Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.[OH:3][N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]2[N:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]3[CH2:33][C:32]([CH3:35])([CH3:34])[N:31]([OH:36])[C:30]([CH3:38])([CH3:37])[CH2:29]3)[N:20]=[C:19]([NH:39][CH2:40][CH2:41][CH2:42][CH2:43][CH:44]3[CH2:49][C:48]([CH3:51])([CH3:50])[N:47]([OH:52])[C:46]([CH3:54])([CH3:53])[CH2:45]3)[N:18]=2)[CH2:6][C:5]1([CH3:56])[CH3:55].S([O-])([O-])=O.[Na+].[Na+].[C:63]([OH:67])([CH3:66])([CH3:65])[CH3:64]>O.C(OCC)(=O)C>[OH:67][C:63]([CH3:66])([CH3:65])[CH2:64][O:52][N:47]1[C:46]([CH3:54])([CH3:53])[CH2:45][CH:44]([CH2:43][CH2:42][CH2:41][CH2:40][NH:39][C:19]2[N:18]=[C:17]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:7]3[CH2:6][C:5]([CH3:56])([CH3:55])[N:4]([O:3][CH2:64][C:63]([CH3:66])([OH:67])[CH3:65])[C:9]([CH3:11])([CH3:10])[CH2:8]3)[N:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]3[CH2:33][C:32]([CH3:34])([CH3:35])[N:31]([O:36][CH2:64][C:63]([CH3:66])([OH:67])[CH3:65])[C:30]([CH3:38])([CH3:37])[CH2:29]3)[N:20]=2)[CH2:49][C:48]1([CH3:51])[CH3:50]
Reactant: CC(C)(C)O
Reactant: CC1(C)CC(CCCCNc2nc(NCCCCC3CC(C)(C)N(O)C(C)(C)C3)nc(NCCCCC3CC(C)(C)N(O)C(C)(C)C3)n2)CC(C)(C)N1O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(O)CON1C(C)(C)CC(CCCCNc2nc(NCCCCC3CC(C)(C)N(OCC(C)(C)O)C(C)(C)C3)nc(NCCCCC3CC(C)(C)N(OCC(C)(C)O)C(C)(C)C3)n2)CC1(C)C
Temperature: 60 °C
Yield: 37.2 %

Procedure:
A solution of 40 g (0.35 mol) of 30% aqueous hydrogen peroxide is added over 1.25 hours to a mixture of 11.7 g (0.011 mol) of 2,4,6-tris[N-(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl]butylamino}-s-triazine and 3.0 g (0.015 mol) of ferrous chloride tetrahydrate in 100 g of tert-butyl alcohol and 9 g of water. The reaction temperature is maintained at 60-65° C. during the peroxide addition. Two equal portions (2 g, 0.29 mol) of 50% aqueous hydrogen peroxide are added to the reaction mixture while the temperature is maintained at 60° C. for 9.5 hours. After the reaction mixture is diluted with ethyl acetate and cooled to room temperature, a solution of 100 g of 20% aqueous sodium sulfite is added. The reaction mixture is heated at 60° C. for one hour to decompose the excess peroxide. The aqueous layer is extracted with ethyl acetate, and the combined organic layers are concentrated. The crude product is purified by flash chromatography on silica gel with 2:1 (v/v) cyclohexane/ethyl acetate to afford a material which is triturated with 1:1 (v/v) cyclohexane/acetone to give 4.0 g of the title compound as a white solid, melting at 172-176° C.
Reaction SMILES: C([Si](CC)(CC)[O:4][C:5]1([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:9][C:8](=[O:11])[CH:7]=[CH:6]1)C.Cl.C(O)C>O>[OH:4][C:5]1([C:12]([F:13])([F:14])[F:15])[CH:6]=[CH:7][C:8](=[O:11])[CH:9]=[CH:10]1
Reactant: CC[Si](CC)(CC)OC1(C(F)(F)F)C=CC(=O)C=C1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C1C=CC(O)(C(F)(F)F)C=C1
Yield: 90 %

Procedure:
A mixture of 200 mg (0.68 mmol) of 4-triethylsiloxy-4-trifluoromethyl-2,5-cyclohexadien-1-one and 1 mL of a solution of 1 part 37% hydrochloric acid in 9 parts absolute ethanol was heated at reflux overnight and poured into 10 mL of water. The resulting aqueous mixture was extracted with three 10 mL portions of dichloromethane. Combination, drying (MgSO4), and concentration of the organic layers afforded a residue which was purified by PTLC (one 2 mm silica gel plate eluted with 1% methanol--99% dichloromethane) to give 109 mg (89% yield) of 4-hydroxy-4-trifluoromethyl-2,5-cyclohexadien-1-one. An analytical sample was obtained by crystallization from dichloromethane-hexane: mp 84-86° C.; 1H NMR (CDCl3) δ 3.40 (broad s, 1H), 6.40 (d, 2H, J=10 Hz), 6.89 (d, 2H, J=10 Hz); 13C NMR (CDCl3) 70.2 (q, JCF =30 Hz), 125. 0 (q, JCF =286H), 132.2 (d), 142. 7 (d), 184.5 (s) ppm; 19F NMR (CDCl3) relative to CFCl3) -79.6 ppm (s); IR (KBr) 3374, 3105, 3022, 2919, 1693, 1671, 1632, 1620, 1396, 1249, 1235, 1195, 1174, 1089, 1078, 1003, 988, 980, 973, 863, 698 cm-1; mass spectrum (70 eV) m/z (relative intensity) 178 (5, M30), 109 (100), 81 (34), 53 (36). Anal. Calcd. for C7H5F3O2:C, 47.20; H, 2.83. Found: C, 47.42; H, 2.80.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[OH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([SH:22])[C:14]=1[C:15]([OH:17])=[O:16].Cl>[OH-].[Na+]>[C:6]1([CH:2]([S:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:13]([OH:12])[C:14]=2[C:15]([OH:17])=[O:16])[C:3]([OH:5])=[O:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: O=C(O)c1c(O)cccc1S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1c(O)cccc1SC(C(=O)O)c1ccccc1

Procedure:
α-Bromophenylacetic acid (0.26 g, 1.2 mmol) was added to a solution of 2-hydroxy-6-mercaptobenzoic acid (0.20 g, 1.2 mmol) in 1N aqueous sodium hydroxide (25 ml). The reaction mixture was stirred at reflux temperature for 1 hour under a nitrogen atmosphere. The cooled reaction mixture was acidified with 2N hydrochloric acid. The solid that precipitated out was collected by filtration, washed with water, and dried in vacuo over calcium sulfate; yield 0.20 g (38%). NMR (CDCl3, 60 MHz): δ4.86 (s, SCHCO2H) p.p.m.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])=[CH:10][N:11]=1)[C:5]([O:7]C)=[O:6].O1CCC[CH2:14]1.C[Al](C)C.[Cl-].[NH4+]>CCOC(C)=O.CCOC(C)=O.CCCCCC>[F:12][C:9]1[C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]([CH3:14])=[N:11][CH:10]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1cc(Br)ncc1F
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(C(=O)O)c(F)cn1
Reaction time: 0.17 h
Yield: 374.8 %

Procedure:
To a solution of methyl 2-bromo-5-fluoroisonicotinate (1.0 g, 4.27 mmol) in tetrahydrofuran (25 ml) tetrakis(triphenylphosphine)palladium (495.0 mg, 0.43 mmol) was added. The mixture was stirred for 10 min, and then trimethylaluminum (5.13 ml, 1.00 M in heptane, 5.13 mmol) was added. The mixture was refluxed for 4 h, and the reaction was monitored by TLC (10% EtOAc-Hexane). Then, the reaction was diluted with EtOAc (75 ml) and a few drops of saturated. ammonium chloride were added. The mixture was filtered through a small silica gel pad, followed by removal of the solvent. The crude product was re-dissolved in 5N NaOH solution in water and stirred at room temperature for 2 hours. The crude product was purified on Flashmaster II to afford 250 mg of 5-fluoro-2-methylisonicotinic acid.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH3:11])=[CH:6][CH:5]=1.[C:13](Cl)(=[O:17])[CH:14]([CH3:16])[CH3:15].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:13]([N:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:12])=[O:2])=[CH:5][CH:6]=1)[CH3:11])(=[O:17])[CH:14]([CH3:16])[CH3:15]
Reactant: CNc1ccc(C(=O)OC)cc1
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)N(C)c1ccc(C(=O)O)cc1
Reaction time: 3 h
Yield: 87.4 %

Procedure:
4-Methylamino-benzoic acid methyl ester (0.41 g) were suspended in chloroform (20 ml). Isobutyryl chloride (0.79 g) in chloroform (10 ml) was added dropwise for 30 minutes and then dropwise triethylamine (1 ml) dissolved in chloroform (5 ml). The reaction mixture was stirred for 3 hours and the solvent was evaporated. 1M NaOII(aq) (40 ml) was added and the mixture stirred overnight. The solution was filtered to remove unsolved material and then acidified with 2M HCl(aq). Filtration and drying in vacuum yielded 0.48 g of the title product.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1.[OH-].[Na+].Cl>O1CCCC1.O>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:15])=[O:2])=[CH:5][C:6]=1[N+:12]([O-:14])=[O:13])#[N:11]
Reactant: COC(=O)c1ccc(C#N)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Cyano-3-nitro-benzoic acid methyl ester (13.4 g, 61.6 mmol) was dissolved in tetrahydrofuran (74 ml) and aqueous sodium hydroxide (1M) (73.9 ml) was added. The reaction mixture was stirred at 25° C. for 4 hours. Then the reaction mixture was diluted with water (700 ml) and acidified with aqueous hydrochloric acid (1M). The mixture was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. 4-Cyano-3-nitro-benzoic acid (12.0 g) was used in the next step without further purification. 1H-NMR (400 MHz, DMSO-d6): 13.00 (bs, 1H), 8.79 (s, 1H), 8.40 (d, 1H), 8.30 (d, 1H) ppm.
Reaction SMILES: [O:1]=[C:2]1[N:9]2[CH:4]([CH2:5][CH2:6]OC2(C)C)[CH:3]1[CH:12]([CH3:14])C.[Si:15](N1C(C=C)CC1=O)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].O=C1N2C(CCOC2(C)C)C1.C(I)C>>[CH2:12]([CH:3]1[CH:4]([CH:5]=[CH2:6])[N:9]([Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:2]1=[O:1])[CH3:14]
Reactant: C=CC1CC(=O)N1[Si](C)(C)C(C)(C)C
Reactant: CC(C)C1C(=O)N2C1CCOC2(C)C
Agent: CC1(C)OCCC2CC(=O)N21
Solvent: CCI
Product: C=CC1C(CC)C(=O)N1[Si](C)(C)C(C)(C)C

Procedure:
Following the procedure for the preparation of 8-oxo-2,2-dimethyl-7α-isopropyl-3-oxa-1-azabicyclo[4.2.0]octane (Example 4a, above), except that an equivalent amount of 1-(t-butyl-dimethylsilyl)-4-vinyl-2-azetidinone is substituted for the 8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo [4.2.0]octane of Example 4a and using ethyl iodide instead of isopropyl iodide, the title compound is obtained.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(N(C(C)C)CC)(C)C.CS(C)=O>[CH2:20]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])[CH:10]=[O:11])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: OC[C@@H](Cc1ccccc1F)N(Cc1ccccc1)Cc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C[C@@H](Cc1ccccc1F)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (R)-2-dibenzylamino-3-(2-fluoro-phenyl)-propan-1-ol (1 g, 2.9 mmol) in 2 mL of diisopropyl-ethyl-amine at 10° C. is slowly added a solution of sulfur trioxide pyridine complex (1.4 g, 8.6 mmol) in 5 mL of DMSO. The reaction is allowed to stir at room temperature for 45 minutes after which time the reaction is quenched by addition of ice water. The product is extracted into ether and the combined organic phases are washed with water, 5% citric acid, and brine. The organic layer is dried over sodium sulfate, filtered, and concentrated under reduce pressure to give the title compound.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:23][C:24]([NH2:26])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cu](C#N)[C:28]#[N:29].C(N)CN>CN1CCCC1=O>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:28]#[N:29])=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:23][C:24]([NH2:26])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[Cu]C#N
Reactant: NC(=O)Cc1cnc(Nc2ccc(Br)cc2)cc1NCc1ccccc1
Solvent: NCCN
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(Nc2cc(NCc3ccccc3)c(CC(N)=O)cn2)cc1
Temperature: 180 °C
Reaction time: 3 h
Yield: 14.9 %

Procedure:
20 mg of 4-(benzylamino)-6-[(4-bromophenyl)amino]pyridine-3-carboxyamide (the compound of Example 54) was dissolved in 0.4 mL of 1-methyl-2-pyrrolidinone, to which 5 mg of copper cyanide (I) was added, and stirred at 180° C. for 3 hours. After cooling, a 30% aqueous solution of ethylenediamine was added to the reaction mixture, extracted with chloroform, the extract was washed with water, and dried on anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=10:1) to obtain 2.3 mg (13%) of the title compound as a light brown solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[Cl:12][C:13]1[CH:21]=[C:20](F)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16].[F:26][C:27]1[CH:28]=[CH:29][C:30]([CH3:39])=[C:31]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=1.Cl>O>[Cl:12][C:13]1[CH:21]=[C:20]([N:36]2[CH2:35][CH2:34][N:33]([C:31]3[CH:32]=[C:27]([F:26])[CH:28]=[CH:29][C:30]=3[CH3:39])[CH2:38][CH2:37]2)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: Cc1ccc(F)cc1N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1N1CCN(c2cc(Cl)c(C(=O)O)cc2[N+](=O)[O-])CC1
Yield: 76.7 %

Procedure:
In a 20 ml scintillation vial equipped with a magnetic stir bar and fitted with a nitrogen inlet, the potassium carbonate (201.60 mg, 1.46 mmol) was suspended in clean, dry N,N-dimethylformamide (2.00 ml, 25.83 mmol) and the 2-chloro-4-fluoro-5-nitro-benzoic acid 1b (160.10 mg, 0.73 mmol) was added to the reaction mixture and stirred until it appeared all the organic solid was taken up into solution. The 1-(5-fluoro-2-methyl-phenyl)-piperazine 16d (170.00 mg, 0.88 mmol) was added to the reaction and the reaction mixture was allowed to stir at room temperature under a nitrogen atmosphere overnight. The reaction mixture was diluted with 10 ml of water and treated with 10 ml of 2N HCl. The product mixture was stirred until no further gas evolved and was then filtered under vacuum. The orange solid that was collected was washed with water and dried under high vacuum. The product, 2-chloro-4-[4-(5-fluoro-2-methyl-phenyl)-piperazin-1-yl]-5-nitro-benzoic acid 16e (222.30 mg, 0.56 mmol), was isolated as a yellow solid and was carried on without further purification. LCMS (m/e)=394 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]=[CH:6][C:7]1[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)C.[Li+].[OH-]>C1COCC1.O>[C:17]1([C:8]2[C:7]([CH:6]=[CH:5][C:4]([OH:23])=[O:3])=[CH:12][CH:11]=[C:10]([C:13]([F:16])([F:14])[F:15])[N:9]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)C=Cc1ccc(C(F)(F)F)nc1-c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C=Cc1ccc(C(F)(F)F)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.5 %

Procedure:
To a suspension of 3-(2-phenyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid ethyl ester (20 mg, 0.062 mmol) in THF (1 ml) was added an aqueous solution of 0.5 N-LiOH (0.3 ml), and the mixture was stirred for 3 hours at room temperature. The resulting residue was dissolved in H2O and then washed three times with EtOAc, acidified with 1N HCl to pH 1˜2. The solution was extracted three times with methylene chloride and then dried over anhyd. Na2SO4 and concentrated in vacuo to give 3-(2-phenyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (19 mg, 96%). To a suspension of N-(4-aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (21 mg, 0.074 mmol) in THF (3 mL) was added N-methylmorpholine (0.015 ml, 0.148 mmol). The mixture was stirred for 5 minutes, to which were added 3-(2-phenyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (19 mg, 0.065 mmol) and 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMTMM, 19 mg, 0.068 mmol). The mixture was stirred overnight at room temperature and was concentrated under reduced pressure. The residue was diluted with EtOAc and water. The organic layer was washed with saturated sodium bicarbonate, 1N HCl and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by recrystallization from Et2O to give N-(3-ethynyl-5-fluoro-4-methane sulfonylamino-benzyl)-3-(2-phenyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide (18 mg, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)=[C:4](I)[CH:3]=1.C([Li])CCC.CON(C)[C:24](=[O:36])[CH2:25][CH2:26][N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)=[C:4]([C:24](=[O:36])[CH2:25][CH2:26][N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:32])[CH3:33])[CH:3]=1
Reactant: CC1(C)COC(c2ccc(Cl)cc2I)=N1
Reactant: CON(C)C(=O)CCN(C)C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(CCC(=O)c1cc(Cl)ccc1C1=NC(C)(C)CO1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37.5 %

Procedure:
To a solution of 2-(4-chloro-2-iodophenyl)-4,4-dimethyl-4,5-dihydrooxazole (3.3 g, 9.7 mmol) in dry THF (30 mL) at −78° C. was added n-butyl lithium (2.5 M in hexane, 4.0 mL, 10.0 mmol) drop wise. After stirring for 30 min, a solution of tert-butyl 3-(methoxy(methyl)amino)-3-oxopropyl(methyl)carbamate (2.0 g, 8.1 mmol) in dry THF (5 mL) was added. The reaction mixture was warmed slowly to 0° C. then stored in refrigerator (4° C.) over night. The reaction was then warmed to room temperature and stirred 7 h. The reaction was quenched with 1N HCl, diluted with brine and ethyl acetate. After separation, the organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (120 g column, 0% ethyl acetate in hexanes to 50% ethyl acetate in hexanes) to give product (1.2 g, 38%). 1H NMR (CD3OD) δ 7.75 (d, J=7.6 Hz, 1H), 7.55-7.60 (m, 2H), 4.10-4.20 (m, 2H), 3.58 (t, J=6.8 Hz, 2H), 3.05-3.15 (m, 2H), 2.88 (s, 3H), 1.43 (s, 9H), 1.35 (s, 6H); MS EI m/z 395 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:18][CH2:17]2)=[CH:12][N:11]=1)[CH3:9])(C)(C)C.[ClH:20].O1CCOCC1>C(Cl)Cl>[ClH:20].[CH:16]1([C:13]2[CH:14]=[CH:15][C:10]([C@@H:8]([NH2:7])[CH3:9])=[N:11][CH:12]=2)[CH2:18][CH2:17]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C2CC2)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@H](N)c1ccc(C2CC2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.9 %

Procedure:
A solution of (S)-tert-butyl-1-(5-cyclopropylpyridin-2-yl)ethylcarbamate (Method 31; 2.04 g, 7.78 mmol) in DCM (10 ml) was treated with HCl/dioxane (9.72 ml, 4 N, 38.8 mmol) and stirred at room temperature for 2 hours. The solvent was removed to give the title compound (1.73 g, 93%) as white solid. 1H NMR (400 MHz) δ 8.60 (br, 3H), 8.50 (s, 1H), 7.62 (m, 1H), 7.56 (m, 1H), 4.52 (m, 1h), 2.03 (m, 1H), 1.50 (d, J=6.8 Hz, 1H), 1.04 (m, 2H), 0.79 (m, 2H). MS: Calcd.: 162. Found: [M+H]+ 163.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([OH:17])=O)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22]1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH2:27]([N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:15]([C:10]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:17])[CH2:22][CH2:23]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
4′-Trifluoromethyl-biphenyl-carboxylic acid (5.0 g) was dissolved in dimethylformamide (50 mL), and to this solution were added at room temperature 4-amino-1-benzylpiperidine (3.55 g), 1-hydroxybenzotriazole hydrate (3.0 g) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (3.58 g). The mixture was stirred at room temperature overnight, and the reaction solution was concentrated in vacuo to precipitate crystals. The crystals were washed successively with saturated aqueous sodium bicarbonate and water, and dried in vacuo to give the title compound (7.42 g).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][CH3:19])[C:6]=2[N:7]=1.[CH2:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH:21]=[CH2:22]>>[CH2:20]([N:23]1[CH2:28][CH2:27][N:26]([C:2]2[N:3]=[CH:4][C:5]3[C:11](=[O:12])[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][CH3:19])[C:6]=3[N:7]=2)[CH2:25][CH2:24]1)[CH:21]=[CH2:22]
Reactant: C=CCN1CCNCC1
Reactant: CCOC(=O)c1cn(CC)c2nc(Cl)ncc2c1=O
Product: C=CCN1CCN(c2ncc3c(=O)c(C(=O)OCC)cn(CC)c3n2)CC1
Yield: 79 %

Procedure:
2-(4'-Allyl-piperazino)-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine is prepared, in a yield of 79%, by condensing 2-chloro-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine with 1-allyl-piperazine, as indicated in the preceding Examples. It is a solid which melts in two stages; melting point 131°C, solidification, followed by melting point 143°C [after recrystallization from a mixture of benzene (1 volume) and isopropyl ether (1 volume)].
Reaction SMILES: [H][H].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[O:8][C@@H:9]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:10][CH2:11][N:12]1[CH2:17][CH:16]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1>[Pd].C(O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[O:8][C@@H:9]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:10][CH2:11][N:12]1[CH2:13][CH2:14][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)[CH2:16][CH2:17]1
Reactant: [H][H]
Reactant: COc1ccc(O[C@H](CCN2CC=C(c3ccc([N+](=O)[O-])cc3)CC2)c2ccccc2)cc1OC
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(O[C@H](CCN2CCC(c3ccc(N)cc3)CC2)c2ccccc2)cc1OC

Procedure:
A 25-mL RB flask, equipped with a hydrogen-filled balloon, was charged with 1-[(3R)-3-(3,4-dimethoxyphenoxy)-3-phenylpropyl]-4-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine (63.0 mg, 0.133 mmol), palladium on carbon (5.0 mol-eq %, 0.00665 mmol, 7.04 mg) and ethanol (2.0 mL) at room temperature. After 1 hr the reaction mixture was filtered through a plug of Celite 545 and concentrated under reduced pressure. The crude product (54.1 mg, 89.4%) was used in next reaction without further purification.
Reaction SMILES: [I:1][C:2]1[C:3]([O:25][CH3:26])=[C:4]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[C:14](I)[C:13]=2[O:23][CH3:24])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:27]([Li])CCC.CI>C1COCC1.[Cl-].[NH4+]>[CH3:26][O:25][C:3]1[C:2]([I:1])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]([CH3:27])[C:13]=1[O:23][CH3:24]
Reactant: [Li]CCCC
Reactant: COc1c(I)cc2ccccc2c1-c1c(OC)c(I)cc2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1c(C)cc2ccccc2c1-c1c(OC)c(I)cc2ccccc12
Temperature: 25 °C

Procedure:
To a −80° C. solution of (+/−)-3,3′-diiodo-2,2′-dimethoxy-1,1′-binaphthyl (2.016 g, 3.6 mmol) in THF (dry, distilled, 80 mL, 0.044 M) was added n-butyl lithium (2.8 mL, 3.9 mmol) dropwise. The reaction mixture turned yellow and was stirred for 1 h before the addition of methyl iodide (dry, distilled, 0.35 mL, 5.6 mmol). The reaction mixture was allowed to gradually warm to room temperature. After stirring for a further 3 h saturated aqueous ammonium chloride solution (4 drops) was added. The reaction mixture was evaporated to dryness, the residue taken up in diethyl ether and washed with water. The organic layer was dried (MgSO4), filtered and the filtrate evaporated to dryness to give a pale yellow solid. Purification of the crude material by flash column chromatography (4% ethyl acetate/hexane) yielded (+/−)-2,2′-dimethoxy-3-iodo-3′-methyl-1,1′-binaphthyl.