Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][C@H:26]([CH2:31][CH3:32])[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].CO.Cl>O>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][C@H:26]([CH2:31][CH3:32])[CH2:27][C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CC[C@@H](N)CC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC[C@H](CC(=O)O)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 130 °C
Yield: 73 %

Procedure:
1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (75 mg, 0.234 mmol) and 3-(R)-amino-pentanoic acid (82 mg, 0.7 mmol) were placed in a CEM 10 mL Microwave vessel and sodium methoxide-methanol solution (0.5M; 1.4 mL, 0.7 mmol) was added via syringe. The vessel was sealed and heated to 130° C. in a CEM microwave apparatus for 150 minutes. The reaction mixture was diluted with water and treated with 1N hydrochloric acid. The crude precipitate was purified by MPLC (methylene chloride-ethyl acetate) to provide the title compound as an off-white solid in 73% yield. MS ESI(−) m/e: 403.9928 (M−1).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=O)=[CH:12][CH:11]=2)[CH:2]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[C:24]([O:34][CH3:35])[CH:23]=1>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:29][CH2:30][N:31]([C:14]([C:13]3[CH:12]=[CH:11][C:10]([N:3]4[C:4]5=[N:5][CH:6]=[CH:7][CH:8]=[C:9]5[N:1]=[CH:2]4)=[CH:20][CH:19]=3)=[O:16])[CH2:32][CH2:33]2)=[C:24]([O:34][CH3:35])[CH:23]=1
Reactant: COc1cc(F)ccc1N1CCNCC1
Reactant: CCOC(=O)c1ccc(-n2cnc3cccnc32)cc1
Product: COc1cc(F)ccc1N1CCN(C(=O)c2ccc(-n3cnc4cccnc43)cc2)CC1
Yield: 16.1 %

Procedure:
Using ethyl 4-(imidazo[4,5-b]pyridin-3-yl)benzoate (300 mg) described in Preparation Example 77 and 1-(4-fluoro-2-methoxyphenyl)piperazine (236 mg) and by the reaction and treatment in the same manner as in Example 170, the title compound (78 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[N:12]([O-])=[O:13].[Na+]>O.Cl>[N:12]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)=[O:13]
Reactant: Oc1cccc2cccnc12
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=Nc1ccc(O)c2ncccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a mixture of 8-hydroxyquinoline (58 g, 0.4 mol) in distilled water, concentrated hydrochloric acid (75 ml) and ice (200 g) was added NaNO2 (30 g) in water (100 ml) at 0-4° C. during 1 hr. The reaction mixture was kept at 0° C. overnight and then filtered by washing with cold water to give 5-nitroso-8-hydroxyquinoline hydrochloide (95%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10]C)[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(F)cc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1cc(O)cc(F)c1
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
Under nitrogen atmosphere, 1-fluoro-3,5-dimethoxybenzene (25 g, 160 mmol) was diluted in CH2Cl2 (200 mL, 0.8M) and then cooled to −15° C. Next, BBr3 (176 mL, 176 mmol, 1M in CH2Cl2) was slowly added to the reaction mixture. The reaction mixture was stirred at −15° C. for one and a half hours and at room temperature for 10 minutes. The reaction mixture was then cooled to 0° C. and slowly quenched with water (150 mL). The aqueous layer was then extracted with methylene chloride (3×100 mL). The organic extracts were dried over sodium sulfate and concentrated. Silica gel chromatography (1%-30% EtOAc/Hexanes) gave the mono demethylated product (50-1) (15 g, 67%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18]Cl)=[CH:10][CH:9]=1.[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24]>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][N:35]2[CH2:36][CH2:37][CH:32]([C:28]3[CH:27]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])[CH:31]=[CH:30][CH:29]=3)[CH2:33][CH2:34]2)=[CH:10][CH:9]=1
Reactant: O=C(CCCCCl)c1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 (K2CO3) using 1-(4-chlorophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 441.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.[F:19][C:20]([F:34])([F:33])[CH2:21][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:23][OH:24]>CCOCC>[CH3:15][C:10]1[N:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[C:8](=[O:16])[N:7]([CH3:17])[C:6]1[CH:18]=[C:2]([O:24][CH2:23][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:21][C:20]([F:34])([F:33])[F:19])[CH:3]=[CH:4][C:5]2=1
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(Cl)ccc21
Reactant: CC(C)(C)OC(=O)NC(CO)CC(F)(F)F
Solvent: CCOCC
Product: Cc1nccc2c1c(=O)n(C)c1cc(OCC(CC(F)(F)F)NC(=O)OC(C)(C)C)ccc21
Yield: 49 %

Procedure:
8-Chloro-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one and tert-butyl (4,4,4-trifluoro-1-hydroxybutan-2-yl)carbamate were used for ether synthesis as described in Example 16, Part H to afford tert-butyl (1-((4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4,4,4-trifluorobutan-2-yl)carbamate (0.22 g, 0.473 mmol, 49% yield) as a semi-solid. LC/MS (ESI) m/e 466.2 [(M+H)+, calcd for C23H27F3N3O4 466.2]; LC/MS retention time (method D): tR=0.82 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[CH:12]=[N:13][OH:14].C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[CH2:12][NH:13][OH:14]
Reactant: ON=Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: ONCc1ccccc1Nc1c(Cl)cccc1Cl
Yield: 90.9 %

Procedure:
To a solution of 2-[(2,6-dichlorophenyl)amino]benzaldehyde oxime (4.0 g, 13.6 mmol) in glacial acetic acid (20 ml) is added sodium cyanoborohydride (2.05 g,33 mmol) in small portions over a period of two hours. The reaction mixture is diluted with ethyl acetate (200 ml) and neutralized with lN NaOH. The organic layer is collected and the solvent is evaporated. 2-[(2,6-Dichlorophenyl)amino]-N-hydroxybenzenemethanamine (3.5 g, 91%) is isolated as an oil by flash chromatography (silica, 3:1 chloroformethyl acetate). The compound is not further purified, but used directly in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][C:3]=1[O:24][CH3:25].[CH2:26]([CH2:30][C:31](=O)[CH3:32])[C:27]([CH3:29])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.ClCCl>[CH3:32][C:31]1[N:1]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[CH2:14][N:13]4[CH:21]=[CH:22][CH:23]=[C:12]4[CH2:11]3)=[O:9])=[CH:4][C:3]=2[O:24][CH3:25])[C:27]([CH3:29])=[CH:26][CH:30]=1
Reactant: CC(=O)CCC(C)=O
Reactant: COc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: c1ccccc1
Product: COc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1-n1c(C)ccc1C
Temperature: 25 °C

Procedure:
A solution of (4-amino-3-methoxy-phenyl)[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone prepared in the manner of Albright et al., E.P.636625-A2 (0.675g, 2 mmol) and acetonyl acetone (0.3 mL, 2.5 mmol) in benzene (100 mL) was treated with a crystal of para-toluenesulfonic acid. The stirred solution was warmed to reflux for 46 hrs using a Dean Stark trap. The reaction was cooled to room temperature, diluted with dichloromethane (100 mL), washed with saturated aqueous sodium bicarbonate then water. The residue (oil, 0.900 g) was flash chromatography on silica gel eluting with 20% ethyl acetate in hexane to yield 0.610 g of the title compound as a white foam. Recrystallization of a sample of this material yielded yellow crystals, m.p. 141–144° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[O-2].[Mg+2].[Cl:9][C:10]1[S:14][C:13]([S:15](Cl)(=[O:17])=[O:16])=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20]>O.C1COCC1>[OH:4][CH2:3][CH:2]([NH:1][S:15]([C:13]1[S:14][C:10]([Cl:9])=[C:11]([N+:19]([O-:21])=[O:20])[CH:12]=1)(=[O:17])=[O:16])[CH2:5][OH:6]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)sc1Cl
Reactant: NC(CO)CO
Agent: [Mg+2]
Agent: [O-2]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(S(=O)(=O)NC(CO)CO)sc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
To a stirred solution of 2-amino-1,3-propanediol (0.5 g, 5.49 mmol) in water (2 ml) was added at room temperature magnesium oxide (1.11 g, 27.5 mmol) and THF (6 ml). The suspension was stirred at room temperature for 30 min and a solution of 5-chloro-4-nitrothiophene-2-sulfonyl chloride (2.88 g, 10.9 mmol) in THF (2 ml) was added. The light yellow suspension was stirred at room temperature for 1 h and, after filtration on Dicalit, evaporated. Water (60 ml) was added and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (70 ml), dried (MgSO4) and evaporated. The crude product was further purified by column chromatography on silica gel (heptane/ethyl acetate 1:1) and subsequent crystallization from ethyl acetate/hexane to yield 5-chloro-4-nitro-thiophene-2-sulfonic acid (2-hydroxy-1-hydroxymethyl-ethyl)-amide (0.76 g, 44%) as a light yellow solid. MS (ISP) 314.9 [(M−H)−], mp 142° C.
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[CH:17][C:16]([N:19]=[N:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Br:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]Br.[OH-].[K+]>C(O)C>[Br:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:27][C:24]1[CH:23]=[CH:22][C:21]([N:20]=[N:19][C:16]2[CH:15]=[CH:14][C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:18][CH:17]=2)=[CH:26][CH:25]=1
Reactant: CCCCCCCCCCCCc1ccc(N=Nc2ccc(O)cc2)cc1
Reactant: BrCCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCc1ccc(N=Nc2ccc(OCCCCCCCCCCBr)cc2)cc1
Temperature: 25 °C

Procedure:
A 3000 ml three-necked round bottom flask was equipped with magnetic stirring, a heating mantle, a reflux condenser, and a nitrogen atmosphere. The flask was charged with 4-dodecyl-4'-hydroxyazobenzene (60.0 g, 0.164 mol), 1,10-dibromodecane, (66.95 g, 0.223 mol), potassium hydroxide (9.75 g, 0.174 mol), and ethanol (1260 ml). The stirring mixture was refluxed for seven hours. During the course of the reaction, a yellow precipitate formed in the reaction mixture. The reaction mixture then was cooled to room temperature and chilled in an ice-water bath. A crude product was isolated by suction filtration, washed with water, then with hexane. The product was recrystallized from ethyl acetate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]2[O:15][CH2:14][CH2:13][CH2:12][O:11]2)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[F:16][C:17]([F:25])([F:24])[C:18]([F:23])([F:22])C([O-])=O.[Na+].CN(C=O)C>[Cu]I.C1(C)C=CC=CC=1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:18]([F:23])([F:22])[C:17]([F:25])([F:24])[F:16])=[CH:3][C:4]=1[CH:10]1[O:15][CH2:14][CH2:13][CH2:12][O:11]1
Reactant: COc1ccc(Br)cc1C1OCCCO1
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Agent: [Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(C(F)(F)C(F)(F)F)cc1C1OCCCO1
Temperature: 140 °C
Yield: 93.6 %

Procedure:
A 50 ml round bottom flask equipped with Dean-Stark trap and reflux condenser was charged with Compound 38 (1.0 g, 3.66 mmol), sodium pentafluoropropionate (1.29 g, 6.95 mmol) and copper(I) iodide (1.46 g, 7.69 mmol), DMF (15 ml) -toluene (6 ml). The slurry was heated to 120-140° C. (bath temperature) and toluene (6 ml) was removed by distillation. The reaction mixture was heated at 140° C. (inner temperature) for 15 h. The mixture was diluted with water (40 ml) —toluene (15 ml) —ethyl acetate (60 ml). The mixture was filtered through a pad of celite and the filter cake was washed with ethyl acetate. The filtrate was washed with water, and brine, dried(MgSO4) and concentrated in vacuo to give crude product. The crude product was purified by column chromatography on silica gel with hexane-ethyl acetate(10:1-5:1) to give Compound 39 (1.07 g) as a pale yellow oil
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][OH:14])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=[O:4].[C:15](Cl)(=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH3:1][N:2]([CH2:12][CH2:13][O:14][C:15](=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=[O:4]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: Cc1ccc(C(=O)N(C)CCO)cc1
Product: CCCCCCCCCCCC(=O)OCCN(C)C(=O)c1ccc(C)cc1

Procedure:
N-methyl-N-(2-lauroyloxyethyl)-p-toluamide was prepared by the procedure of example 1 from 19 gms. (0.1 mole) of N-methyl-N-(2-hydroxyethyl)-p-toluamide and 22 gms. (0.1 mole) of lauroyl chloride. The structure of the final product was characterized on the basis of IR and NMR spectral analyses as described in example 1.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([S:18]([NH:21][CH3:22])(=[O:20])=[O:19])[N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([OH:9])=O.[NH2:23][CH2:24][C:25]1[C:26]([F:42])=[C:27]([O:32][C:33]2[CH:34]=[C:35]([CH:38]=[C:39]([Cl:41])[CH:40]=2)[C:36]#[N:37])[C:28]([Cl:31])=[CH:29][CH:30]=1>>[Cl:1][C:2]1[N:3]=[C:4]([S:18]([NH:21][CH3:22])(=[O:19])=[O:20])[NH:5][C:6]=1[C:7]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([O:32][C:33]2[CH:34]=[C:35]([C:36]#[N:37])[CH:38]=[C:39]([Cl:41])[CH:40]=2)[C:26]=1[F:42])=[O:9]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: CNS(=O)(=O)c1nc(Cl)c(C(=O)O)n1COCC[Si](C)(C)C
Product: CNS(=O)(=O)c1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Yield: 53.2 %

Procedure:
4-chloro-2-[(methylamino)sulfonyl]-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.12 mmol) and 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.040 g, 0.13 mmol) were employed using a procedure similar to that described herein to provide the title compound (0.034 g, 54%) as a white solid after deprotection and purification by Reverse-Phase HPLC (water:acetonitrile with 0.1% formic acid). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.55 (s, 1H), 7.40 (s, 2H), 7.27 (s, 1H), 7.24 (s, 1H), 4.63 (s, 2H), 2.70 (s, 3 H). ES-LCMS: m/z 532.1, 534.1, 536.0 (M+1).
Reaction SMILES: BrCC(N1C[CH2:9][N:8]([C:11](=O)[C:12]2[CH:17]=[C:16](C)[CH:15]=[C:14](C)[CH:13]=2)[CH2:7][CH:6]1[C:21]1[CH:26]=[CH:25]C(Cl)=C(Cl)C=1)=O.Cl.[O:30]1CCOCC1.[OH-].[Na+]>C(Cl)Cl.O>[CH2:11]([N:8]1[CH2:7][CH2:6][C:21](=[O:30])[CH:26]([CH3:25])[CH2:9]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cc(C)cc(C(=O)N2CCN(C(=O)CBr)C(c3ccc(Cl)c(Cl)c3)C2)c1
Reactant: C1COCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC1CN(Cc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of compound 3 (Ar2 =3,4-dichlorophenyl) (16 g, 28.49 mmol) in CH2Cl2 (142.5 mL) at 0° C. was added 4N HCl-dioxane solution (71.24 mL, 284.9 mmol) through a dropping funnel. The reaction was gradually warmed up to RT and stirred for 4 h. After completion the solvents were evaporated to give a light yellow solid which was dissolved in H2O (400 mL) and brought to pH 10 with 1N NaOH. The product was extracted from basic aqueous solution with CH2Cl2 (200 mL, 4×), dried over MgSO4, filtered and concentrated to give compound 4 (Ar2 =3,4-dichlorophenyl) as a light yellow solid (12.5 g, 27.09 mmol, 95%). FAB MS [M+1]+ 35 Cl 461.1 Compound 4 was the key intermediate which was used to couple with various aromatic acid for the synthesis of many compounds.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][C@@H:3]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:2]1.CCN(CC)CC.Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>C(Cl)Cl>[CH2:1]1[C:5]2([CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]2)[CH2:4][C@@H:3]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:2]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]
Reactant: CCOC(=O)[C@@H]1CC2(CCN(C(=O)OC(C)(C)C)CC2)CN1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CC2(CCN(C(=O)OC(C)(C)C)CC2)CN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
(3S)-8-Tert-butyl 3-ethyl 2,8-diazaspiro[4.5]decane-3,8-dicarboxylate [Example 24 in US Pat. Pub. No. 2012/0101280](50 g, 160 mmol) in CH2Cl2 (500 mL), and Et3N (51.7 g, 512 mmol) was cooled to 0° C. Benzyl chloroformate (34.1 g, 205 mmol) was added dropwise and the mixture was stirred at 0° C. for 3 h. The reaction mixture was washed with water, extracted with CH2Cl2, dried over Na2SO4, and concentrated in vacuo to provide (S)-2-benzyl 8-tert-butyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3,8-tricarboxylate as a light yellow oil which was used directly without further purification.
Reaction SMILES: [F:1][C:2]([F:13])([C:9]([F:12])([F:11])[F:10])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].FC(F)(F)S(O[CH2:20][C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])(=O)=O.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[F:1][C:2]([F:13])([C:9]([F:10])([F:11])[F:12])[CH2:3][C:4]([CH2:20][C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])([C:7]#[N:8])[C:5]#[N:6]
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)F)C(F)(F)F
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CC(C#N)(CC(F)(F)C(F)(F)F)CC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 10 h
Yield: 1.4 %

Procedure:
In 20 ml of acetone, 2.1 g of 2-(2,2,3,3,3-pentafluoropropyl)malononitrile and 4.5 g of 2,2,3,3,3-pentafluoropropyl trifluoromethanesulfonate were dissolved, 2.2 g of potassium carbonate was added and the mixture was stirred at room temperature for 10 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture and the mixture was extracted with t-butyl methyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.05 g of 2,2-bis(2,2,3,3,3-pentafluoropropyl)malononitrile (hereinafter, referred to as the present compound (93)).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[CH:9][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[N:11][CH:12]=1)[CH3:2].[ClH:28]>CCO.O1CCOCC1>[ClH:28].[ClH:28].[NH:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:10]2[N:11]=[CH:12][C:7](/[CH:6]=[CH:5]/[C:4]([O:3][CH2:1][CH3:2])=[O:27])=[CH:8][CH:9]=2)[CH2:15][CH2:16]1
Reactant: CCOC(=O)/C=C/c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1ccc(NC2CCNCC2)nc1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-({5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-2-pyridyl}amino)-1-piperidinecarboxylate (2.8 g) in EtOH (20 ml) was added 4N HCl in dioxane (18.6 ml), the mixture was stirred at 23° C. for 30 minutes. The precipitate was collected, washed with IPE, dried under reduced pressure to give ethyl (2E)-3-[6-(4-piperidylamino)-3-pyridyl]acrylate dihydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:19][C:20]1([CH3:36])[C:24]([CH3:26])([CH3:25])[O:23][B:22]([C:27]2[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=2)[O:21]1>C1COCC1.ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:31](=[O:32])[C:30]2[CH:29]=[CH:28][C:27]([B:22]3[O:23][C:24]([CH3:25])([CH3:26])[C:20]([CH3:36])([CH3:19])[O:21]3)=[CH:35][CH:34]=2)[CH:3]=1
Reactant: Cc1ccnc(N)c1
Reactant: CC1(C)OB(c2ccc(C(=O)Cl)cc2)OC1(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccnc(NC(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 41.4 %

Procedure:
To a stirred solution of 4-methylpyridin-2-amine (7.86 mmol, 850 mg) in THF (50 mL) was added dropwise a solution of 1M LiHMDS in THF (8.0 mmol, 8 mL) at room temperature. After the reaction mixture turned dark green, a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl chloride (9.6 mmol, 2.56 g) in dichloromethane (55 mL) was added dropwise. The mixture was stirred at room temperature for 2.5 h and was then concentrated. 3% aq. Citric acid solution (18 mL) was added and the mixture was extracted with dichloromethane (2×15 mL). The combined organic layer was washed with 3% aq. citric acid solution, dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in THF (15 mL) and 6M NaOH solution (15 mL) was added. The mixture was stirred for 4 h. at room temperature. Ethyl acetate was added and the layers were separated. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica (eluent: DCM/MeOH=98/2 to DCM/MeOH=95/5) to yield 1.1 g of N-(4-methylpyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (40.7%).
Reaction SMILES: [Cl:1][CH:2]([O:4][C:5](Cl)=[O:6])[CH3:3].[CH3:8][C:9]1([CH3:19])[CH2:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([OH:18])[C:11]=2[O:10]1.N1C=CC=CC=1>ClCCl>[C:5](=[O:6])([O:18][C:17]1[C:11]2[O:10][C:9]([CH3:19])([CH3:8])[CH2:13][C:12]=2[CH:14]=[CH:15][CH:16]=1)[O:4][CH:2]([Cl:1])[CH3:3]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CC1(C)Cc2cccc(O)c2O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Cl)OC(=O)Oc1cccc2c1OC(C)(C)C2
Temperature: 20 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
21.5 g (0.15 mole) of 1-chloroethylchloroformate are added in a single portion to a solution of 2,3-dihydro-2,2-dimethyl-7-benzofuranol (24.6 g; 0.15 mole) in dichloromethane (150 ml). The mixture is cooled to between 0° and 5° C., and 12 g (0.15 mole) of pyridine are added dropwise. The mixture is stirred for 3 hours at 20° C. The organic phase is then washed with 2×50 ml of iced water. It is dried over magnesium sulphate and the solvent is evaporated. A yellow oil is obtained which is distilled. 34.1 g of the expected carbonate is then recovered (84% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([F:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].[I:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([F:22])[CH:16]=1)[C:9]([C:28]1[CH:29]=[CH:30][C:25]([I:24])=[CH:26][CH:27]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: Ic1ccc(I)cc1
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(F)c1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(I)cc1)c1ccc(Cl)c(F)c1

Procedure:
The title compound was prepared from rac-[(4-chloro-3-fluoro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 1) and 1,4-di-iodobenzene in analogy to Example 1a): MS (ISN): 487.9 (M−H)− and 413.9 ((M-tBuOH)−H)−.