Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]2=[N:14]1)[CH2:10][C:11]#[CH:12]>>[F:8][C:7]1[C:2]([C:12]#[C:11][CH2:10][CH2:9][N:13]2[N:14]=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=[N:17]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: C#CCCn1nc2ccccc2n1
Reactant: Fc1cccnc1Cl
Product: Fc1cccnc1C#CCCn1nc2ccccc2n1
Yield: 27.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-chloro-3-fluoropyridine (42 mg, 0.32 mmol) and 2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole (50 mg, 0.29 mmol, Example 109(D)). Reaction time: 13 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 21 mg (80 μmol, 27%) of 2-(4-(3-fluoropyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH:9][CH:10]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13])[C:3]=1[O:20][CH2:21][CH:22]([OH:24])[CH3:23].[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.C(OCC)(=O)C>N1C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH:9][CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:16]([O:18][CH3:19])=[O:17])[C:3]=1[O:20][CH2:21][CH:22]([O:24][S:31]([C:28]1[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=1)(=[O:33])=[O:32])[CH3:23]
Reactant: COC(=O)C(=CNc1ccc(F)c(F)c1OCC(C)O)C(=O)OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)C(=CNc1ccc(F)c(F)c1OCC(C)OS(=O)(=O)c1ccc(C)cc1)C(=O)OC
Temperature: 5 °C
Reaction time: 72 h
Yield: 92.2 %

Procedure:
To a solution of 2.07 g of the compound obtained in Example 6 in 4.2 ml of pyridine was added 1.49 g of p-toluenesulfonyl chloride and the mixture was stirred at an external temperature of 5° C. for 3 days. To the mixture was added ethyl acetate, and the solution was washed successively with 1 N hydrochloric acid, a saturated sodium bicarbonate aqueous solution and water, and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography to yield 2.76 g of the titled compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:3]=1.[C:21]([C:24]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)([CH3:26])[CH3:25])([OH:23])=[O:22].O.Cl>C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][NH:10][C:4]1[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:29]2[CH:28]=[C:27]([C:24]([CH3:26])([CH3:25])[C:21]([OH:23])=[O:22])[CH:32]=[CH:31][CH:30]=2)[CH:3]=1
Reactant: CC(C)(C(=O)O)c1cccc(B(O)O)c1
Reactant: COc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Temperature: 130 °C
Yield: 87.3 %

Procedure:
A solution of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine (0.51 mmol) and 3-(1-carboxy-1-methyl-ethyl)-phenyl boronic acid (0.61 mmol) in acetonitrile (2.5 mL) and aqueous sodium carbonate solution (0.4 M, 2.5 mL) is degassed with nitrogen for 5 minutes before addition of tetrakistriphenylphosphine palladium (0) (29.5 mg, 5 mol %). The reaction vessel is sealed and heated under microwave to 130° C. for 30 minutes. To the reaction mixture is added 2 mL of water, the pH is adjusted to about 7 using 2 N aqueous HCl and this mixture is extracted three times with ethyl acetate (30 mL). The combined extracts are washed with brine, dried over sodium sulfate and concentrated. The residue is subjected to silica gel chromatography to afford 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid as a solid (205 mg, 75%). LC/MS: RT=2.39 minutes, MS: 460 (M+H); 1H NMR [300 MHz, (CD3)2SO]: δ 12.38 (1H, s), 7.36-8.00 (7H, m), 6.58 (1H, s), 3.84 (3H, s), 3.58 (2H, m), 2.98 (2H, m), 1.54 (6H, s).
Reaction SMILES: [CH3:1]CCCCC.[H-].[Na+].[Br:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13]([OH:15])=[O:14]>CN(C=O)C.CCOC(C)=O>[Br:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13]([O:15][CH3:1])=[O:14]
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: CCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a mixture of hexane washed 60% disp. NaH (2.28 g, 57 mmol) in DMF (250 mL), 0° C., was added 3-bromo-4-methylbenzoic acid (10.03 g, 46.6 mmol). After 30 min, the reaction was warmed to room temperature, diluted with EtOAc (1.25 L) and washed with H2O (5×250 mL). The organic layer was MgSO4 dried and concentrated. The residue was chromatographed (˜375 g silica, 10% EtOAc/CH2Cl2) to give the desired product as a solid (16.68 g, 63%); IR(CHCl3): 1260, 1294, 1437, 1721 cm−1; NMR(300 MHz, CDCl3): 2.46 (s, 3H); 3.92 (s, 3H); 7.31 (d, 1H, J=7.8 Hz); 7.88 (d, 1H, J=7.8 Hz); 8.21 (s, 1H); MS(FD): 228.0.
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:36][CH2:37][NH2:38])=[CH:6][CH:5]=1.[CH3:40][O:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[S:48](Cl)(=[O:50])=[O:49]>>[CH:23]([N:15]1[C:16]2[C:21](=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:13]([CH2:12][CH2:11][NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:39])=[O:2])=[CH:5][CH:6]=2)=[C:14]1[CH2:36][CH2:37][NH:38][S:48]([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=1[O:41][CH3:40])(=[O:50])=[O:49])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COc1ccccc1S(=O)(=O)Cl
Reactant: COC(=O)c1ccc(NCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: COc1ccccc1S(=O)(=O)NCCc1c(CCNc2ccc(C(=O)O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Yield: 85 %

Procedure:
The intermediate from example 142 step 12 was treated with 2-methoxy-benzenesulfonyl chloride according to the procedure in Example 87 step 2 to generate the desired product in 85% yield.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C-:8]#[N:9].[K+].[C:11]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>O.C(O)C>[NH2:9][CH2:8][C:11]1([N:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: [C-]#N
Reactant: O=C1CCCCC1
Reactant: C1CCNCC1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: NCC1(N2CCCCC2)CCCCC1

Procedure:
Piperidine hydrochloride (24.1 g. 0.2 mole) and KCN (13.0 g. 0.2 mole) were dissolved in water (80 ml) and ethanol (160 ml). To this stirred solution was added dropwise a solution of cyclohexanone (19.6 g., 0.2 mole) in ethanol (40 ml), the mixture refluxed for 24 hr. Ethanol was then removed under reduced pressure and the residue extracted with chlorofrom. The extract was washed with water, dried (Na2SO4) and evaporated under reduced pressure to give a pale, amber oil (27.0 g. 68.8%) which crystallized on standing. Recrystallization from ethanol afforded colourless plates of 1-(1-cyanocyclohexyl)piperidine m.p. 67°-8°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:5]=[CH:6][C:7]=1[NH2:8].[Cl-].Cl[C:19](=[N+:21]([CH2:24][CH3:25])[CH2:22][CH3:23])Cl>>[C:11]([C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[N:1][C:2]=2[CH:3]=1)#[N:12]
Reactant: N#Cc1ccccc1-c1ccc(N)c(N)c1
Reactant: CC[N+](CC)=C(Cl)Cl
Agent: [Cl-]
Product: CCN(CC)c1nc2cc(-c3ccccc3C#N)ccc2[nH]1

Procedure:
2-(3,4-Diaminophenyl)benzonitrile (4.78 mmoles, 1.0 g) was reacted as described in Example 31 with (dichloromethylene) diethylammonium chloride (1.435 mmoles, 2.73 g prepared following the procedure described in Angew. Chem. Int. Ed. 12:806 (1973)) to yield 0.91 g of 5-(2-cyanophenyl)-2-diethylamino-1H-benzimidazole.
Reaction SMILES: C(N(CC)CC)C.[CH2:8](CN)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)[C:28]2C=CC=[CH:32][C:27]=2N=N1.[C:44]([O:47]CC)(=[O:46])[CH3:45]>C(Cl)Cl>[CH2:8]([O:47][C:44](=[O:46])[CH2:45][CH:27]([CH3:32])[CH3:28])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CCOC(C)=O
Reactant: NCCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(R)-2-[carboxymethyl(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester (Example 1) (1.05 grams, 2.41 mmol) in methylene chloride (20 mL) were added sequentially triethylamine (0.84 mL, 6.0 mmol),N-benzylmethylamine (0.34 mL, 2.63 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (1.17 grams, 2.69 mmol). The mixture was stirred at room temperature overnight and then diluted with ethyl acetate. The solution was washed with 0.5N hydrochloric acid solution and brine, dried over magnesium sulfate and concentrated under vacuum. The residue was chromatographed on silica gel using 35% ethyl acetate in hexane (plus a small amount of methylene chloride to load the sample on the column) affording 2-(R)-2-[benzylmethylcarbamoylmethyl)(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester as a clear oil, 1.14 grams (88%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39][CH:40]([C:44](O)=[O:45])[C:41](O)=[O:42])([CH3:32])[CH3:31]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:10][C:41](=[O:42])[C:40]([S:39][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH:30]([CH3:31])[CH3:32])=[C:44]([OH:45])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2ccc(Cl)cc2)oc1=O

Procedure:
The title compound was prepared by Method A using 4'-chloroacetophenone (2.33 g, 15.1 mmol), trimethylsilyl triflate (3.5 mL, 18.1 mmol), triethylamine (4.26 mL, 30.6 mmol), methylene chloride (30 mL), and diethyl ester of [(2-isopropylphenyl)thio] propanedioic acid (3.11 g, 10.0 mmol) m.p. 148-151° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.25 (d, 6H), 3.41 (m, 1H), 6.86 (s, 1H), 6.92 (m, 1H), 7.08 (m, 2H), 7.27 (m, 1H), 7.62 (m, 2H), 7.86 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][O:14][CH3:15])=[C:6](I)[CH:5]=1.[CH3:18][Zn]C.C1COCC1>C1COCC1.C(OCC)(=O)C.C1C=CC([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)=CC=1>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:5]=[C:6]([CH3:18])[C:7]([O:12][CH2:13][O:14][CH3:15])=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: COCOc1c(I)cc(C(=O)OC)cc1OC
Reactant: C[Zn]C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCOc1c(C)cc(C(=O)OC)cc1OC
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-iodo-5-methoxy-4-methoxymethoxybenzoic acid methyl ester (700 mg) in THF (7 mL) were added tetrakis(triphenylphosphine)palladium(0) (115 mg) and 2M dimethylzinc/THF solution (1.20 mL), and the mixture was stirred at 80° C. for 30 minutes. The reaction solution was diluted with ethyl acetate, washed with 1N hydrochloric acid, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title compound (767 mg) as a crude purified product of pale yellow oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.[C:22](=[S:24])=O.[CH3:25][C:26]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:27]=1[CH2:28]Cl>C(Cl)(Cl)Cl>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:22]([CH2:28][C:27]1[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:26]=1[CH3:25])=[S:24]
Reactant: Cc1ccc(C)c(CCl)c1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C=S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=S)Cc1cc(C)ccc1C
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
10.8 G (0.05 mol) of L-phenylalanine methylester hydrochloride was added to 100 ml of chloroform. To the mixture was added 13.9 ml (0.1 mol) of triethylamine while cooling with ice. 20 Ml of a chloroform solution containing 3.0 g (0.05 mol) of carbonyl sulfide was dropwise added to the solution at a temperature of from 5° to 10° C. in 20 minutes. After stirring at the same temperature for 30 minutes, 30 ml of chloroform solution containing 7.7 g (0.05 mol) of 2.5-dimethylbenzylchloride was dropwise added to the solution in 30 minutes. After this, the mixture was stirred at room temperature for 1 hour. After completion of reaction, the reaction mixture was washed with 100 ml of water, 100 ml of 2N-hydrochloric acid and 150 ml of water in order twice and was dried over anhydrous sodium sulfate in a similar manner to that described in Example 2. After filtration of the drying agent, the syrup-like substance obtained by removing the solvent of the filtrate in vacuo was crystallized from 30 ml of ethylacetate and 50 ml of n-hexane to yield 10.8 g of white crystals.
Reaction SMILES: CN1C2C(C(F)(F)F)=CC(NC3C=NC=CC=3)=CC=2C2CNCCC12.[CH3:26][N:27]1[C:35]2[C:30](=[CH:31][C:32]([NH:38][C:39]3[CH:40]=[N:41][CH:42]=[CH:43][C:44]=3C(F)(F)F)=[CH:33][C:34]=2[C:36]#[N:37])[C@@H:29]2[CH2:49][NH:50][CH2:51][CH2:52][C@H:28]12.BrC1C([O:60][CH:61]([CH3:63])[CH3:62])=NC=CC=1.CC([O-])(C)C.[Na+]>>[CH:61]([O:60][C:40]1[C:39]([NH:38][C:32]2[CH:31]=[C:30]3[C:35](=[C:34]([C:36]#[N:37])[CH:33]=2)[N:27]([CH3:26])[C@H:28]2[CH2:52][CH2:51][NH:50][CH2:49][C@@H:29]32)=[CH:44][CH:43]=[CH:42][N:41]=1)([CH3:63])[CH3:62]
Reactant: CC(C)Oc1ncccc1Br
Reactant: CN1c2c(C#N)cc(Nc3cnccc3C(F)(F)F)cc2[C@@H]2CNCC[C@@H]21
Agent: CC(C)(C)[O-]
Agent: CN1c2c(cc(Nc3cccnc3)cc2C(F)(F)F)C2CNCCC21
Agent: [Na+]
Product: CC(C)Oc1ncccc1Nc1cc(C#N)c2c(c1)[C@@H]1CNCC[C@@H]1N2C

Procedure:
The title compound was prepared by following the general method for (5-methyl-6-trifluoromethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indol-8-yl)-pyridin-3-yl-amine (Method B) as a tan solid (32 mg, 21%) from (4aS,9bR)-8-amino-6-cyano-3,4,4a,9b-tetrahydro-1H-pyrido[4,3-b]indole-2,5-dicarboxylic acid tert-butyl ester (Example 162, 150 mg, 0.46 mmol), 3-bromo-2-iso-propoxypyridine (91 mg, 0.42 mmol) and NaOt-Bu (66 mg, 0.69 mmol). 1H NMR (300 MHz, CDCl3) δ 7.58 (dd, J=5.0, 1.4 Hz, 1H), 7.18–6.97 (m, 3H), 6.71 (dd, J=7.6, 5.0 Hz, 1H), 5.83 (br s, 1H), 5.41 (sept, J=6.2 Hz, 1H), 3.53–3.48 (m, 1H), 3.33–3.01 (m, 4H), 2.99–2.80 (m, 2H), 2.79–2.61 (m, 1H), 2.59–2.01 (m, 1H), 2.00–1.80 (m, 2H), 1.39 (d, J=6.2 Hz, 6H); APCI MS m/z 364 [C21H25N5O+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:27]C1C=CC(C2CCC3C(=CC=C(O)C=3)O2)=CC=1>>[F:27][C:24]1[CH:23]=[CH:22][C:21]([CH:16]2[CH2:15][CH2:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([O:10][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=4)[CH:12]=3)[O:17]2)=[CH:26][CH:25]=1
Reactant: Oc1ccc2c(c1)CCC(c1ccc(F)cc1)O2
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccc(F)cc2)O3)nc1

Procedure:
2-[2-(4-Fluorophenyl)chroman-6-yloxy]-5-nitropyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 160 mg of 2-(4-fluorophenyl)chroman-6-ol. The product was purified on preparative TLC-plate covered with silica gel using heptane-ethyl acetate (4:1) as an eluant. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (dd, 1H, J 2.9, 0.4 Hz), 8.60 (dd, 1H, J 9.1, 2.9 Hz), 7.51 (m, 2H), 7.24 (m, 1H), 7.20 (dd, 1H, J 9.1, 0.4 Hz), 7.01 (d, 1H, J 2.8 Hz), 6.96 (dd, 1H, J 8.7, 2.8 Hz), 6.91 (d, 1H, 8.7 Hz), 5.15 (dd, 1H, J 10.3, 2.2 Hz), 2.94 (m, 1H), 2.76 (m, 1H), 2.17 (m, 1H), 2.01 (m, 1H).
Reaction SMILES: CO[C:3]([C:5]1[C:6]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][C:7]=2[N:8]=[CH:9][N:10]=1)=[O:4].[CH:22]1([CH2:28][NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CO>[CH2:15]([N:12]1[CH2:13][CH2:14][C:6]2[C:5]([C:3]([NH:29][CH2:28][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:4])=[N:10][CH:9]=[N:8][C:7]=2[CH2:11]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCC1CCCCC1
Reactant: COC(=O)c1ncnc2c1CCN(Cc1ccccc1)C2
Solvent: CO
Product: O=C(NCC1CCCCC1)c1ncnc2c1CCN(Cc1ccccc1)C2

Procedure:
Into a 50 ml round bottom flask was combined 7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4-carboxylic acid methyl ester (0.125 g, 0.411 mmol), C-cyclohexyl-methylamine (0.010 g, 0.88 mmol), and methanol (10 ml). The mixture was heated at reflux for 24 hrs. The mixture was allowed to cool, reduced in vacuo, and purified by flash chromatography using a methylene chloride:methanol gradient (0-10%). The combined fractions were reduced in vacuo to yield the title compound. (0.0177 g, 10.9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[F:44][C:45]1[CH:50]=[CH:49][C:48]([C@@H:51]([NH2:53])[CH3:52])=[CH:47][CH:46]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:53][C@H:51]([C:48]2[CH:49]=[CH:50][C:45]([F:44])=[CH:46][CH:47]=2)[CH3:52])=[O:42])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: C[C@H](N)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@@H](C)c4ccc(F)cc4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. A solution of (1S)-1-(4-fluorophenyl)ethylamine (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (34 mg, yield 76%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C@H:29]2[CH2:31][O:30]2)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C@H:29]([OH:30])[CH2:31][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:25][CH:24]=1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: Clc1ccc(OC[C@H]2CO2)cc1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C[C@@H](O)COc3ccc(Cl)cc3)CC1)O2

Procedure:
Compound 183 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2R)-2-[(4-chlorophenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=155-157° C.; 400 MHz 1H NMR (CDCl3) δ: 8.05 (dd, J=6.4, 7.6 Hz, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.68-7.64 (m, 1H), 7.51-7.47 (m, 1H), 7.25-7.22 (m, 2H), 6.86-6.84 (m, 2H), 4.14-4.11 (m, 1H), 3.98-3.96 (m, 2H), 2.94 (brs, 3H), 2.80-2.77 (m, 2H), 2.70-2.62 (m, 2H), 2.56-2.50 (m, 1H), 2.17 (d, J=13.6 Hz, 2H), 1.96-1.84 (m, 2H); LCMS: 486 [M+H]; enantiomeric excess determined from chiral HPLC: 98%; Chiral HPLC Rt=33.67 min.
Reaction SMILES: C(=[O:5])C(C)C.[C:6](N)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(NC=C(C)C)(=O)C1C=CC=CC=1.[CH3:28][C@H:29]1[CH2:34][C@@H:33]([OH:35])[C@H:32]([CH:36]([CH3:38])[CH3:37])[CH2:31][CH2:30]1.N1C=CC=CC=1>C1COCC1>[C:6]([OH:13])(=[O:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:28][C@H:29]1[CH2:34][C@@H:33]([OH:35])[C@H:32]([CH:36]([CH3:38])[CH3:37])[CH2:31][CH2:30]1
Reactant: NC(=O)c1ccccc1
Reactant: CC(C)C=O
Agent: CC(C)=CNC(=O)c1ccccc1
Agent: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(O)c1ccccc1
Temperature: 250 °C

Procedure:
0.10 mol of isobutyraldehyde and 0.20 mol of benzamide are heated together at 100° C. with stirring, and the product solid is heated in a sublimator at 250° C. and 1 mm Hg until formation of the enamide 1-benzoylamino-2-methylpropene is complete. A 70 mL stainless steel high pressure reactor fitted with a Pyrex glass liner and magnetic stir bar is charged with THF (5 mL), L-menthol (0.5 mmol), Co2 (CO)8 (0.05 mmol), pyridine (0.25 mmol), and 1-benzoylamino-2-methylpropene (0.5 mmol). The reactor is sealed, pressurized to 1500 psig with 15:1 CO:H2 and stirred for 24 hours at 100° C. The product mixture, isolated after removal of gas from the reactor vessel, contains a mixture of two diastereomeric valine derivatives, N-benzoyl-L-valine L-menthyl ester and N-benzoyl-D-valine L-menthyl ester. These diastereomers are separated by column chromatography on silica gel with benzene-ethyl acetate eluent and are separately hydrolyzed by heating to 100° C. in 1N HCl for 2 hours to give pure L- and D-valine, benzoic acid, and L-menthol, which is thereafter recycled to a repeat of the foregoing hydrocarboxylation reaction.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][C:18]1[CH:28]=[C:21]2[C:22]([CH:26]=O)=[CH:23][CH:24]=[CH:25][N:20]2[N:19]=1.O>O1CCCC1>[CH3:17][C:18]1[CH:28]=[C:21]2[C:22](/[CH:26]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:23][CH:24]=[CH:25][N:20]2[N:19]=1
Reactant: Cc1cc2c(C=O)cccn2n1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cccn2nc(C)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.2 %

Procedure:
Under nitrogen atmosphere, to a suspension of sodium hydride (2.70 g, 61.8 mmol) in tetrahydrofuran (42 mL) was added a solution of ethyl diethylphosphonoacetate (13.8 g, 61.8 mmol) in tetrahydrofuran (20 mL) at 0° C., and the mixture was stirred for 20 min. To the reaction mixture was added a solution of 2-methylpyrazolo[1,5-a]pyridine-4-carbaldehyde (9.00 g, 56.2 mmol) in tetrahydrofuran (50 mL), and the mixture was warmed to room temperature over 4 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=3/1) to give the title compound (11.8 g, yield 91%).