Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([O:14][CH3:15])=[O:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[OH:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][CH:30]=1)[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:20]([C:19]1[CH:18]=[C:17]([CH:30]=[CH:29][CH:28]=1)[O:16][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([O:14][CH3:15])=[O:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)(=[O:21])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(c1ccccc1)c1cccc(O)c1
Reactant: COC(=O)C1(c2ccc(CBr)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(c2ccc(COc3cccc(C(=O)c4ccccc4)c3)cc2)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 104.6 %

Procedure:
Methyl 1-(4-(bromomethyl)phenyl)cyclopropanecarboxylate (2.478 g, 9.207 mmol) was added to a mixture of 3-hydroxybenzophenone (2.19 g, 11.05 mmol) and potassium carbonate (3.054 g, 22.10 mmol) in dimethyl formamide (46 mL). The reaction mixture was stirred at 60° C. for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic extracts were washed with 10% aqueous potassium carbonate (×5), 2M NaOH (×5), brine and dried (magnesium sulfate), filtered, and concentrated under reduced pressure to afford the title compound (3.721 g, quantitative yield). The material was used directly in the next step with no further purification.
Reaction SMILES: [CH2:1]([N:3]1CN(C)C[N:5]([C:10]2[S:11][C:12]3[C:18]([C:19]4[CH:24]=[C:23]([CH2:25][N:26]5[CH2:29][C:28]([OH:31])([CH3:30])[CH2:27]5)[CH:22]=[CH:21][N:20]=4)=[CH:17][C:16]([C:32]4[CH:33]=[N:34][C:35]([C:38]([OH:41])([CH3:40])[CH3:39])=[N:36][CH:37]=4)=[CH:15][C:13]=3[N:14]=2)[C:4]1=[O:42])[CH3:2].Cl>CO.C(Cl)Cl>[CH2:1]([NH:3][C:4]([NH:5][C:10]1[S:11][C:12]2[C:18]([C:19]3[CH:24]=[C:23]([CH2:25][N:26]4[CH2:27][C:28]([OH:31])([CH3:30])[CH2:29]4)[CH:22]=[CH:21][N:20]=3)=[CH:17][C:16]([C:32]3[CH:33]=[N:34][C:35]([C:38]([OH:41])([CH3:40])[CH3:39])=[N:36][CH:37]=3)=[CH:15][C:13]=2[N:14]=1)=[O:42])[CH3:2]
Reactant: CCN1CN(C)CN(c2nc3cc(-c4cnc(C(C)(C)O)nc4)cc(-c4cc(CN5CC(C)(O)C5)ccn4)c3s2)C1=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)O)nc3)cc(-c3cc(CN4CC(C)(O)C4)ccn3)c2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.4 %

Procedure:
An ice-cold solution of ii (0.25 g, 0.42 mmol) in MeOH-DCM (0.50 and 10 mL respectively) was purged with HCl (g) for 10 min and the mixture stirred at RT for 16 h. The solvent was evaporated and the residue triturated with a mixture of MeOH and Et2O to obtain Compound 2 (0.225 g, 90%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:28]=[CH:27][CH:26]=[CH:25][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:24])[CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:12][CH:11]=1)=[O:5])C.[OH-].[K+]>O.C(O)C>[C:4]([C:6]1[CH:28]=[CH:27][CH:26]=[CH:25][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:24])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:12][CH:11]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)CCC(C)c1ccc(OCc2ccccc2C(=O)OCC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(CCC(=O)O)c1ccc(OCc2ccccc2C(=O)O)cc1
Yield: 74.4 %

Procedure:
A mixture of 14 g of ethyl 4-[4-(2-ethoxycarbonylbenzyloxy)-phenyl]pentanoate, 31 g of potassium hydroxide in 40 ml of water and 250 ml of 95% of ethanol was heated under reflux overnight. The solution was concentrated and the residue was dissolved in water, cooled and acidified with cold conc hydrochloric acid. The mixture was extracted with ether, and the extract was dried over anhydrous sodium sulfate, filtered and evaporated. Trituration with hexane afforded 8.9 g (72%) of product, mp 104°-106°. Recrystallization from acetonitrile gave an analytical sample, mp 115°-117.5°.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[C:12](OC(=O)C)(=[O:14])[CH3:13].S(=O)(=O)(O)O>>[F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH:4][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cc([N+](=O)[O-])ccc1F
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
5.0 g (32 mmol) of 2-fluoro-5-nitroaniline were admixed with 10 ml (110 mmol) of acetic anhydride and 0.1 ml of conc. sulfuric acid and stirred at 100° C. for 1.5 hours. The solution was added to 100 ml of ice/water, and the precipitate which formed was filtered off and washed with water. The crude product was purified by chromatography (1:1 ethyl acetate/heptane) on silica gel (yield 5.4 g, 85%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH:16]2[C:21]([OH:23])=O)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].CN(C=O)C.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[NH2:42][OH:43]>ClCCl.C1COCC1>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH:16]2[C:21]([NH:42][OH:43])=[O:23])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: NO
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCOCC2C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)N2CCOCC2C(=O)NO)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
A solution of 4-([4-(2-butynyloxy)phenyl]sulfonyl}-morpholine-3-carboxylic acid (0.52 g, 1.53 mmol) and DMF (0.24 mL, 3.1 mmol) in dichloromethane (6 mL) was cooled in an ice bath and oxalyl chloride (1.54 mL of 2M in CH2Cl2; 3.1 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 10 minutes and at room temperature for 2 hours and then recooled to 0°. A THF (4.5 mL) solution of triethyl amine (0.86 mL, 6.13 mmol) and hydroxylamine (0.56 mL of 50% hydroxyamine in water, 9 mmol) was added in one portion. The reaction was stirred at room temperature overnight. After removing the solvent, the oily residue was diluted with ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and evaporated to obtain 0.42 g of 4-([4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-3-morpholinecarboxamide. Yield˜77.8%. mp 68-72° C. Electrospray Mass Spec 355.2(M+H)+.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:21])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>N1C=CC=CC=1.C1C=CC=CC=1>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[O:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2OC(=O)c1ccccc1

Procedure:
Treat 13β-ethyl-17β-hydroxy-gon-4-en-3-one (2 g.) in pyridine (20 cc.) with benzoyl chloride (3 cc.) in benzene (10 cc.) at -10°. Keep the mixture at that temperature for 18 hours and then pour into 2N hydrochloric acid (200 cc.). Extract the product with ether and wash, dry and evaporate the extracts. Triturate the residue with a mixture of ether and hexane. Filter the crystalline material obtained and dissolved in benzene and purify by chromatography on neutral alumina. Recrystallize from a mixture of ethyl acetate and hexane to give the title compound, m.p. 141°-9°; ultraviolet light absorption peak at 237 mμ(ε27,300).
Reaction SMILES: C([C:3](CC)([C:7]([C:9]([O-:11])=[O:10])=O)[C:4]([O-])=[O:5])C.[Na+].[Na+].C(O)(=O)C.[CH:20]([NH2:22])=[NH:21].[OH-].[Na+].C>O>[OH:5][C:4]1[N:22]=[CH:20][N:21]=[C:7]([C:9]([OH:11])=[O:10])[CH:3]=1
Reactant: CCC(CC)(C(=O)[O-])C(=O)C(=O)[O-]
Reactant: N=CN
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc(O)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
63.5 g (287 mmol) sodium diethyl-oxalacetate and 30.2 g (287 mmol) formamidine acetate were added to 24.1 g (597 mmol) NaOH in 3.6 L water. The mixture was stirred overnight at RT. Then activated charcoal was added and the mixture was refluxed for 1 h. It was filtered hot and after cooling acidified with aqueous HCl. The solution was concentrated to dryness by rotary evaporation. The residue contained the desired product and was used in the next step without further purification.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[CH2:6]([N:10]1[CH:15]=[CH:14][C:13](O)=[CH:12][C:11]1=[O:17])[CH2:7][CH2:8][CH3:9]>CN(C=O)C>[Br:3][C:13]1[CH:14]=[CH:15][N:10]([CH2:6][CH2:7][CH2:8][CH3:9])[C:11](=[O:17])[CH:12]=1
Reactant: CCCCn1ccc(O)cc1=O
Reactant: O=P(Br)(Br)Br
Solvent: CN(C)C=O
Product: CCCCn1ccc(Br)cc1=O
Temperature: 110 °C
Yield: 92 %

Procedure:
Phosphorus oxybromide (5.4 g, 18.9 mmol) was added to a solution of intermediate D5 (1.44 g, 8.6 mmol) in DMF (140 ml) and the mixture was heated at 110° C. for 1 hour. After cooling in an ice bath, the solution was partitioned between water and EtOAc. After three extractions with EtOAc, the combined organic fractions were dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate D6 (1.82 g, 93%).
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([O:20][C:21]3[C:22]([CH3:31])=[N:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>O>[CH3:33][O:32][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[O:9][CH2:8][CH2:7][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)[N:17]=[CH:16][CH:15]=[C:14]2[O:20][C:21]1[C:22]([CH3:31])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCN1CCOCC1
Temperature: 80 °C
Reaction time: 72 h
Yield: 40.8 %

Procedure:
N,N-Dimethylformamide (1.5 ml) was added to 7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 353) (50 mg), potassium carbonate (53 mg), and morpholine (33 mg), and the mixture was stirred at 80° C. for 3 days. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (23 mg, yield 41%).
Reaction SMILES: [CH3:1][C:2]([CH2:16][CH2:17][CH:18]=[C:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][O:13]2)=[CH:8][CH:7]=1.C(OO)(=[O:26])C>>[O:26]1[C:19]([CH2:20][CH3:21])([CH2:22][CH3:23])[CH:18]1[CH2:17][CH2:16][C:2]([CH3:1])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][O:13]2)=[CH:8][CH:7]=1
Reactant: CCC(=CCCC(C)=CCOc1ccc2c(c1)OCCC2)CC
Reactant: CC(=O)OO
Product: CCC1(CC)OC1CCC(C)=CCOc1ccc2c(c1)OCCC2

Procedure:
Following the procedure of Example 17, 7-(3-methyl-7-ethyl-2,6-nonadienyloxy)-chromane and peracetic acid are reacted to form 7-(6,7-epoxy-3-methyl-7-ethyl-2-nonenyloxy)-chromane, nD20 = 1.5303.
Reaction SMILES: C1(C)C=CC(S([N:9]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@H:10]2[C:18]([O:20][CH3:21])=[O:19])=O)=CC=1.FC(F)(F)C(O)=[O:26]>C(#N)C>[NH2:9][C@@H:10]([C@@H:11]([OH:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)[C@@H]1[C@H](c2ccccc2)N1S(=O)c1ccc(C)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COC(=O)[C@@H](N)[C@@H](O)c1ccccc1
Temperature: 45 °C
Reaction time: 6 h

Procedure:
Into a 50-mL round-bottomed flask equipped with a magnetic stir bar were placed 0.315 g (1.0 mmol) (2S,3S)-(+)-N-(p-toluenesulfinyl)-2-carbomethoxy-3-phenylaziridine (prepared according to Example 1), 10 mL acetonitrile and 2 mL 50% aqueous trifluoroacetic acid. The reaction mixture was stirred for 6 h at 45° C., the solvent was removed and the residue treated with H2O (5 mL). After washing the aqueous solution with ether (2×10 mL), the aqueous phase was brought to pH 10 with concentrated NH4OH and extracted with CHCl3 (2×10 mL). After drying (MgSO4), the organic phase was filtered and concentrated to give the titled compound in impure form, which was purified by flash chromatography (ether:CH3CN:NH4OH; 10:1:0.2) to afford the titled compound (0.138 g, 71%) as a viscous oil: [α]D20 +11.0° (c 1.8, MeOH) ([α]D20 -10.97° (c 1.4, MeOH) according to Beulshausen, T. et al. Liebigs Ann. Chem. 1991, 1207 for the (2R,3S)-isomer); 1H NMR (CDCl3) δ2.10 (bs, 3H, NH2, OH) 3.65 (d, J=4.5 Hz, 1H, CH), 3.69 (s, 3H, CH3), 4.91 (d, J=4.5 Hz, 1H, CH) 7.36-7.26 (m, 5H, aromatic); 13C NMR (CDCl3) δ52.2, 60.6, 74.1, 126.0, 127.8, 128.4, 140.9, 173.7.
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][NH:7][C:8](=[O:16])[CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])([CH3:3])[CH3:2].[CH3:17][Si:18]([CH2:21]Cl)([CH3:20])[CH3:19]>C(N(CC)CC)C>[CH:1]([N:4]([CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH2:5][CH2:6][NH:7][C:8](=[O:16])[CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)CCl
Reactant: CC(C)NCCNC(=O)CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)N(CCNC(=O)CN1CCCC1=O)C[Si](C)(C)C
Temperature: 150 °C
Reaction time: 24 h
Yield: 50.7 %

Procedure:
A mixture of 5.00 g (22.0 mmol) of N-[2-(isopropylamino)ethyl]-2-oxo-pyrrolidineacetamide, 8.10 g (66.0 mmol) of trimethylsilylmethyl chloride, 30 ml of triethylamine and 50 ml of N,N-dimethylformaide was stirred at 150° C. for 24 hours in a shield tube. After cooled, the reaction mixture was concentrated in vacuo and chromatographed the residue on alumina column to afford 3.5 g (Yield: 51.3%) of the desired compound as colorless oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[C@@H:3]([NH:30]C(=O)OC(C)(C)C)[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]3[NH:18][CH:19]=[C:20]([NH:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=4)[C:13]=23)[CH2:8][CH2:7]1)=[O:5].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:30][C@H:3]([CH:2]([CH3:38])[CH3:1])[C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]3[NH:18][CH:19]=[C:20]([NH:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=4)[C:13]=23)[CH2:10][CH2:11]1)=[O:5]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(c2ccnc3[nH]cc(NC(=O)c4cccnc4)c23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@@H](N)C(=O)N1CCN(c2ccnc3[nH]cc(NC(=O)c4cccnc4)c23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
(R)-tert-Butyl 3-methyl-1-(4-(3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-1-oxobutan-2-ylcarbamate (0.014 g, 0.027 mmol) was placed in DCM (3 mL) at room temperature. TFA (0.5 mL) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness. The resulting residue was dissolved in minimal DCM and then added dropwise to a stirring solution of 1M HCl in ether. The resulting solid was filtered, washed with ether, and dried to give (R)—N-(4-(4-(2-amino-3-methylbutanoyl)piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (0.009 g, 63% yield) as the trihydrochloride salt. MS APCI (+) m/z 422 detected.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([NH2:23])[C:19]([NH2:22])=[CH:20][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:22][C:19]2[C:18]([NH2:23])=[CH:17][C:16]([F:15])=[CH:21][CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Nc1ccc(F)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1cc(F)ccc1NC1CCN(Cc2ccccc2)CC1
Yield: 5.9 %

Procedure:
The title compound was prepared from 750 mg 1-benzyl-4-piperidone, 1.0 g of 4-fluoro-benzene-1,2-diamine and 1.0 g sodium triacetoxyborohydride in 10 mL of THF, using a procedure analogous to that described in Example 95, Step A to provide 70 mg of the title compound as a brown solid.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH:11]=[CH:12][N:13]=[CH:14]3)=[O:7])=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CCOC(C)=O.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>[CH:14]1[C:15]2[C:10](=[C:9]([NH:8][C:6]([C:5]3[CH:19]=[CH:20][C:2]([C:26]4[CH:25]=[CH:24][CH:23]=[C:22]([CH3:21])[CH:27]=4)=[CH:3][CH:4]=3)=[O:7])[CH:18]=[CH:17][CH:16]=2)[CH:11]=[CH:12][N:13]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: O=C(Nc1cccc2cnccc12)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2ccc(C(=O)Nc3cccc4cnccc34)cc2)c1
Temperature: 25 °C

Procedure:
To a solution of 4-bromo-N-isoquinolin-5-ylbenzamide (D94) (50 mg, 0.153 mmol) in toluene (2 ml) and ethanol (0.4 ml) under an argon atmosphere was added 3-methyl-phenylboronic acid (21 mg, 0.153 mmol), 2M sodium carbonate solution (0.15 ml) and tetrakis(triphenylphosphine)palladium (0) (5 mg, 0.05 mmol). The reaction was heated at reflux for 18 h, then cooled to room temperature and diluted with EtOAc. The mixture was washed with sat. aq. sodium bicarbonate solution and water, dried over MgSO4 and concentrated to give the crude product which was purified by SPE column chromatography. Elution with 50% EtOAc/40-60° C. petroleum ether gave the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.32 (s, 1H), 8.62 (d, 1H), 8.34 (d, 1H), 8.22 (br, 1H), 8.07 (d, 2H), 7.90, (d, 1H), 7.78 (d, 2H), 7.70 (m, 3H), 7.47 (m, 2H), 7.40 (t, 1H), 2.47 (s, 3H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[C:17](=S)=[S:18]>C(O)C.O>[SH:18][C:17]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1
Reactant: S=C=S
Reactant: Nc1ccccc1Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Sc1nc2ccccc2n1-c1ccccc1
Yield: 74 %

Procedure:
To 18.6 g (0.10M) of N-phenyl-o-phenylenediamine in 100 ml ethanol, 4.8 g (0.12M) of sodium hydroxide in 20 ml water is added followed by 13 g (0.17M) of carbon disulfide. The mixture is heated to reflux for 5 hours. The reaction mixture is poured into 300 ml water and solid is collected. The crude material is recrystallized from ethanol and the recrystallized material weighs 25 g (74% yield) and melts at 195°-7° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](/[CH:8]=[N:9]/[C:10]2[C:15]([CH:16]([CH3:18])[CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[CH:4][CH:3]=1.[BH3-]C#N.[Na+].CC(O)=O.CO>O>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:9][C:10]2[C:15]([CH:16]([CH3:17])[CH3:18])=[CH:14][CH:13]=[CH:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1cccc(C(C)C)c1/N=C/c1cccc(Br)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1NCc1cccc(Br)n1

Procedure:
A mixture of 25.0 g (134 mmol) of 6-bromopyridine-2-carbaldehyde, 23.8 g (134 mmol) of 2,6-diisopropylaniline and 1.15 g (6.70 mmol) of TsOH in 600 ml of toluene was refluxed for 15 min using a Soxhlet apparatus filled with CaCl2. The obtained solution was evaporated to dryness, and the residue was re-crystallized from 100 ml of methanol to give the imine product N-[(1E)-(6-bromopyridin-2-yl)methylene]-2,6-diisopropylaniline as a yellow crystalline solid (23.9 g). In argon atmosphere, a mixture of 22.4 g (65.0 mmol) of N-[(1E)-(6-bromopyridin-2-yl)methylene]-2,6-diisopropylaniline, 6.53 g (104 mmol) of NaBH3CN, 2 ml of AcOH and 430 ml of methanol was refluxed for 12 h. The obtained mixture was cooled, poured into 1000 ml of water, and then extracted with 3×200 ml of ethyl acetate. The combined extract was dried over MgSO4 and evaporated to dryness. The residue was purified by flash chromatography on silica gel 60 (40-63 μm, eluent: hexane-ethyl acetate=10:1, vol.). Yield 19.8 g (43%) of a yellow oil. Anal. calc. for C18H23BrN2: C, 62.25; H, 6.68; N, 8.07. Found: C, 62.40; H, 6.77; N, 7.96. 1H NMR (CDCl3): δ 7.50 (m, 1H, 4-H in 6-bromopyridyl), 7.38 (m, 1H, 5-H in 6-bromopyridyl), 7.28 (m, 1H, 3-H in 6-bromopyridyl), 7.01-7.11 (m, 3H, 3,4,5-H in 2,6-diisopropylphenyl), 4.16 (s, 2H, CH2N), 3.93 (br.s, 1H, NH), 3.31 (sep, J=6.9 Hz, 2H, CHMe2), 1.22 (d, J=6.9 Hz, 12H, CHMe2).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]12[CH2:13][CH:10]([CH2:11][CH2:12]1)[CH2:9][CH:8]2[NH:14][C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]([S:23][CH3:24])[N:16]=1.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>O1CCCC1>[NH2:22][CH2:21][C:20]1[C:15]([NH:14][CH:8]2[CH2:9][CH:10]3[CH2:13][CH:7]2[CH2:12][CH2:11]3)=[N:16][C:17]([S:23][CH3:24])=[N:18][CH:19]=1
Reactant: CSc1ncc(C#N)c(NC2CC3CCC2C3)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CSc1ncc(CN)c(NC2CC3CCC2C3)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.3 %

Procedure:
To a stirred 0° C. suspension of 2.5 g (65.3 mmol) of LAH in 100 mL of tetrahydrofuran is added dropwise a solution of 8.5 g (32.6 mmol) of 4-(bicyclo[2.2.1]hept-2-yl-amino)-2-(methylthio)-5-pyrimidinecarbonitrile in 375 mL of tetrahydrofuran. The reaction is allowed to warm slowly to room temperature overnight. The mixture is recooled to 0° C. and treated with a saturated solution of ammonium sulfate until there is no more effervescence. After stirring for another 15 minutes, the gray solids are filtered and washed four times with hot ethyl acetate. The combined organic washes are concentrated, and the residue is purified by chromatography on silica gel that is eluted with methanol/dichloromethane 1:9 followed by 2:8 to obtain 5.8 g (68%) of the title compound.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[O:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=2)[O:21][CH2:22][C:23]([OH:25])=O)=[CH:14]1.[NH2:29][C:30]1[CH:39]=[CH:38][C:37]([Br:40])=[CH:36][C:31]=1[C:32]([O:34][CH3:35])=[O:33].ON1C2C=CC=CC=2N=N1.CN1C=CN=C1>O.CC(N(C)C)=O>[Br:40][C:37]1[CH:38]=[CH:39][C:30]([NH:29][C:23](=[O:25])[CH2:22][O:21][C:20]2[CH:26]=[CH:27][CH:28]=[C:18]([C:15]3[CH:16]=[CH:17][O:13][CH:14]=3)[CH:19]=2)=[C:31]([CH:36]=1)[C:32]([O:34][CH3:35])=[O:33]
Reactant: O=C(O)COc1cccc(-c2ccoc2)c1
Reactant: COC(=O)c1cc(Br)ccc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Cn1ccnc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1cc(Br)ccc1NC(=O)COc1cccc(-c2ccoc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.5 %

Procedure:
Under ice-cooling, 1.53 g (7.97 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a DMAc (5 mL) solution comprising 1.45 g (6.64 mmol) of [3-(furan-3-yl)phenoxy]acetic acid, 1.60 g (6.97 mmol) of methyl 2-amino-5-bromobenzoate, and 1.08 g (7.97 mmol) of 1-hydroxybenzotriazole, and the mixture was stirred at room temperature for 4 hours. Under ice-cooling, 1.63 g (19.9 mmol) of 1-methylimidazole was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was stirred for 1 hour. The precipitates were collected by filtration and washed with water and IPE, followed by drying under reduced pressure at 50° C. for 3 hours, thereby giving 2.30 g of methyl 5-bromo-2-({[3-(furan-3-yl)phenoxy]acetyl}amino)benzoate (yield: 81%).