flash chromatography (DCM/methanol) to give (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(2-(2-aminopyridin-4-yl)-4-chlorophenoxy)pyrimidine-4-carboxamide as a white solid (189 mg, yield 85%). 1H NMR (CD3OD): 7.82-8.05 (1H, br), 7.6 (2H, m), 7.40 (2H, m), 6.80 (1H, m), 6.60 (2H, m), 4.23-4.10 (1H, m), 1.35 (3′-1, d, J=7.0 Hz). LC/MS: m/z=428 [M+H]+.
Reaction SMILES: C(OC1C(C(O)=O)=NC=CC=1OC)C1C=CC=CC=1.C([O:27][C:28]1[C:29]([C:38]([OH:40])=O)=[N:30][C:31]([O:36][CH3:37])=[CH:32][C:33]=1[O:34][CH3:35])C1C=CC=CC=1.CO[C:43]1[CH:56]=[CH:55][C:46]([O:47][C:48]2[CH:54]=[CH:53][C:51]([NH2:52])=[CH:50][CH:49]=2)=[CH:45][CH:44]=1.O(C1C=CC(N)=CC=1)C1C=CC=CC=1>>[OH:27][C:28]1[C:29]([C:38]([NH:52][C:51]2[CH:50]=[CH:49][C:48]([O:47][C:46]3[CH:55]=[CH:56][CH:43]=[CH:44][CH:45]=3)=[CH:54][CH:53]=2)=[O:40])=[N:30][C:31]([O:36][CH3:37])=[CH:32][C:33]=1[O:34][CH3:35]
Reactant: COc1cc(OC)c(OCc2ccccc2)c(C(=O)O)n1
Reactant: COc1ccc(Oc2ccc(N)cc2)cc1
Agent: COc1ccnc(C(=O)O)c1OCc1ccccc1
Agent: Nc1ccc(Oc2ccccc2)cc1
Product: COc1cc(OC)c(O)c(C(=O)Nc2ccc(Oc3ccccc3)cc2)n1

Procedure:
The procedure of Example 29 was repeated, except that 3-benzyloxy-4-methoxypicolinic acid was changed to 3-benzyloxy-4,6-dimethoxypicolinic acid and 4-(4′-methoxyphenoxy)aniline was changed to 4-phenoxyaniline. Thus, the title compound was prepared.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][C:6]([CH3:29])=[C:7]([C:23]([O:25][CH2:26][CH2:27][Br:28])=[O:24])[CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:9]=1[C:10]([O:12][CH3:13])=[O:11].[CH2:30]([O:32][CH2:33]Cl)[CH3:31].C1(C)C=CC=CC=1>O1CCCC1.O>[CH2:30]([O:32][CH2:33][N:5]1[C:6]([CH3:29])=[C:7]([C:23]([O:25][CH2:26][CH2:27][Br:28])=[O:24])[CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:4]1[CH3:3])[CH3:31]
Reactant: CCOCCl
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCBr)C1c1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOCN1C(C)=C(C(=O)OC)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCCBr)=C1C
Temperature: 0 °C
Yield: 72.5 %

Procedure:
10.65 g of a 80% suspension of sodium hydride in liquid paraffin are suspended in 300 ml of anhydrous tetrahydrofuran. A solution of 120 g of 3-methyl 5-(2-bromoethyl) (±)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate and 28.4 g of chloromethyl ethyl ether in 300 ml of anhydrous tetrahydrofuran is slowly added dropwise in the course of 4 h at -5° to -7° C., while stirring. After the mixture has been stirred for a further hour at 0° C., 600 ml of toluene and 210 ml of water are added in succession. The phases are separated, and the organic phase is washed with water, dried overnight and evaporated in vacuo. The residue is dissolved in 390 ml of warm ethanol and the stirred solution is then cooled. The product crystallises out during this procedure. It is cooled to 0° C., filtered off under suction, washed with ice-cold ethanol and dried. 98.5 g of the title compound of m.p. 72.5°-74° C. are obtained.
Reaction SMILES: [CH:1]1([N:4]([CH3:20])[CH:5]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]3[CH:10]=[C:9]([C:17](O)=[O:18])[CH:8]=[CH:7][C:6]2=3)[CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(OCC)=O.[N-:34]=[N+:35]=[N-:36].[Na+]>O1CCCC1.O>[CH:1]1([N:4]([CH3:20])[CH:5]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]3[CH:10]=[C:9]([C:17]([N:34]=[N+:35]=[N-:36])=[O:18])[CH:8]=[CH:7][C:6]2=3)[CH2:3][CH2:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: CN(C1CC1)C1CCC(C)(C)c2cc(C(=O)O)ccc21
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CN(C1CC1)C1CCC(C)(C)c2cc(C(=O)N=[N+]=[N-])ccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A stirred, cooled (ice bath) solution of 5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydronaphthalene-2 carboxylic acid (Intermediate 56, 0.22 g, 0.83 mmol) in anhydrous tetrahydrofuran (4 mL) was treated with triethyl amine (0.16 mL, 1.1 mmol) followed by ethyl chloroformate (0.10 mL, 1.08 mmol). After 5 h, sodium azide (0.081 g, 1.24 mmol) was added and the reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title product that was used as such for the next reaction (0.24 g, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[CH:7]([NH2:13])[CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1.[C:14]([O:18][C:19]([N:21]([CH2:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:14]([O:18][C:19](=[O:20])[N:21]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:34][NH:13][CH:7]2[C:6]3[N:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12][C:11]=3[CH2:10][CH2:9][CH2:8]2)=[CH:36][CH:37]=1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: COc1cnc2c(c1)CCCC2N
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C=O)cc1)Cc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cnc2c(c1)CCCC2NCc1ccc(CN(Cc2ccccn2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
Using General Procedure B: To a solution of (3-methoxy-5,6,7,8-tetrahydroquinolin-8-yl)-amine (0.27 g, 1.5 mmol) and 4-[[N-(t-butoxycarbonyl)-N-(2-pyridinylmethyl)amino]methyl]benzaldehyde (prepared as described by Bridger et al, U.S. patent application Ser. No. 09/535,314) (0.57 g, 1.7 mmol) in CH2Cl2 (15 mL) was added NaBH(OAc)3 (0.48 g, 2.3 mmol) and the mixture stirred at room temperature for 16 h. Purification of the crude material by column chromatography on silica gel (5% MeOH/CH2Cl2) gave {4-[(3-methoxy-5,6,7,8-tetrahydroquinolin-8-ylamino)-methyl]-benzyl}-pyridin-2-ylmethyl-carbamic acid tert-butyl ester (0.43 g, 58%). 1H NMR (CDCl3) δ 1.45 (m, 9H), 1.77 (m, 2H), 2.00 (m, 1H), 2.12 (m, 1H), 2.77 (m, 2H), 3.80 (m, 1H), 3.81 (s, 3H), 3.85 (d, 1H, J=12.0 Hz), 3.95 (d, 1H, J=12.0 Hz), 4.44 (br s, 2H), 4.55 (br s, 2H), 6.88 (d, 1H, J=1.5 Hz), 7.15 (m, 2H), 7.23 (br s, 2H), 7.34 (d, 2H, J=6.0 Hz), 7.62 (t, 1H, J=7.5 Hz), 8.11 (d, 1H, J=1.5 Hz), 8.52 (d, 1H, J=6.0 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][C:13](=[O:15])[CH3:14])[N:3]=1.C(N(CC)CC)C.ClC1C(NC=O)=C([NH:33][C@H:34]2[CH2:38][C@@H:37]([CH2:39][OH:40])[CH:36]=[CH:35]2)N=C(NC(=O)C)N=1.CO>C(O)C>[Cl:11][C@H:6]1[C:7]([NH:8][CH:9]=[O:10])([NH:33][C@@H:34]2[CH2:38][C@H:37]([CH2:39][OH:40])[CH:36]=[CH:35]2)[CH:2]=[N:3][C:4]([NH:12][C:13](=[O:15])[CH3:14])=[N:5]1
Reactant: CC(=O)Nc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: CC(=O)Nc1nc(Cl)c(NC=O)c(N[C@@H]2C=C[C@H](CO)C2)n1
Solvent: CO
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)NC1=N[C@@H](Cl)C(NC=O)(N[C@H]2C=C[C@@H](CO)C2)C=N1

Procedure:
(1S,4R)-4-Amino-2-cyclopentene-1-methanol dibenzoyl-D-tartrate prepared as described in Example 13 (2.76 g, 9.02 mmol) was dissolved in water (20 mL) and applied to a column of 65 mL of Amberlite IA-400 (OH- form) anion exchange resin. The column was washed with water. Basic fractions were combined and evaporated to a residual oil which was dried by evaporation of absolute ethanol and then at 0.5 mm to give (1S,4R)-4-amino-2-cyclopentene-1-methanol (1.2 g) as a pale yellow oil (darkens rapidly in air) which was used immediately. This oil was dissolved in ethanol (5 mL) and added to a solution of N-(4,6-dichloro-5-formamido-2-pyrimidinyl)acetamide (2.07 g, 8.31 mmol), prepared as described in Example 15, and triethylamine (2.50 g, 24.8 mmol). The resulting dark solution was heated (oil bath 75°-80° C.) under nitrogen for 50 minutes. The solution was evaporated to a syrup which was applied to a silica gel column. Title compound was eluted with 3 to 5% methanol-chloroform as a pale yellow solid foam (1.59 g, 54%); 1H-NMR identical with that of crystallized sample. Such a sample was crystallized from ethanol to give white granules, m.p. 194°-195° C.; 1H-NMR (DMSO-d6) identical with that of the title compound of Example 15; [α]D20 +2.7°, [α]578 ° +3.6°, [α]54620 +2.9°, [α]43620 -2.5°, [α]36520 -41.2° (c=0.238, methanol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:18]2[C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[N:14]([CH3:22])[C:13]=2[N:12]=[C:11](Cl)[C:10]=1[C:24]#[N:25].[C:26]1([CH:32]([NH2:40])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.NCC1C(N2CCOCC2)=NC2N(C)C(=O)N(C)[C:50](=[O:51])C=2C=1C1C=C(F)C=CC=1Br>>[NH2:25][CH2:24][C:10]1[C:11]([NH:40][CH:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[N:12][C:13]2[N:14]([CH3:22])[C:15](=[O:21])[N:16]([CH3:20])[C:17](=[O:19])[C:18]=2[C:9]=1[C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[O:51][CH3:50]
Reactant: NC(Cc1ccccc1)c1ccccc1
Reactant: Cn1c(=O)c2c(-c3cc(F)ccc3Br)c(C#N)c(Cl)nc2n(C)c1=O
Reactant: Cn1c(=O)c2c(-c3cc(F)ccc3Br)c(CN)c(N3CCOCC3)nc2n(C)c1=O
Product: COc1ccc(F)cc1-c1c(CN)c(NC(Cc2ccccc2)c2ccccc2)nc2c1c(=O)n(C)c(=O)n2C

Procedure:
The title compound was prepared from Compound 47a (Example 42) and 1,2-diphenylethanamine, according to procedure described in the synthesis of Compound 47. MS [m+H] calc'd C32H31FN5O3 540; found 540.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]([CH2:16][C:17]1[CH:22]=[C:21]([CH2:23][OH:24])[CH:20]=[CH:19][N:18]=1)[CH2:6]/[CH:7]=[CH:8]/[C:9]#[C:10][C:11]([O:14][CH3:15])([CH3:13])[CH3:12])[CH3:4].Br[CH2:26]/[CH:27]=[CH:28]/[C:29]1[CH:33]=[CH:32][S:31][CH:30]=1.C(OCC)C>O1CCCC1>[CH2:3]([N:5]([CH2:16][C:17]1[CH:22]=[C:21]([CH2:23][O:24][CH2:26]/[CH:27]=[CH:28]/[C:29]2[CH:33]=[CH:32][S:31][CH:30]=2)[CH:20]=[CH:19][N:18]=1)[CH2:6]/[CH:7]=[CH:8]/[C:9]#[C:10][C:11]([O:14][CH3:15])([CH3:13])[CH3:12])[CH3:4]
Reactant: BrC/C=C/c1ccsc1
Reactant: CCN(C/C=C/C#CC(C)(C)OC)Cc1cc(CO)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCN(C/C=C/C#CC(C)(C)OC)Cc1cc(COC/C=C/c2ccsc2)ccn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 53.6 %

Procedure:
11.6 mg of 60% oily sodium hydride was suspended in 0.5 ml of tetrahydrofuran at 0 ° C., under a nitrogen atmosphere, and a tetrahydrofuran solution( 2 ml) of 87.5 mg of (E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-4-hydroxymethyl-2-pyridylmethylamine was added dropwise. The mixture was stirred for 20 minutes, and a tetrahydrofuran solution (1 ml) of 50 mg of (E)-3-bromo-1-(3-thienyl)-1-propene was added dropwise. The mixture was stirred overnight at room temperature, and then ice water and ethyl ether were added. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The desiccant was separated by filtration, and the solvent was evaporated under reduced pressure. The residue was purified by medium-pressure liquid chromatography [silica gel column, chloroform→chloroform/methanol=20/1] to give 56 mg (yield 46%) of the captioned compound as a pale yellow oil.