Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]([Si:29]([CH3:46])([CH3:45])[O:30][C@H:31]1[CH2:39][CH2:38][CH2:37][C@@:36]2([CH3:40])[C@H:32]1[CH2:33][CH2:34][C@@H:35]2[C@H:41]([CH3:44])[CH:42]=O)([CH3:28])([CH3:27])[CH3:26]>ClCCl>[C:25]([Si:29]([CH3:46])([CH3:45])[O:30][C@H:31]1[CH2:39][CH2:38][CH2:37][C@@:36]2([CH3:40])[C@H:32]1[CH2:33][CH2:34][C@@H:35]2[C@H:41]([CH3:42])[CH:44]=[C:2]([Br:5])[Br:1])([CH3:27])([CH3:28])[CH3:26]
Reactant: BrC(Br)(Br)Br
Reactant: C[C@H](C=O)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@H](C=C(Br)Br)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Temperature: -20 °C
Yield: 81 %

Procedure:
Typically, tetrabromomethane (16.8 g; 50.6 mmol) is dissolved in dichloromethane (80 ml). Triphenylphosphine (26.5 g; 101.1 mmol) in solution in dichloromethane (40 ml) is added dropwise. The reaction mixture is cooled to -20° C. and the compound (S)-2-[(1R,3aR,4S,7aR)-4-(tert-Butyl-dimethyl-silanyloxy)-7a-methyl-octahydro-inden-1-yl]-propan-1-al (J. Org Chem: 1992, 57, 3173 ) in solution in dichloromethane (30 ml) is added dropwise. The reaction mixture is allowed to reach room temperature and is then poured on ice. The mixture is extracted twice with ethyl-acetate (250 ml); the organic phase is washed twice with brine (100 ml), dried over sodium sulfate. After evaporation of the solvents and flash-chromatography over silica gel (hexanes/ethyl acetate 98:2) the compound (1R,3aR,4S,7aR)-4-(tert-Butyl-dimethyl-silanyloxy)-1-[(S)-3,3-dibromo-1-methyl-allyl]-7a-methyl-octahydro-indene (8.94 g; Yield 81%) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[CH2:25][SH:26]>>[CH2:1]([N:5]1[C:9]2=[C:10]([S:26][CH2:25][C:19]3[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=3[Cl:17])[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4]
Reactant: SCc1ccc(Cl)cc1Cl
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Product: CC=CCn1c(C)c(C)c2cnnc(SCc3ccc(Cl)cc3Cl)c21
Yield: 63.2 %

Procedure:
The title compound (cis/trans=16:84) was prepared as pale brown crystals in 63.2% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=22/78) and 2,4-dichlorophenylmethanethiol.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]([C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)=O.[Br-:24].[Li+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O>[Br:24][CH2:6][CH2:7][N:8]([C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [Br-]
Reactant: CCOC(=O)C(=O)N(CCOS(C)(=O)=O)N=Cc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Li+]
Solvent: CC(C)=O
Product: CCOC(=O)C(=O)N(CCBr)N=Cc1ccccc1
Reaction time: 3 h

Procedure:
3.4 g. of the ethyl ester product from part (b) are dissolved in 100 ml. of acetone. 1.3 g. (50% excess) of lithium bromide and 0.1 g. of 18-Crown-6 (1,4,7,10,13,16-hexaoxacyclooctadecane) are added and the mixture is stirred for three hours at 50°. After the reaction has been completed as determined by TLC, the solvent is distilled off and the reaction mixture is taken up in 50 ml. of methylene chloride and shaken with 50 ml. of water. The organic phase is dried and concentrated to yield the crude product as an oil which, after scratching, crystallizes in several hours. Recrystallization from isopropanol yields purified [1-(2-bromoethyl)-2-(phenylmethylene)hydrazino]oxoacetic acid, ethyl ester; m.p. 56°-57°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]=[C:10]=[O:11].Cl.[F:13][C:14]1[N:38]=[CH:37][C:17]2[N:18]=[CH:19][N:20]=[C:21]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[C:25]([CH3:36])[CH:24]=3)[C:16]=2[CH:15]=1.CCN(CC)CC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]([N:33]1[CH2:32][CH2:31][CH:30]([O:29][C:26]2[CH:27]=[CH:28][C:23]([NH:22][C:21]3[C:16]4[CH:15]=[C:14]([F:13])[N:38]=[CH:37][C:17]=4[N:18]=[CH:19][N:20]=3)=[CH:24][C:25]=2[CH3:36])[CH2:35][CH2:34]1)=[O:11]
Reactant: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1OC1CCNCC1
Reactant: O=C=Nc1c(F)cccc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1OC1CCN(C(=O)Nc2c(F)cccc2F)CC1
Yield: 76.8 %

Procedure:
2,6-difluorophenyl Isocyanate (0.199 g, 1.28 mmol) was added to a solution of (6-Fluoro-pyrido[3,4-d]pyrimidin-4-yl)-[3-methyl-4-(piperidin-4-yloxy)-phenyl]-amine hydrochloride (T) (500 mg, 1.28 mmol) and NEt3 (0.388 g, 3.84 mmol) in CH2Cl2 (20 mL). After 1 h the reaction was quenched with water, the layers were separated and the organic layer was washed with 1N NaOH and water, dried over Na2SO4, and concentrated. Purification by flash column chromatography (CH2Cl2/MeOH 97:3) afforded the title compound as a yellow solid (0.50 g, 77%). LRMS: 509.2 (MH+); 1H NMR (DMSO-d6, 400 MHz): δ 9.90 (s, 1H), δ 8.86 (s, 1H), δ 8.58 (s, 1H), δ 8.28 (s, 1H), δ 8.19 (s, 1H), δ 7.55-7.58 (m, 2H), δ 7.20-7.27 (m, 1H), δ 7.04-7.10 (m, 3H), δ 4.58-4.61 (m, 1H), δ 3.69-3.73 (m, 2H), δ 3.33-3.98 (m, 2H), δ 2.19 (s, 3H), δ 1.91-1.96 (m, 2H), δ 1.60-1.66 (m, 2H).
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][C:24]([O:26]CC)=O)=[CH:18][CH:17]=2)[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[NH2:42][OH:43]>C(O)C.[OH-].[Na+]>[O:1]([C:8]1[N:13]=[C:12]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[O:43][N:42]=[C:24]([OH:26])[CH:23]=3)=[CH:18][CH:17]=2)[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=Cc1ccc(OCc2cccc(Oc3ccccc3)n2)cc1
Reactant: NO
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Oc1cc(-c2ccc(OCc3cccc(Oc4ccccc4)n3)cc2)on1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 3-(4-((6-phenoxypyridin-2-yl)methoxy)phenyl)prop-2-enoate (20.2 mg) in ethanol (1 ml), 0.05 ml of 50% aqueous hydroxylamine solution and 0.03 ml of 2N aqueous sodium hydroxide were added, and the reaction solution was stirred overnight at room temperature. The reaction solution was acidified with 10% aqueous citric acid, then extracted with chloroform, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and residue obtained was purified by preparative thin layer chromatography (Kieselgel™ 60 F254, Art5744, made by Merck & Co., chloroform/methanol (8:1)) to afford the title compound as a white solid.
Reaction SMILES: [Mg].II.[CH3:4]I.[N:6]1([CH2:11][CH:12]2[C:21](=O)[C:20]3[CH:19]=[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])[CH:17]=[CH:16][C:15]=3[CH2:14][CH2:13]2)[CH:10]=[CH:9][N:8]=[CH:7]1.Cl>C(OCC)C.O1CCCC1.O>[N:6]1([CH2:11][C:12]2[CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:23]([OH:25])=[O:24])=[CH:19][C:20]=3[C:21]=2[CH3:4])[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)c1ccc2c(c1)C(=O)C(Cn1ccnc1)CC2
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1=C(Cn2ccnc2)CCc2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To a suspension of anhydrous magnesium (0.23 g) and a small crystal of iodine in anhydrous diethyl ether (3 ml) a solution of methyl iodide (1.3 g) in anhydrous diethyl ether (6 ml) is added dropwise. The mixture is refluxed for 1 hour then cooled to room temperature. To this mixture a solution of tert-butyl 5,6,7,8-tetrahydro-7-(1H-imidazol-1-ylmethyl)-8-oxo-2-naphthalenecaboxylate (1.0 g) in anhydrous tetrahydrofuran (25 ml) is added dropwise. The reaction mixture, after stirring at room temperature for 2 hours, is poured into water, neutralized with diluited hydrochloric acid and extracted with methylene chloride. The organic layer is dried over sodium sulfate and evaporated to dryness. The residue is taken up with trifluoracetic acid and refluxed for 45 minutes. The resulting solution is evaporated under reduced pressure and the residue is purified by silica gel column chromatography, eluiting with methylene chloride-methanol-acetic acid (180:20:2), to give 0.6 g of 5,6-dihydro-7-(1H-imidazol-1-ylmethyl)-8-methyl-2-naphthalenecarboxylic acid
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.I[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12]C=1.[C-:16]1([N:21]2[C:25](=[O:26])[NH:24][NH:23][C:22]2=[O:27])[CH:20]=[CH:19][CH:18]=[CH:17]1.[CH-]1C=CC=C1.[Fe+2:33]>O1CCCC1>[C-:16]1([N:21]2[C:22](=[O:27])[N:23]=[N:24][C:25]2=[O:26])[CH:17]=[CH:18][CH:19]=[CH:20]1.[CH-:12]1[CH:13]=[CH:14][CH:15]=[CH:10]1.[Fe+2:33]
Reactant: O=c1[nH][nH]c(=O)n1-[c-]1cccc1
Reactant: Ic1ccccc1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C1N=NC(=O)N1[c-]1cccc1

Procedure:
With reference to EXAMPLE 1-2, 11 mg (0.034 mmol) of iodobenzene diacetate was added to a mixture of 10 mg (0.035 mmol) of 4-ferrocenylurazole and 0.5 mL of tetrahydrofuran at room temperature. The mixture was stirred for an hour to give the tetrahydrofuran solution of 4-ferrocenyl-1,2,4-triazoline-3,5-dione. A tetrahydrofuran (0.5 mL) solution of 10 mg (0.026 mmol) of cholecalciferol (VD3, manufactured by Solvay Pharmaceutical, Co.) was added to the solution obtained, followed by stirring at room temperature for an hour. The resulting mixture was concentrated under reduced pressure and the residue obtained was purified by thin layer silica gel chromatography (hexane:ethyl acetate=2:1) to give 11 mg (63%) of the titled cholecalciferol/4-ferrocenyl-1,2,4-triazoline-3,5-dione adduct (VD3-FTAD) as a yellow oily substance.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>CCO>[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([S:10]([C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][CH:7]=2)(=[O:12])=[O:11])[CH2:17][CH2:16]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: CCO
Product: CN1CCN(S(=O)(=O)c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-nitrobenzenesulfonyl chloride (664 mg, 3.0 mmol) and methylpiperazine (600 mg, 6.0 mmol) in EtOH was stirred for 2 h at RT. The reaction was concentrated and triturated in Et2O to yield a yellowish solid, 3-[(4-methylpiperazinyl) sulfonyl]-1-nitrobenzene, and was used in next step without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:14]([N:15]2[CH2:19][CH:18]([C:20]([O:22]C(C)(C)C)=[O:21])[N:17]([CH3:27])[C:16]2=[O:28])=[CH:13][CH:12]=[CH:11][N:10]=1>ClCCl>[Cl:8][C:9]1[C:14]([N:15]2[CH2:19][CH:18]([C:20]([OH:22])=[O:21])[N:17]([CH3:27])[C:16]2=[O:28])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CN1C(=O)N(c2cccnc2Cl)CC1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)N(c2cccnc2Cl)CC1C(=O)O
Temperature: 25 °C
Reaction time: 36 h
Yield: 113.1 %

Procedure:
Trifluoroacetic acid (2.5 ml) was added to a solution of 1,1-dimethylethyl 1-(2-chloro-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (579 mg, 1.857 mmol) in dichloromethane (10 ml) and the solution was stirred at room temperature for 36 hours. The solvent was evaporated under vacuum azeotroping with toluene and the residue dried under heated vacuum overnight 1-(2-chloro-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylic acid (537 mg, 70.4% yield) which was used crude in the next step. LC/MS MH+=256.
Reaction SMILES: [CH2:1]([N:3]1[CH:25]=[CH:24][C:6]2[NH:7][C:8]([N:11]3[CH2:16][CH2:15][N:14](CC4C=CC=CC=4)[CH2:13][CH2:12]3)=[N:9][CH2:10][C:5]=2[C:4]1=[O:26])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([N:3]1[CH:25]=[CH:24][C:6]2[NH:7][C:8]([N:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)=[N:9][CH2:10][C:5]=2[C:4]1=[O:26])[CH3:2]
Reactant: CCn1ccc2c(c1=O)CN=C(N1CCN(Cc3ccccc3)CC1)N2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCn1ccc2c(c1=O)CN=C(N1CCNCC1)N2
Yield: 94.1 %

Procedure:
Dissolved in 20 ml of ethanol was 1.0 g of the 1,4,5,6-tetrahydro-6-ethyl-5-oxo-2-(4-benzylpiperazino)pyrido[4,3-d]pyrimidine obtained in Referential Example 31, followed by an addition of 10% Pd-C. The resultant mixture was stirred at 70° C. for 2.5 hours in a hydrogen atmosphere. After removal of the catalyst by filtration, the filtrate was concentrated to obtain 0.7 g of 1,4,5,6-Tetrahydro-6-ethyl-5-oxo-2-piperazinopyrido[4,3-d]pyrimidine as crystals (yield: 95%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=2[CH3:20])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].B.P(C1CCCCC1)(C1CCCCC1)C1CCCCC1.CC([O-])=O.[K+].Cl[C:47]1[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][C:48]=1[CH2:57][OH:58].C([O-])([O-])=O.[K+].[K+]>O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O1CCOCC1>[OH:58][CH2:57][C:48]1[CH:49]=[C:50]([C:53]([F:54])([F:55])[F:56])[CH:51]=[CH:52][C:47]=1[C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=2[CH3:20])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: OCc1cc(C(F)(F)F)ccc1Cl
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(Br)c2)c(C)c1
Agent: [Pd]
Agent: B
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CO)c2)c(C)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To methyl 3′-bromo-4′-methoxy-2-methylbiphenyl-4-carboxylate (80.0 g, 0.239 mol), pinacole borane (72.8 g, 0.287 mol), Pd(dba)2 (4120 mg, 7.17 mmol), P(Cy)3 (2140 mg, 7.65 mmol), and KOAc (70.3 g, 0.717 mol) was added dioxane (1.2 L). The reaction was heated to 80° C. and stirred for 3 hours. The reaction was then cooled to room temperature and filtered. The solids were dissolved with EtOAc (800 mL), washed with brine (400 mL, twice), and concentrated. The residue was dissolved in THF (300 mL), and [2-chloro-5-(trifluoromethyl)phenyl]methanol (47.1 g, 0.223 mol) and (t-Bu2P)2ferrocene PdCl2 were added. A solution of K2CO3 (83.7 g, 0.606 mol in water (214 mL) was added and the mixture was heated to 45° C. and stirred for 9 hours. The reaction was cooled to room temperature and diluted with EtOAc (428 mL), and washed with water (428 mL) and brine (428 mL). To the organic material was added 21.5 g charcoal (Darco KB −100 mesh) and the mixture was stirred for 1 hour. The mixture was filtered, and the solid material was washed with EtOAc (428 mL). The filtrate was concentrated and then re-dissolved in MeOH (677 mL) and left to stand for 1 hour. To the mixture was added water (169 mL) over 2 hours, and then the mixture was left to stand for 1 hour. The resulting solids were washed with a solution of MeOH and water (4:1, 170 mL, three times) and dried to afford methyl 2″-(hydroxymethyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.B(F)(F)F.[CH3:16][CH2:17]OCC>C(O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:16][CH3:17])=[O:10])=[CH:6][CH:7]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: CCOCC
Agent: FB(F)F
Solvent: CCO
Product: CCOC(=O)Cc1ccc(N)cc1

Procedure:
A solution of 8.2 g. of 4-aminophenylacetic acid, 150 ml. of absolute ethanol, and 3 ml. of boron trifluoride etherate is heated to reflux for 15 hours. The solution is concentrated by distillation and then evaporated to dryness in vacuo. The residue is dissolved in ethyl ether, washed with aqueous sodium bicarbonate, dried, and evaporated to yield ethyl 4-aminophenylacetate. A mixture of 5.0 g. of this amine, 9.7 g. of 14-(trimethylsilyl)tetradecyl bromide, 4.2 g. of anhydrous potassium carbonate and 40 ml. of hexamethylphosphoramide is heated at 80° C. for 7 hours. The mixture is then cooled, diluted with water, and extracted with ethyl ether. The ether extracts are washed with water, dried and evaporated. The residue is recrystallized yielding ethyl 4-[14-(trimethylsilyl)tetradecylamino]phenylacetate. A mixture of 6.0 g. of this ester, 7.0 g. of potassium hydroxide and 100 ml. of ethanol-water is heated to reflux for 4 hours. While hot, the mixture is adjusted to pH 7 with concentrated hydrochloric acid.. The mixture is diluted with water, cooled and filtered. Recrystallization of the precipitate yields the title product as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([OH:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].N12CCCN=C1CCCCC2.O>CN(C)C=O>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][O:19][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:16]([O:17][CH3:18])=[CH:15][C:12]=1[CH:13]=[O:14])[CH3:26]
Reactant: COc1cc(C=O)c(O)cc1OCc1ccccc1
Reactant: CCOC(=O)CBr
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CCOC(=O)COc1cc(OCc2ccccc2)c(OC)cc1C=O
Temperature: 25 °C

Procedure:
4-Benzyloxy-2-hydroxy-5-methoxybenzaldehyde (2.9 g), ethyl bromoacetate (2.3 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.1 g) in N,N-dimethylformamide (30 ml) were heated at 100° C. under nitrogen for 5 hours. After cooling to room temperature, water was added and the mixture extracted with ethyl acetate. Ethyl acetate was washed with 1 N NaOH and 1 N HCl, dried with Na2SO4 and evaporated to dryness.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[CH:11]=[C:10](Br)[C:9](=[O:13])[N:8]([C@H:14]3[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]3)[C:6]=2[N:7]=1.[B-](F)(F)(F)[C:23]1[NH:27][N:26]=[CH:25][CH:24]=1.[K+].C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[CH:11]=[C:10]([C:25]3[CH:24]=[CH:23][NH:27][N:26]=3)[C:9](=[O:13])[N:8]([C@H:14]3[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]3)[C:6]=2[N:7]=1
Reactant: Cc1nc(N)nc2c1cc(Br)c(=O)n2[C@H]1CC[C@H](O)CC1
Reactant: F[B-](F)(F)c1ccn[nH]1
Agent: [K+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc(N)nc2c1cc(-c1cc[nH]n1)c(=O)n2[C@H]1CC[C@H](O)CC1
Temperature: 100 °C

Procedure:
A mixture of 2-amino-6-bromo-8-((trans)-4-hydroxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (100 mg, 0.283 mmol), potassium 1H-pyrazole-5-trifluoroborate (98.5 mg, 0.566 mmol), and triethylamine (197 uL, 1.42 mmol) in ethanol (3.0 mL) was bubbled with argon. PdCl2(dppf)1:1 w/CH2Cl2 was added, the vial was sealed and the mixture was bubbled with argon again, then heated in the microwave for 30 minutes at 100° C., then 60 minutes at 150° C. The reaction mixture was concentrated and purified by flash chromatography eluting with 1:1 ethyl acetate:chloroform/7 N ammonia in methanol (0.5-7%). The fractions containing the desired product were combined and concentrated and the solids were recrystallized from methanol/chloroform to afford 2-amino-8-((trans)-4-hydroxycyclohexyl)-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (32 mg, 33%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=1)([O-:13])=[O:12].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:17]2[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(CCO)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(CCOc2ccc([N+](=O)[O-])cc2)cc1
Yield: 80.1 %

Procedure:
A mixture of 2-(4-methylphenyl)ethyl alcohol (VIII) (13.6 g, 0.1 mole), 4-nitrochlorobenzene (IX: X=Cl) (15.8 g, 0.1 mole), toluene (92 g), tetra-n-butylammonium bromide (3.2 g, 0.01 mole) and a 50% aqueous sodium hydroxide solution (24 g) was stirred vigorously at 50° to 60° C. for 5 hours. The organic layer was separated, washed with water two times and then concentrated in vacuo. By recrystallizing the crude product from 95% ethanol, 20.6 g (yield, 80%) of 4-[2-(4-methylphenyl)ethoxy]nitrobenzene (VI) were obtained as white crystals.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[C:14]([O:17][CH2:18][CH:19]1[CH:24]=[CH:23][C@H:22]([NH2:25])[CH2:21][O:20]1)(=[O:16])[CH3:15].C(N(CC)C(C)C)(C)C>C(O)(C)C>[C:14]([O:17][CH2:18][CH:19]1[CH:24]=[CH:23][C@H:22]([NH:25][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[CH:11]=[CH:12][S:13][C:3]=23)[CH2:21][O:20]1)(=[O:16])[CH3:15]
Reactant: CC(=O)OCC1C=C[C@H](N)CO1
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(=O)OCC1C=C[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CO1
Temperature: 90 °C
Yield: 82.7 %

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (156 mg, 0.727 mmol), [(5S)-5-amino-5,6-dihydro-2H-pyran-2-yl]methyl acetate (129 mg, 0.754 mmol) and N,N-diisopropylethylamine (0.26 mL, 1.5 mmol) in isopropyl alcohol (1.7 mL) was heated at 90° C. for 2 h. The reaction mixture was concentrated and purified with flash chromatography to give the desired product (0.21 g 83%). LCMS calculated for C15H16N3O5S (M+H)+: m/z=350.1. Found: 350.0.
Reaction SMILES: [Cl-].[C:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([NH3+:15])[CH3:14])=[CH:9][CH:8]=1)([CH3:5])([CH3:4])[CH3:3].C([O:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:36]2[C:44]3[C:39](=[CH:40][C:41]([C:45](O)=[O:46])=[CH:42][CH:43]=3)[C:38]([CH3:48])=[C:37]2[CH3:49])=[CH:31][CH:30]=1)=[O:22])(C)(C)C>>[C:2]([O:6][C:7]1[CH:8]=[CH:9][C:10]([C@@H:13]([NH:15][C:45]([C:41]2[CH:40]=[C:39]3[C:44](=[CH:43][CH:42]=2)[N:36]([CH2:35][C:32]2[CH:31]=[CH:30][C:29]([C:24]4[C:23]([C:21]([OH:22])=[O:20])=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:34][CH:33]=2)[C:37]([CH3:49])=[C:38]3[CH3:48])=[O:46])[CH3:14])=[CH:11][CH:12]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: C[C@H]([NH3+])c1ccc(OC(C)(C)C)cc1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Agent: [Cl-]
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc(OC(C)(C)C)cc3)cc12

Procedure:
The title compound was prepared following the same general synthetic procedure as described in Steps 3-4, Example 2, starting with (S)-1-(4-(tert-butoxy)phenyl)ethanaminium chloride and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of (S)-1-(4-(tert-butyl)phenyl)ethanaminium chloride and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 574 [M+1]+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([C:14]1[CH:15]=[C:16]([C:24](=[O:26])[CH3:25])[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[C:19]=1[OH:20])([CH3:13])([CH3:12])[CH3:11].[CH3:27][O:28][CH2:29]Cl>O1CCCC1>[C:10]([C:14]1[CH:15]=[C:16]([C:24](=[O:26])[CH3:25])[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[C:19]=1[O:20][CH2:27][O:28][CH3:29])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(O)c(C(C)(C)C)c1
Reactant: COCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1c([N+](=O)[O-])cc(C(C)=O)cc1C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
Diisopropylethylamine (65 ml, 373 mmol) was added to a solution of 1-[3-(tert-butyl)-4-hydroxy-5-nitrophenyl]-1-ethanone (58.6 g, 247 mmol) in tetrahydrofuran (350 ml) under a nitrogen atmosphere while cooling on ice, and then chloromethyl methyl ether (24.5 ml, 322 mmol) was added dropwise. After stirring at the same temperature for 30 minutes, ice water (250 ml) was added and extraction was performed twice with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid water, water, saturated aqueous sodium hydrogencarbonate and brine in that order. The organic layer was dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure to yield the title compound (69.4 g, 99.9% yield) as a light brown oil. This was used without purification for the following reaction.