Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:19]2[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[N:23][CH:24]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:8]([C:5]1[N:6]=[CH:7][C:2]([C:19]2[CH:24]=[N:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: CC(=O)c1ccc(Br)cn1
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: Cc1ccccc1
Product: CC(=O)c1ccc(-c2ccc(C#N)nc2)cn1
Temperature: 77.5 °C
Reaction time: 6 h
Yield: 80.6 %

Procedure:
To a stirred solution of 1-(5-bromopyridin-2-yl)ethanone (0.2 g, 1 mmol) in toluene (10 mL) and ethanol (5 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (0.46 g, 2 mmol) and Pd(PPh3)4 (0.057 g, 0.05 mmol). The reaction mixture was purged with argon for 5 min, 2M Na2CO3 solution (3.5 mL, 0.74 g, 7 mmol) was added, and the reaction mixture was stirred at 75-80° C. for 6 h. The reaction mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution (2×100 mL), and extracted into ethyl acetate (2×100 mL). The organic layer was washed with brine and ice-cold water (2×100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography (100-200μ silica gel, using 15-16% ethyl acetate in hexane) to obtain 6′-acetyl-[3,3′-bipyridine]-6-carbonitrile as white solid (0.18 g, 80% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.24 (dd, 1H), 9.20 (dd, 1H), 8.54 (dd, 1H), 8.46 (dd, 1H), 8.23 (dd, 1H), 8.09 (dd, 1H), 2.68 (s, 3H); LC-MS m/z calculated for [M+H]+ 224.07. found 224.1.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[C:7]([OH:15])=[C:8]([CH3:14])[C:9]([CH3:13])=[C:10]([CH:12]=1)O.[C:16]([O:19][CH2:20][CH2:21][C:22]([OH:26])([CH3:25])[CH:23]=[CH2:24])(=[O:18])[CH3:17]>C(Cl)Cl.[N+](C)([O-])=O>[C:16]([O:19][CH2:20][CH2:21][C:22]1([CH3:25])[CH2:23][CH2:24][C:12]2[C:10](=[C:9]([CH3:13])[C:8]([CH3:14])=[C:7]([OH:15])[C:6]=2[CH3:5])[O:26]1)(=[O:18])[CH3:17]
Reactant: C=CC(C)(O)CCOC(C)=O
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Product: CC(=O)OCCC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To an ice-cooled mixture of 3.37 g. of aluminum chloride and 40 ml. of methylene chloride was added, dropwise, 3.37 ml. of nitromethane. The resulting solution was stirred 5 minutes, and then 5.114 g. of trimethylhydroquinone was added in one portion. The green mixture was cooled to 20° and a solution of 5.35 g. of 3-hydroxy-3-methyl-4-pentenyl acetate in 20 ml. of methylene chloride was added over 1.0 hour. The mixture was allowed to warm to room temperature, kept there for 2 hours and poured into ice-H2O. The mixture was extracted with methylene chloride and the organic solutions were washed with saturated sodium bicarbonate solution and brine and dried over sodium sulfate. Solvent removal gave crude (±)-2-(2-acetoxyethyl)-6-hydroxy-2,5,7,8-tetramethylchroman as a red oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].C(N1C=CN=C1)(N1[CH:17]=[CH:16]N=C1)=O.C(O)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([O:7][CH2:16][CH3:17])=[O:6]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccnc(Cl)c1
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1ccnc(Cl)c1
Yield: 95.9 %

Procedure:
In 400 ml of tetrahydrofuran was dissolved 31.5 g of 2-chloroisonicotinic acid, and 32.5 g of 1,1′-carbonyldiimidazole was added thereto. The mixture was stirred under ice-cooling for an hour. To the solution was added 50 ml of ethanol, and the mixture was stirred at room temperature for 2 hours. The solution was concentrated, and extracted by adding ethyl acetate and water. The organic layer was dried over magnesium sulfate, and the residue was vacuum dried, to give 35.6 g of ethyl 2-chloroisonicotinate as shown in Table 132 below.
Reaction SMILES: FC(F)(F)CCCCCCCCCCCCCCCN[C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1.C(COC)OC.C(Cl)[Cl:37]>>[ClH:37].[C:23]([Cl:37])(=[O:24])[C:22]1[CH:26]=[CH:27][CH:19]=[CH:20][CH:21]=1
Reactant: ClCCl
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Solvent: COCCOC
Product: Cl
Product: O=C(Cl)c1ccccc1

Procedure:
A cold solution of 25 g. of 4-[15-(trifluoromethyl)pentadecylamino]benzoic acid in 500 ml. dimethoxyethane-methylene chloride (4:1) is prepared and dry hydrochloric acid is bubbled through the solution until no more precipitate forms. The solution is treated with 25 ml. thionyl chloride and refluxed until all of the precipitate has dissolved. The solvents are evaporated to yield 4-[15-(trifluoromethyl)pentadecylamino)]benzoyl chloride hydrochloride as an orange, semi-crystalline mass.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]=1[OH:28])[CH:23]=O)[CH3:18].[NH2:32][C:33]([NH2:35])=[O:34].Cl>CCO.CO.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:35][C:33](=[O:34])[NH:32][CH:23]([C:22]3[CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]([OH:28])=[C:20]([O:19][CH2:17][CH3:18])[CH:21]=3)[C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccccc1)c1ccc(Cl)cc1
Reactant: NC(N)=O
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOc1cc(C2NC(=O)NC(c3ccc(Cl)cc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 7.8 %

Procedure:
A mixture of 1-(4-chlorophenyl)-2-phenylethanone (350 mg, 1.52 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (320 mg, 1.52 mmol), and urea (272 mg, 4.53 mmol) in anhydrous EtOH (15 mL) was added concentrated HCl solution (0.5 mL), and the reaction mixture was refluxed for overnight. TLC (EtOAc:MeOH=10:1) showed that about 30% of starting materials were consumed, and the reaction mixture was concentrated. The residue was purified by column chromatography (EtOAc:MeOH=40:1) and preparative HPLC to afford the product Compound 36 as a yellow solid (55.1 mg, yield: 7.8%). 1H NMR (DMSO-d6 400 MHz): δ 10.30 (s, 1H), 8.79 (s, 1H), 7.55 (s, 1H), 7.42 (s, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 7.18 (s, 1H), 7.00-7.10 (m, 3H), 6.82 (d, J=7.2 Hz, 2H), 5.20 (d, J=2.4 Hz, 1H), 4.00-4.10 (m, 2H), 1.33 (t, J=6.8 Hz, 3H); MS (ESI): m/z 466.0 [M+1]+.
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C@H:6]1[N:16]2[C@@H:10]([S:11][CH2:12][CH2:13][C@H:14]([NH:18]C(=O)OC(C)(C)C)[C:15]2=[O:17])[CH2:9][CH2:8][CH2:7]1.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[NH2:18][C@H:14]1[CH2:13][CH2:12][S:11][C@H:10]2[CH2:9][CH2:8][CH2:7][C@@H:6]([C:2]3[O:1][CH:5]=[N:4][N:3]=3)[N:16]2[C:15]1=[O:17]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](c3nnco3)N2C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCS[C@H]2CCC[C@@H](c3nnco3)N2C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a solution of tert-butyl (4S,7S,10aS)-7-(1,3,4-oxadiazol-2-yl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (22 mg, 0.060 mmol) in DCM (0.6 mL) at 0° C., was added TFA (0.323 mL, 4.20 mmol). The mixture was stirred at rt for 1.5 hr. The reaction was concentrated to give (4S,7S,10aS)-4-amino-7-(1,3,4-oxadiazol-2-yl)hexahydro-2H-pyrido[2,1-b][1,3]thiazepin-5 (7H)-one 2,2,2-trifluoroacetate (23 mg, 0.060 mmol, 100% yield). Anal. Calcd. for C11H16N4O2S m/z 268.4. found: 269.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:41][C:42]([N:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:41][CH2:42][N:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)=[CH:36][CH:37]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: O=C(CCl)N1CCCCC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCCCC2)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 41.5 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and 2-chloro-1-piperidin-1-ylethanone (8.8 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (6.8 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2[N:9]=[C:10](O)[C:11]3[O:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:7]=1.C([O-])(O)=O.[Na+].O=P(Cl)(Cl)[Cl:26]>C(Cl)Cl>[Cl:26][C:10]1[C:11]2[O:16][CH2:15][CH2:14][C:12]=2[N:13]=[C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:18])[N:9]=1
Reactant: Oc1nc(-c2cc(Cl)ccc2F)nc2c1OCC2
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc(Cl)cc1-c1nc(Cl)c2c(n1)CCO2
Temperature: 25 °C
Yield: 73 %

Procedure:
A suspension of 2-(5-chloro-2-fluorophenyl)-6,7-dihydrofuro[3,2-d]pyrimidin-4-ol (100 mg, 0.36 mmol, 1 eq) in POCl3 (5 ml) was stirred under reflux for 1 h. The solution cooled to rt and concentrated under reduced pressure to give a white solid which was dissolved in methylene chloride. The solution was cooled to 0° C. and ice was added followed by sat. NaHCO3. The organic layer was separated, washed with brine, dried (MgSO4), filtered and evaporated in vacuo to provide a crude white solid which was purified by flash column chromatography (1:9 EtOAc:Hexane) to afford 4-chloro-2-(5-chloro-2-fluorophenyl)-6,7-dihydrofuro[3,2-d]pyrimidine (78 mg, 73%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:15][CH:16]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH:17]([OH:23])[C:18]([O:20]CC)=[O:19].[OH-].[K+].C(OCC)(=O)C.S([O-])(O)(=O)=O.[K+]>C(O)C.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[S:15][CH:16]([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[CH:17]([OH:23])[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)C(O)C(Sc1cc(Oc2ccccc2)ccc1N)c1ccc(OC)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: COc1ccc(C(Sc2cc(Oc3ccccc3)ccc2N)C(O)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.9 %

Procedure:
3.28 g of ethyl 3-(2-amino-5-phenoxyphenyl)thio-2-hydroxy-3-(4-methoxyphenyl)propionate [prepared as described in step (a) above] were dissolved in 20 ml of ethanol, and a solution of 615 mg of 85% (by weight purity) caustic potash dissolved in 5 ml of water were added to the resulting solution. The solution was then stirred at room temperature for 2 hours, after which 50 ml of water and 70 ml of ethyl acetate Were added thereto, followed by an aqueous solution of potassium hydrogen sulfate sufficient to adjust the pH to a value of 3. The precipitate which formed was collected by filtration, to give 1.44 g of the title compound. The filtrate was separated, and the ethyl acetate layer was recovered, washed, dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The residue was triturated in diethyl ether and then filtered to give a further 0.76 9 of the title compound. This substance was used in the subsequent step without purification.
Reaction SMILES: Cl[CH2:2][O:3][CH2:4][CH2:5][Si:6]([CH3:9])([CH3:8])[CH3:7].[Br:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([CH3:20])[CH:19]=1)[NH:16][N:15]=[CH:14]2.CN(C1CCCCC1)C1CCCCC1>C1COCC1>[Br:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([CH3:20])[CH:19]=1)[N:16]([CH2:2][O:3][CH2:4][CH2:5][Si:6]([CH3:9])([CH3:8])[CH3:7])[N:15]=[CH:14]2
Reactant: Cc1cc(Br)cc2cn[nH]c12
Reactant: C[Si](C)(C)CCOCCl
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: Cc1cc(Br)cc2cnn(COCC[Si](C)(C)C)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.95 mL (11.0 mmol) (2-chloromethoxy-ethyl)-trimethyl-silane were added to 2.11 g (10.0 mmol) 5-bromo-7-methyl-1H-indazole and 1.80 mL (12.3 mmol) N-methyldicyclohexylamine in 50 mL THF and stirred overnight at RT. The precipitate formed was filtered off and the filtrate was evaporated down. The residue was purified by flash chromatography.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[C:9]([N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[CH3:16])[CH:8]=[CH:7][C:6]=1[N+:17]([O-:19])=[O:18])C.Cl.O>C(O)(C)C>[CH3:16][C:12]1[N:11]([C:9]2[CH:8]=[CH:7][C:6]([N+:17]([O-:19])=[O:18])=[C:5]([CH:10]=2)[CH:4]=[O:3])[CH:15]=[CH:14][N:13]=1
Reactant: CCOC(OCC)c1cc(-n2ccnc2C)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: Cc1nccn1-c1ccc([N+](=O)[O-])c(C=O)c1
Reaction time: 1 h
Yield: 88.8 %

Procedure:
A mixture of 5-(2-methylimidazol-1-yl)-2-nitrobenzaldehyde diethyacetal (735 mg), conc-HCl (2.0 ml), water (4.0 ml) and isopropyl alcohol (4.0 ml) was heated under stirring for 1 hour and cooled. The mixture was extracted with dichloromethane and the extract was dried with Na2SO4 and filtered. The filtrate was distilled to give 494 mg (88%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[O:16][CH2:15][CH2:14][CH2:13][O:12]1.[OH-].[CH2:18]([N+:25](C)(C)C)[C:19]1C=CC=[CH:21][CH:20]=1.CCO.C(C#N)C=C>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:20]([CH3:21])[CH2:19][C:18]#[N:25])[C:6](=[O:11])[C:5]12[O:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: O=C1Nc2ccc(Br)cc2C12OCCCO2
Agent: C=CCC#N
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(CC#N)N1C(=O)C2(OCCCO2)c2cc(Br)ccc21
Temperature: 80 °C
Reaction time: 24 h
Yield: 50.4 %

Procedure:
To a solution of 5′-bromospiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one (2.00 g, 7.04 mmol) and benzyltrimethylammonium hydroxide (40% aqueous solution, 0.768 mL, 1.69 mmol, 0.24 mole %) in abs. EtOH (32 mL) was added allyl cyanide (1.42 mL, 17.6 mmol, 2.5 eq) all at one time at room temperature and the mixture was heated at 80° C. for 2.5 hr. Additional benzyltrimethyl-ammonium hydroxide (0.77 mL) was added and the heating continued another 24 hr. The reaction was cooled to room temperature and poured into H2O (100 mL). The reaction mixture was extracted with EtOAc (3×). The combined organic extracts were concentrated. The crude product was purified on Biotage KP silica gel eluting with CH2Cl2/CH3OH/NH4OH (97/2/1) to give the title compound as a white solid (0.299 g, 16% ). Anal. Calc'd for: C15H15BrN2O3: C, 51.3; H, 4.3; N, 7.98. Found: C, 51.55; H, 4.47; N 7.99. NMR (300 Mz, DMSO-d6): consistent. MS: (ES+) m/z 350/352 [M+]; one Br pattern observed. m.p.: 112-113° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-])=O)=[CH:9][CH:8]=1.[Cl-:27].[NH4+]>C(O)C.O.[Fe]>[ClH:27].[F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccccc1Oc1ccc(OCc2ccc(F)c(F)c2)cc1
Reactant: [Cl-]
Agent: [Fe]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cl
Product: Nc1ccccc1Oc1ccc(OCc2ccc(F)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 148.8 %

Procedure:
To a solution of 1-[4-(3,4-difluorobenzyloxy)phenoxy]-2-nitrobenzene (0.96 g, 2.7 mmol) in ethanol (50 ml) were an iron powder (0.75 g, 13.4 mg-atom) and a solution of ammonium chloride (0.09 g, 1.7 mmol) in water (10 ml), followed by reflux for 3 hours. The reaction solution was cooled to room temperature, and after removal of the insoluble matter by filtration, the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and dried over magnesium sulfate. After removal of the drying agent, 4 N hydrogen chloride-ethyl acetate solution (2 ml) was added, followed by stirring for 30 minutes. The precipitated crystals were collected by filtration and dried to give the title compound (0.92 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)=[CH:5][C:4]=1F)#[N:2].[C:23]([O-])([O-])=[O:24].[K+].[K+]>CO.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)=[CH:5][C:4]=1[O:24][CH3:23])#[N:2]
Reactant: COC(=O)c1ccc2c(ccn2-c2ccc(C#N)c(F)c2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc2c(ccn2-c2ccc(C#N)c(OC)c2)c1
Temperature: 75 °C
Yield: 102 %

Procedure:
A solution of 95 mg (0.32 mmol) of compound 9m was combined with 120 mg (0.87 mmol) of K2CO3 in 8 mL of MeOH and heated at 75° C. for 5 h. The mixture was cooled, diluted with water, and extracted with CH2Cl2. The organic solution was concentrated to give 100 mg (100%) of 9n as a white solid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)=O)(C)(C)C.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[C:40]2[O:41][C:42]([CH3:45])([CH3:44])[O:43][C:39]=2[CH:38]=[C:37]([C:46](Cl)=[O:47])[CH:36]=1.[C:49]1(=O)[CH2:52]C[CH2:50]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:6]1([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:13][N:14]([CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C:46]([C:37]2[CH:36]=[C:35]([O:34][CH3:33])[C:40]3[O:41][C:42]([CH3:45])([CH3:44])[O:43][C:39]=3[CH:38]=2)=[O:47])[CH2:52][CH2:49][CH2:50]1
Reactant: O=C1CCC1
Reactant: COc1cc(C(=O)Cl)cc2c1OC(C)(C)O2
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNCc1ccc2ccccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)N(Cc2ccc3ccccc3c2)C[C@@H]2CCCN2C2CCC2)cc2c1OC(C)(C)O2
Reaction time: 1.5 h

Procedure:
Experimental conditions analogous Example 58, from 0.35 g (1.01 mmol) of (S)-2-{[(naphthalen-2-ylmethyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester, 10 mL dichloromethane, 169 μL (1.21 mmol) of triethylamine, and 0.27 g (1.12 mmol) of 7-methoxy-2,2-dimethyl-benzo[1,3]dioxole-5-carbonyl chloride. The crude mixture was filtered through silica and the compound was deprotected in 10 mL 10% trifluoroacetic acid/dichloromethane in 1.5 hours. The reaction mixture was treated with aqueous sodium bicarbonate, and extracted with dichloromethane. The crude material was dissolved in 10 mL of dichloromethane, to this mixture was added 0.21 g (3.0 mmol) of cyclobutanone and 0.636 g (3.0 mmol) of sodium triacetoxyborohydride. After overnight the reaction was quenched with aqueous sodium bicarbonate and di-tert-butyl dicarbonate. The organic layer was separated, the residue was purified using flash chromatography (7N ammonia in methanol, 0-3% in dichloromethane), gave 76 mg of off white solid as a free base. LC-MSD, m/z for C31H36N2O4 [M+H]+: 501.7. 1H NMR (400 MHz, CDCl3/HCl): δ 1.7 (s, 6 H), 1.9-2.7 (m, 10 H), 2.8-3.0 (m, 1 H), 3.5-3.7 (m, 1 H), 3.8 (s, 3 H), 3.8-4.0 (m, 4 H), 4.9-5.0 (m, 1 H), 5.2-53 (m, 1 H), 6.7 (s, 1H), 6.8 (s, 1 H), 7.2-7.3 (m, 1H), 7.4-7.5 (m, 2 H), 7.7 (s, 1 H), 7.8-7.9 (m, 3 H), 12.2-12.3 (m, 1 H).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C:7](=O)[CH2:8][CH3:9])[C:3]([OH:5])=[O:4].Cl.[Cl:12][C:13]1[CH:30]=[CH:29][C:16]([C:17]([N:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)N)=[O:18])=[CH:15][CH:14]=1>C(O)(=O)C>[Cl:12][C:13]1[CH:30]=[CH:29][C:16]([C:17]([N:19]2[C:21]3[C:22](=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[C:8]([CH3:9])=[C:7]2[CH2:6][CH:2]([CH3:1])[C:3]([OH:5])=[O:4])=[O:18])=[CH:15][CH:14]=1
Reactant: COc1ccc(N(N)C(=O)c2ccc(Cl)cc2)cc1
Reactant: CCC(=O)CC(C)C(=O)O
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc2c(c1)c(C)c(CC(C)C(=O)O)n2C(=O)c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
2-methyl-4-oxohexanoic acid (27.6 mg, 0.19 mmol) was added to a stirred solution of 4-chloro-N-(4-methoxyphenyl)benzohydrazide hydrochloride (50 mg, 0.16 mmol) in acetic acid (0.5 mL), the mixture was heated at 80° C. under nitrogen for 3 h, then it was allowed to cool to ambient temperature and stirred overnight. Ice-water (2 mL) was poured into the cold reaction mixture and the formed precipitate was collected by filtration, carefully washed with water and dried in vacuo to yield the title compound (27 mg, 44%) as an off-white solid. C21H20ClNO4, Mr=385.84; 1H NMR (400 MHz, DMSO-d6) d: 1.01 (d, J=6.8 Hz, 3H), 2.19 (s, 3H), 2.54 (sex, J=7.2 Hz, 1H), 2.91-3.19 (m, 2H), 3.76 (s, 3H), 6.46 (d, J=9.2 Hz, 1H), 6.64 (dd, J=2.4/9.0 Hz, 1H), 7.02 (d, J=2.4 Hz, 1H); LCMS (ESI) tR: 2.78 min (>99%, ELSD), m/z: 386.1 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1.[NH2:15][C:16]([CH3:30])([CH2:19][N:20]1[N:24]=[C:23]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:22]2=[N:21]1)[C:17]#[N:18]>C(Cl)Cl>[Cl:29][C:27]1[CH:26]=[CH:25][C:23]2=[N:24][N:20]([CH2:19][C:16]([NH:15][C:8](=[O:9])[C:7]3[CH:11]=[CH:12][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=3)([C:17]#[N:18])[CH3:30])[N:21]=[C:22]2[CH:28]=1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: CC(N)(C#N)Cn1nc2ccc(Cl)cc2n1
Solvent: ClCCl
Product: CC(C#N)(Cn1nc2ccc(Cl)cc2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 55.6 %

Procedure:
4-trifluoromethoxybenzoyl chloride (0.34 g) was added to a solution of 2-amino-3-(5-chloro-2H-benzotriazol-2-yl)-2-methylpropionitrile (0.3 g) in dry DCM mixed with TEA (0.27 mL). The reaction mixture was stirred 48 hours at room temperature. Silica gel was added to the reaction mixture and solvent evaporated under reduced pressure. The resulting crude product loaded on silica gel was purified by chromatography (SiO2, heptane/EA) to afford the title compound as a white solid (0.3 g, 54%). Rf=0.7 (1:1 EA/heptane). MS (ES): M/Z [M+H]=424. 1H NMR: (400 MHz, DMSO-d6): 1.74 (s, 3H), 5.39-5.49 (m, 2H), 7.48 (dd, J=9.1, 1.9 Hz, 1H), 7.51 (br d, J=8.0 Hz, 2H), 7.93 (m, 2H), 8.01 (dd, J=9.1, 0.6 Hz, 1H), 8.13 (dd, J=1.9, 0.6 Hz, 1H) and 8.92 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −57.09 (s, 3F).
Reaction SMILES: CC1(C)CC2C(=CC=CC=2)C1.C[O:13][C:14](=[O:28])[C:15](=O)[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH2:21][C:20]([CH3:26])([CH3:25])[CH2:19]2>>[CH3:25][C:20]1([CH3:26])[CH2:19][C:18]2[C:22](=[CH:23][CH:24]=[C:16]([CH2:15][C:14]([OH:28])=[O:13])[CH:17]=2)[CH2:21]1
Reactant: COC(=O)C(=O)c1ccc2c(c1)CC(C)(C)C2
Agent: CC1(C)Cc2ccccc2C1
Product: CC1(C)Cc2ccc(CC(=O)O)cc2C1

Procedure:
2,2-dimethylindan is used for the next reaction in crude state. p0 (e) 2,2-dimethyl-α-oxo-5-indanacetic acid methyl ester is used for the next reaction in crude state.