Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([O:16]CC)=[O:15])[N:10]([CH3:19])[N:9]=[CH:8]2.[Li+].[OH-]>C1COCC1.O>[F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([OH:16])=[O:15])[N:10]([CH3:19])[N:9]=[CH:8]2
Reactant: CCOC(=O)c1cc2c(cnn2C)cc1Oc1ccc([N+](=O)[O-])cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1ncc2cc(Oc3ccc([N+](=O)[O-])cc3F)c(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
To a solution of ethyl 5-(2-fluoro-4-nitrophenoxy)-1-methyl-1H-indazole-6-carboxylate (1.19 g, 3.5 mmol) in THF/H2O (15 mL/5 mL) is added LiOH (0.2 g, 8.3 mmol). After the reaction is stirred at RT for 2 hours, the solvents are removed. The residue is acidified with 2N HCl to pH 5, and extracted with EtOAc (50 mL). The organic phase is washed with saturated aqueous sodium chloride, dried and concentrated to give the product (1.1 g, 100% yield). MS (m/z): 332.0 (M+H).
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[S:25]([N:28]([CH3:30])[CH3:29])(=[O:27])=[O:26].C(N(CC)CC)C>CO>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[S:25](=[O:27])(=[O:26])[N:28]([CH3:29])[CH3:30])[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: CN(C)S(=O)(=O)c1ccc(F)cc1CN
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)c1ccc(F)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Temperature: 50 °C
Reaction time: 8 h
Yield: 12.2 %

Procedure:
(Step 2) To a suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (1.0 g) in methanol (10 ml) was added a solution of 2-(aminomethyl)-4-fluoro-N,N-dimethylbenzenesulfonamide hydrochloride obtained in Step 1 (1.37 g) and triethylamine (1.6 ml) in methanol (5 ml) at room temperature, and the mixture was stirred overnight at 50° C. The reaction solvent was evaporated under reduced pressure, acetic acid (5 ml) was added, and the mixture was stirred at 50° C. for 2 hr. The solvent was evaporated under reduced pressure, the residue was extracted with 1N hydrochloric acid, and the extract was washed with ethyl acetate. The aqueous layer was basified with 1N aqueous sodium hydroxide solution, the mixture was partitioned with ethyl acetate, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in methanol, and 4N hydrogen chloride-ethyl acetate solution (1 ml) was added. The mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized from methanol-ethyl acetate to give the title compound (0.11 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.I[C:21]1[CH:22]=[C:23]([CH:31]=[C:32]([N+:34]([O-:36])=[O:35])[CH:33]=1)[O:24][C:25]1[CH:26]=[N:27][CH:28]=[N:29][CH:30]=1.[CH3:37][N:38](C=O)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[C-]#N.[Zn+2].[C-]#N>[N+:34]([C:32]1[CH:33]=[C:21]([CH:22]=[C:23]([O:24][C:25]2[CH:26]=[N:27][CH:28]=[N:29][CH:30]=2)[CH:31]=1)[C:37]#[N:38])([O-:36])=[O:35]
Reactant: O=[N+]([O-])c1cc(I)cc(Oc2cncnc2)c1
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C-]#N
Product: N#Cc1cc(Oc2cncnc2)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
A mixture of polymer-bound triphenylphosphine (170 mg, 0.437 mmol, 0.150 eq) and palladium(II) acetate (46 mg, 0.20 mmol, 0.070 eq) in DMF (8.7 mL) stirred under argon for 2 h at rt. The supernatant DMF was removed, and fresh DMF (8.7 mL) was added. Compound 20 (1.0 g, 2.9 mmol, 1.0 eq) and zinc cyanide (340 mg, 2.90 mmol, 1.00 eq) were added, and the vial was subjected to microwave irradiation at 150° C. for 25 minutes. The resin was washed with ether, and the collected filtrate was washed (3×) with water and (1×) with brine. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 330 mg (47%) of the title compound as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 9.20 (s, 1H), 8.63 (s, 2H), 8.32 (t, J=1.4 Hz, 1H), 8.07 (t, J=2.2 Hz, 1H), 7.62 (dd, J=2.3, 1.3 Hz, 1H); ES-MS [M+1]+:243.0.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[C:10]=2[CH:9]=[CH:8]1)C>C1COCC1.O>[F:27][C:24]([F:25])([F:26])[O:23][C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:15]2[C:10]3[CH:9]=[CH:8][N:7]([CH2:6][CH2:5][C:4]([OH:28])=[O:3])[C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)CCn1ccc2c(Nc3ccc(OC(F)(F)F)cc3)ncnc21
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCn1ccc2c(Nc3ccc(OC(F)(F)F)cc3)ncnc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
To a solution of 3-[4-(4-Trifluoromethoxy-phenylamino)-pyrrolo[2,3-d]pyrimidin-7-yl]-propionic acid ethyl ester (100 mg, 0.24 mmol) in 5 mL of THF:H2O (3:1)) was added CsCO3 (78 mg, 0.40 mmol). The mixture was heated at 80° C. and stirred for 2 h. The reaction mixture was concentrated and neutralized with acetic acid. The solid was filtered and dried to yield the tile compound as brown solid (67 mg, 77%). MS m/z 367.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[OH:15])=[O:4].[O:16]([CH2:23][CH:24](O)[CH3:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[O:15][CH:24]([CH3:25])[CH2:23][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:4]
Reactant: CC(O)COc1ccccc1
Reactant: COC(=O)c1ccc2ccccc2c1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2ccccc2c1OC(C)COc1ccccc1

Procedure:
To a solution of 1.00 g 1-hydroxy-naphthalene-2-carboxylic acid methyl ester, 0.75 g 1-phenoxy-propan-2-ol and 3.89 g triphenyl phosphine in 60 ml dry THF at 0° C. 3.00 g diisopropylazodicarboxylate were added. After 48 h at room temperature the reaction was concentrated in vacuo, the residue was taken up in ethyl acetate, washed with sat. sodium hydrogen carbonate solution and dryed over magnesium sulphate. The solvent was removed in vacuo and after chromatography on silica (ethyl acetate/heptane) 0.47 g 1-(1-methyl-2-phenoxy-ethoxy)-naphthalene-2-carboxylic acid methyl ester were obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([OH:21])=[C:6]([O:19][CH3:20])[CH:7]=[C:8]2/[CH:13]=[C:14](\[CH3:18])/[C:15]([OH:17])=[O:16])[CH3:2].[C:22](OC(=O)C)(=[O:24])[CH3:23].O>N1C=CC=CC=1>[C:22]([O:21][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2[CH2:1][CH3:2])[C:8](/[CH:13]=[C:14](/[CH3:18])\[C:15]([OH:17])=[O:16])=[CH:7][C:6]=1[O:19][CH3:20])(=[O:24])[CH3:23]
Reactant: CCc1cccc2c(/C=C(\C)C(=O)O)cc(OC)c(O)c12
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CCc1cccc2c(/C=C(/C)C(=O)O)cc(OC)c(OC(C)=O)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
440 mg of (E)-3-(5-ethyl-4-hydroxy-3-methoxy-1-naphthyl)-2-methylpropenoic acid was dissolved in 2.4 ml of pyridine and 0.42 ml of acetic anhydride was added, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and water in this order, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant crystals were washed with hexane to obtain 390 mg of the titled compound as colorless crystals.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:24]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[C:49]([O-])(=[O:51])C.[Na+]>CN(C)C=O>[CH2:31]([N:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=1[CH:49]=[O:51])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]
Reactant: CC(=O)[O-]
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)c1ccccc1C=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
Phosphorus oxychloride (15.3 g, 0.1 mole) was added dropwise with stirring, at 5° C., under nitrogen, to N,N-dimethylformamide (DMF, 50 mL). The resulting orange solution was stirred for 2 hours, then 42 g (0.08 mole) of N,N-dioctadecylaniline was added all at once. The reaction mixture was heated in a water bath to 90° C., and stirring was continued for 4 hours. The hot solution was poured over 200 g of crushed ice and naturalized to pH 6 by a slow addition of solid sodium acetate with vigorous stirring. The greenish-tint crystalline precipitate was filtered by suction, washed with water on the filter and air dried. The light green product was recrystallized from isopropanol to yield 46.5 g (93%) of pale-green crystals mp 65°-66° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9](=[O:11])[CH3:10])=[N:4][N:3]=1.[BH4-].[Na+]>CO.O.O.CC(O)=O>[NH2:1][C:2]1[S:6][C:5]([S:7][CH2:8][CH:9]([OH:11])[CH3:10])=[N:4][N:3]=1
Reactant: CC(=O)CSc1nnc(N)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CC(O)CSc1nnc(N)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To a mixture of 1-(5-amino-1,3,4-thiadiazol-2-ylthio)propan-2-one (700 mg, 3.7 mmol) in 8 mL of 1:1 MeOH/H2O at rt was added a solution of NaBH4 (159 mg, 4.2 mmol) in 1.5 mL of H2O dropwise over 10 min. The suspension was stirred at rt for 1 h and diluted with 0.6 mL of HOAc followed by 6 mL of H2O. The precipitate was filtered, washed with H2O and dried under vacuum to afford 0.608 g of the title compound (86%) as an off-white solid. 1H NMR (400 MHz, MeOH-d3) δ 1.25 (d, J=6.6 Hz, 3H), 3.06-3.21 (m, 2H), 3.90-4.04 (m, 1H). HPLC (Method #1) 0.710 min retention time, (90%). MS (ES): m/z 192 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[CH2:23][CH3:24].[H-].[Na+].[F:27][C:28]([F:41])([O:32][C:33]1[CH:34]=[C:35]([CH2:39]Br)[CH:36]=[CH:37][CH:38]=1)[CH:29]([F:31])[F:30].O>COCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15](=[O:22])[CH:16]([CH2:39][C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([O:32][C:28]([F:27])([F:41])[CH:29]([F:30])[F:31])[CH:34]=3)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[CH2:23][CH3:24]
Reactant: CCOC(=O)CC(=O)c1ccc(Oc2ccc(Cl)c(CC)c2)cc1
Reactant: FC(F)C(F)(F)Oc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1ccc(Oc2ccc(Cl)c(CC)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (6.0 g, 28.8 mmol) in carbon tetrachloride (60 ml) were added N-bromosuccinimide (5.65 g, 31.7 mmol) and 2,2′-azobis(isobutyronitrile) (237 mg, 1.44 mmol), and the mixture was heated under reflux for 6 hrs. After cooling, the reaction solution was filtered, and the filtrate was concentrated to give 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene. To a solution of ethyl 3-(4-((4-chloro-3-ethylphenyl)oxy)phenyl)-3-oxopropionate (10 g, 28.8 mmol) in 1,2-dimethoxyethane (100 ml) was added sodium hydride (60% in oil, 1.15 g, 28.8 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene prepared earlier in 1,2-dimethoxyethane (10 ml), and the reaction solution was stirred at room temperature for 1 hr. The reaction solution was poured into water (100 ml), and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene) to give ethyl 3-(4-((4-chloro-3-ethylphenyl)oxy)phenyl)-3-oxo-2-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)propionate (9.26 g, 58%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([OH:17])=[CH:15][C:14]=1[OH:20]>B(F)(F)F.CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([C:18]2[CH:19]=[C:13]([Cl:12])[C:14]([OH:20])=[CH:15][C:16]=2[OH:17])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: Oc1ccc(Cl)c(O)c1
Agent: FB(F)F
Solvent: CCOCC
Product: O=C(Cc1ccc(Br)cc1)c1cc(Cl)c(O)cc1O
Reaction time: 2 h

Procedure:
This compounds was synthesised in the same manner as described above. 4-Bromophenylacetic acid (7.44 g, 34.6 mmol), 4-chlororesorcinol (5 g, 34.6 mmol), boron trifloride etherate (30 ml). After standing for two hours an orange precipitate formed. This was purified by flash chromatography to give the required compound as an off white solid (10.5 g, 89%); Rf 0.9 hexane/ethyl acetate (20/80).
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:9]2=[O:14].[Cl:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[C:26]([NH:30][C:31](=[O:32])[N:3]([CH2:4][C:5]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:6]=2[CH2:7][N:8]([CH:15]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]2=[O:22])[C:9]3=[O:14])[CH3:2])[CH:27]=[CH:28][CH:29]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: CNCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O)C(=O)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a suspension of 3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.60 g, 1.86 mmol) and 3-chloro-phenyl-isocyanate (0.27 mL, 2.23 mmol) in dry CH2Cl2 (80 ml), was added diisopropylethylamine (0.45 mL g, 2.60 mmol). The mixture was stirred at room temperature overnight. The mixture was quenched with MeOH and filtered. The resulting solid was rinsed with CH2Cl2 (5 mL) to give 3-(3-chloro-phenyl)-1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea (0.68 g, 82%): mp 193-195° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.29 (99%); 1H NMR (DMSO-d6): δ 2.00-2.04 (m, 1H), 2.32-2.38 (m, 1H), 2.56-2.63 (m, 1H), 2.85-2.92 (m, 1H), 2.98 (s, 3H), 4.38 (d, J=17.3 Hz, 1H), 4.45 (d, J=17.3 Hz, 1H), 4.65 (s, 2H), 5.10-5.18 (dd, J=4.5, 13.2 Hz, 1H), 7.00 (d, J=7.8 Hz, 1H), 7.26 (t, J=8.0 Hz, 1H), 7.46-7.41 (In, 2H), 7.53 (t, J=7.5 Hz, 1H), 7.64-7.67 (m, 2H), 8.65 (s, 1H), 11.13 (s, 1H). 13C NMR (DMSO-d6) δ: 22.57, 31.19, 34.76, 46.27, 48.37, 51.60, 118.00, 119.08, 121.42, 121.77, 128.48, 129.85, 129.92, 131.93, 132.69, 133.62, 140.15, 142.04, 155.34, 168.00, 171.01, 172.84. Anal Calcd for C22H21ClN4O4: C, 59.93; H, 4.80; N, 12.71, Cl, 8.04. Found: C, 59.30; H, 4.66; N, 12.33, Cl, 8.36.
Reaction SMILES: NC(CC(C)C)C(O)=O.N[CH:11]([CH:15]([CH3:18])[CH2:16][CH3:17])[C:12]([OH:14])=[O:13].N([O-])=O.[Na+].C(Cl)(Cl)[Cl:24]>Cl>[Cl:24][C@@H:11]([C@@H:15]([CH3:18])[CH2:16][CH3:17])[C:12]([OH:14])=[O:13]
Reactant: CCC(C)C(N)C(=O)O
Reactant: ClC(Cl)Cl
Agent: CC(C)CC(N)C(=O)O
Agent: Cl
Agent: O=N[O-]
Product: CC[C@H](C)[C@H](Cl)C(=O)O
Reaction time: 5.5 h

Procedure:
78.7 g (0.6 mole) 2-amino-4-methyl pentanoic acid (preparation example 1) or 0.6 mole 2-amino-3-methyl pentanoic acid (preparation example 2) was dissolved in 700 ml 6N HCl. Total 91 g (1.3 mole) sodium nitrite powder was divided into several portions and were added To the solution in a span of 2 hours while an ice bath was used. The reaction was carried out for 5-6 hours at 0°-5° C., the reaction mixture was extracted with ethyl ether for three times, washed with saturated NaCl aqueous solution, dried over MgSO4, concentrated, and distilled under reduced pressure twice to yield a transparent liquid product. Yield: I-1: 74.7%; I-2: 69.5%. mp: I-1:92° C./3 mmHg; I-2:88° C./3 mmHg. The optical rotation [α]25D (chloroform): I-1:-I3.98 (neat liquid); I-2: -4.78 (neat liquid).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([C:8]#[N:9])=[CH:4][CH2:3]1.[Cl-].[Ce+3].[Cl-].[Cl-].[BH4-].[Na+]>CO.O>[OH:1][CH:2]1[CH2:7][CH2:6][C:5]([C:8]#[N:9])=[CH:4][CH2:3]1
Reactant: N#CC1=CCC(=O)CC1
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: N#CC1=CCC(O)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 4-oxocyclohex-1-ene-1-carbonitrile (170 mg, 1.40 mmol) in MeOH (2.3 mL) at −78° C. was added cerium (III) chloride (484 mg, 1.96 mmol) in MeOH (4.7 mL). The resulting mixture was allowed to stir for 5 minutes at −78° C. before NaBH4 (48 mg, 1.26 mmol) was added in one portion. The mixture was stirred for 20 minutes and then allowed to warm to ambient temperature. After being stirred for 30 minutes, the reaction mixture was diluted with water and extracted with diethyl ether (3×). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo (23° C. water bath) to afford the title compound.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2.[Sn](Cl)Cl>C(O)C>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:22]=[CH:23][C:24]([NH2:27])=[CH:25][CH:26]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2
Reactant: O=C(NC1CN2CCC1CC2)c1cccc2oc(-c3ccc([N+](=O)[O-])cc3)nc12
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccc(-c2nc3c(C(=O)NC4CN5CCC4CC5)cccc3o2)cc1
Temperature: 25 °C
Yield: 32.2 %

Procedure:
To a solution of N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-nitrophenyl)benzoxazole-4-carboxamide (24 mg 0.06 mmol) in ethanol was added tin(II) chloride (116 mg, 0.61 mmol). The reaction mixture was then heated to reflux for 4 h. The reaction was cooled down to room temperature, then concentrated. The residue was dissolved in ethyl acetate (10 mL). The resulting solution was washed with 1 N NaOH (12 mL), water and brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-aminophenyl)benzoxazole-4-carboxamide (7 mg, 2%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.68 (d, J=6.5 Hz, 1H), 8.13 (d, J=8.0 Hz, 1H), 8.02 (d, J=8.5 Hz, 2H), 7.65 (d, J=8.0 Hz, 1H), 7.39 (t, J=8.0 Hz, 1H), 6.79 (d, J=8.5 Hz, 2H), 4.40-4.36 (m, 1H), 4.19-4.16 (m, 3H), 3.20-2.90 (m, 5H), 2.30-0.80 (m, 5H); MS (ESI+) m/z 363 (M+H); HPLC 96.0% (AUC), tR=12.35 min.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:8]=[C:9]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]2([C:23](=[O:24])[NH:22][C:21](=[O:25])[NH:20]2)[C:12]1=[O:26].O>C(O)(=O)C>[Cl:4][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:11]([CH2:10][C:9]1[CH:27]=[CH:28][C:29]([Cl:30])=[C:7]([Cl:6])[CH:8]=1)[C:12](=[O:26])[C:13]12[C:23](=[O:24])[NH:22][C:21](=[O:25])[NH:20]1
Reactant: O=C1NC(=O)C2(N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=O)C2(N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc12
Reaction time: 0.67 h

Procedure:
Sulphuryl chloride (16.0 ml.) was added during 10 minutes to a stirred mixture of 1'-(3,4-dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (28.2 g.) in acetic acid (400 ml.). The mixture obtained was then stirred at 60°-65° C. for 40 minutes. The clear solution which formed was poured into water (3 l.). The solid which was precipitated was collected by filtration, washed with water and air-dried. Recrystallisation of the crude solid thus obtained from aqueous propan-2-ol gave 5'-chloro-1'-(3,4-dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (15.4 g.), m.p. 257°-259° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[C:2]#[CH:3].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([F:20])=[CH:15][N:14]=1>CO.O.CCOC(C)=O>[Cl:12][C:13]1[N:18]=[C:17]([NH:9][C:8]2[CH:10]=[CH:11][C:5]([O:4][CH2:1][C:2]#[CH:3])=[CH:6][CH:7]=2)[C:16]([F:20])=[CH:15][N:14]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: C#CCOc1ccc(N)cc1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: C#CCOc1ccc(Nc2nc(Cl)ncc2F)cc1
Yield: 243.6 %

Procedure:
Crude 4-(prop-2-ynyloxy)aniline (0.750 g, 5.10 mmol) and 2,4-dichloro-5-fluoropyrimidine (1.27 g, 0.760 mmol) were stirred in MeOH/water (4:1, 35 mL) at room temperature for 18 h. The reaction mixture was diluted with EtOAc (200 mL) and washed with 1N HCl (50 mL) and brine (50 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexanes ramped to EtOAc:hexanes (1:10)) to provide 2-chloro-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-4-pyrimidineamine as a light brown solid (0.514 g). 1H NMR (CDCl3): δ 8.03 (d, J=2.7 Hz, 1H), 7.53 (d, J=8.7 Hz, 2H), 7.02 (d, J=8.7 Hz, 2H), 6.86 (s, 1H), 4.71 (d, J=2.4 Hz, 2H), 2.55 (t, J=2.4 Hz, 1H); LCMS: purity: 99%; MS (m/e): 279 (MH+).
Reaction SMILES: [C:1]1([OH:14])[C:2]([C:7]2[C:8]([OH:13])=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH3:23]>CC(C)=O>[O:14]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([OH:13])=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH2:22][CH3:23]
Reactant: Oc1ccccc1-c1ccccc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccccc1-c1ccccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2′-Ethoxyl-1,1′-biphenyl-2-ol was prepared by modifying the procedure reported in J. Org. Chem. 1981, 46, 4988. In 50 mL of acetone was added 10 g of 2,2′-biphenol and 9.4 g of potassium carbonate. After stirring at room temperature for one hour, a solution of iodoethane (9.2 g in 10 mL of acetone) was added slowly dropwise. The mixture was filtered, washed with acetone, and solvent removed by rotary evaporation. The residue was flashed chromatographed to give 5.1 g of the2′-ethoxyl-1,1′-biphenyl-2-ol as a colorless oil. 1H NMR (C6D6): 7.20 (m, 3H), 7.10 (m, 1H), 7.05 (m, 1H), 6.85 (m, 2H), 6.55 (m, 1H), 3.38 (q, 2H), 0.81 (t, 3H).