Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=[CH:10]2)=[C:4]([Cl:20])[CH:3]=1.C(ON=O)(C)(C)C.[ClH:28]>C(#N)C.[Cu](Cl)Cl>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:28])[CH:3]=[C:4]([Cl:20])[C:5]=1[N:9]1[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=[CH:10]1
Reactant: Nc1cc(Cl)c(-n2cnc(C(F)(F)F)cc2=O)c(Cl)c1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: O=c1cc(C(F)(F)F)ncn1-c1c(Cl)cc(Cl)cc1Cl
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of 1-(4-amino-2,6-dichlorophenyl)-4-trifluoromethylpyrimidin-6-one (as prepared in Preparation 1) (0.9 g) in acetonitrile (10 ml) was added dropwise to a stirred suspension of copper (II) chloride (0.37 g) and t-butylnitrite (1.46 g) in dry acetonitrile (8 ml) while the temperature was maintained between 0° and 5° C. After the addition was complete, the reaction mixture was stirred for a further 1 hour at 5° C., and then allowed to warm slowly to ambient temperature. The reaction mixture was then poured into 20% aqueous hydrochloric acid and extracted into diethyl ether. The combined organic extracts were washed with 20% aqueous hydrochloric acid, dried over anhydrous magnesium sulphate, filtered, and the solvent evaporated under reduced pressure. The residual oil was flushed through a plug of silica gel using petroleum ether (boiling range 60°-80° C.) containing diethyl ether (25% by volume) as eluent. Recrystallisation of the so generated white solid from petroleum ether (boiling range 60°-80° C.) gave 1-(2,4,6-trichlorophenyl)-4-trifluoromethylpyrimidin-6-one.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]=[C:13]([NH:15][O:16][C:17](=[O:25])[NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]([O:26][C:27](OC3C=CC=CC=3)=[O:28])[N:11]=[C:10]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:9]=2[CH:42]=1.O>CO>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]=[C:13]([NH:15][O:16][C:17](=[O:25])[NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]([O:26][C:27](=[O:28])[N:2]([CH3:3])[CH3:1])[N:11]=[C:10]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:9]=2[CH:42]=1
Reactant: O=C(Nc1ccccc1)ONC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1OC(=O)Oc1ccccc1
Reactant: CNC
Solvent: O
Solvent: CO
Product: CN(C)C(=O)OC1N=C(c2ccccc2)c2cc(Cl)ccc2N=C1NOC(=O)Nc1ccccc1

Procedure:
5 ml of a solution of dimethylamine in methanol (content 30 g of dimethylamine in 100 ml) are added to 0.5 g of 7-chloro-5-phenyl-2-phenylcarbamoyloxyamino-3-phenyloxycarbonyloxy-3H-1,4-benzodiazepine in 10 ml of methanol, whilst stirring. The mixture is stirred for 5 hours at room temperature and water is added to it; the residue is filtered off and dried.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=1.[Li]C(C)(C)C.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.Cl>C1COCC1.O>[CH2:11]([O:10][C:4]1[CH:3]=[C:2]([B:18]([OH:23])[OH:19])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])[CH3:12]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCOc1cc(Br)ccc1OC
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(B(O)O)ccc1OC
Temperature: -78 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
A mixture of 4-Bromo-2-ethoxy-1-methoxybenzene (4.00 g, 17.3 mmol) in THF (75 mL) was cooled to −78° C.; during cooling, a precicipitate formed. t-BuLi (22.4 mL, 1.7 M in pentane, 38.1 mmol) was added dropwise, while maintaining the temperature at −78° C. The mixture was stirred at −78° C. for 1 hour following completion of the addition. B(Oi-Pr)3 (9.76 g, 51.9 mmol) was added. The mixture was allowed to gradually warm to room temperature, and then stirred under nitrogen for 16 hours. 3N HCl (20 mL) was added, and the mixture stirred for 10 minutes. The mixture was poured into water (100 mL) and extracted with diethyl ether (3×75 mL), and the combined ethereal layers were washed with water (3×75 mL), dried (MgSO4) and evaporated, providing 3.15 g of the product in 93% yield: 1H NMR (DMSO-d6) δ 1.32 (t, J=7.0 Hz, 3H), 3.75 (s, 3H), 3.99 (q, J=7.0 Hz, 2H), 6.90 (d, J=8.3 Hz, 1H), 7.35-7.37 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1.[CH3:15][C:16]1[C:17]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:18][CH:19]=[C:20]([CH3:22])[CH:21]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:26]2[CH2:27][CH2:28][N:23]([C:17]3[C:16]([CH3:15])=[CH:21][C:20]([CH3:22])=[CH:19][N:18]=3)[CH2:24][CH2:25]2)=[O:8])=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 68.4 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 60 and using 4-bromo-2-methanesulfonylbenzoic acid (2.79 g) and 1-(3,5-dimethylpyridin-2-yl)piperazine (1.91 g) described in Preparation Example 47, the title compound (3.09 g) was obtained. MS (ESI) m/z:452(M+H)+.
Reaction SMILES: O([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]=[CH:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH:16]=2)[N:11]=[CH:10][N:9]=1)C1C=CC=CC=1.[NH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:37])=[O:36])[CH:30]=[CH:29]2>C1(O)C=CC=CC=1>[C:38]1([S:35]([N:31]2[C:32]3[C:28](=[CH:27][C:26]([NH:25][C:8]4[C:17]5[C:12](=[CH:13][CH:14]=[C:15]([CH:18]=[CH:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH:16]=5)[N:11]=[CH:10][N:9]=4)=[CH:34][CH:33]=3)[CH:29]=[CH:30]2)(=[O:36])=[O:37])[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: Nc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Reactant: CC(=O)OCC=Cc1ccc2ncnc(Oc3ccccc3)c2c1
Solvent: Oc1ccccc1
Product: CC(=O)OCC=Cc1ccc2ncnc(Nc3ccc4c(ccn4S(=O)(=O)c4ccccc4)c3)c2c1
Temperature: 100 °C
Yield: 43 %

Procedure:
A mixture of ester 26 (630 mg, 1.97 mmol) and 5-amino-1-phenylsulfonylindole in phenol (3.0 g) was heated at 100° C. for 20 hours. Excess phenol was removed by distillation and the resulting brown oil was purified by silica gel chromatography eluting with 1:1 ethyl acetate:hexanes then ethyl acetate. Quinazoline 27 (430 mg, 43%) was obtained as an off-white waxy solid. 1H NMR (CDCl3; 400 MHz): δ: 8.61 (s, 1H), 7.92 (m, 3H), 7.82 (m, 4H), 7.51 (m, 2H), 7.43 (m, 3H), 6.74 (d, 1H), 6.62 (d, 1H), 6.45 (dt, 1H), 4.74 (dd, 2H), 2.09 (s, 3H).
Reaction SMILES: C([O:4][C@@H:5]([C:7]1[N:8]=[N:9][N:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:11]=1)[CH3:6])(=O)C.O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:18][C:14]1[CH:13]=[C:12]([N:10]2[N:9]=[N:8][C:7]([C@H:5]([OH:4])[CH3:6])=[N:11]2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)O[C@H](C)c1nnn(-c2cccc(Cl)c2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)c1nnn(-c2cccc(Cl)c2)n1
Reaction time: 20 h
Yield: 551.7 %

Procedure:
1.25 g (4.68 mmol) (1R)-1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethyl acetate and 0.48 g (11.4 mmol) lithium hydroxide monohydrate were mixed with 3:1 THF/Water (28 mL) and stirred for 20 h. After acidification with aq. HCl, followed by reducing the volume of the mixture in vacuo, followed by dilution with brine and extraction with DCM. 5.8 g (97%) of the title compound was obtained after evaporation & coevaporation with toluene, followed by drying. 1H NMR: 8.15 (m, 1H), 8.03 (m, 1H), 7.48 (m, 2H), 6.27 (q, 1H), 2.14 (s, 3H), 1.77 (d, 3H).
Reaction SMILES: O[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:13].P(Cl)(Cl)(Cl)=O>>[Cl:13][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1ccnc(O)c1[N+](=O)[O-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccnc(Cl)c1[N+](=O)[O-]

Procedure:
A mixture of 25 g of 2-hydroxy-4-methyl-3-nitropyridine, 12.5 g of phosphorous pentachloride, and 62 ml of phosphorous oxychloride was refluxed for 2 hrs. After cooling, the mixture was poured onto crushed ice and stirred until a precipitate formed. The product was extracted with methylene chloride, dried (sodium sulfate) and concentrated to a brown oil, which was washed with hot hexane. Concentration in vacuo provided 16.2 g of the the title compound, m.p. 45°-47° C.
Reaction SMILES: [CH2:1]=O.[CH:3]1([NH:6][C@H:7]2[CH2:12][CH2:11][C@H:10]3[C@H:13]4[C@H:23]([CH2:24][CH2:25][C@:8]23[CH3:9])[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([OH:26])[CH2:19][CH2:20]2)=[CH:15][CH2:14]4)[CH2:5][CH2:4]1.[OH-].[Na+]>C(O)=O>[CH3:1][N:6]([CH:3]1[CH2:4][CH2:5]1)[C@H:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:9])[C@:21]1([CH3:22])[C:16]([CH2:17][C@@H:18]([OH:26])[CH2:19][CH2:20]1)=[CH:15][CH2:14]3
Reactant: C=O
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2NC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CN(C1CC1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
To a mixture of 10 ml of formic acid and 5 ml of formaldehyde was added 1.4 g of 17β-(cyclopropylamino)androst-5-en-3β-ol. The mixture was heated at reflux for 5 hours, the volume was then reduced to 7.5 ml in vacuo, and 10 ml of 50% (w/w) aqueous sodium hydroxide was added. The aqueous layer was separated and extracted with ethyl acetate and the combined organic extracts were dried over magnesium sulfate The solvent was then removed in vacuo and the product was purified by flash chromatography to give 17β-[N-methyl(cyclopropylamino)]androst-5-en-3β-ol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:31])[CH2:25][C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH3:32][N:33]([CH3:46])[CH2:34][CH2:35][CH2:36][NH:37][C:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][C:39]=1[F:45]>CC(O)C.Cl>[CH3:46][N:33]([CH3:32])[CH2:34][CH2:35][CH2:36][NH:37][C:38]1[CH:43]=[CH:42][C:41]([NH:44][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:17]4[CH:18]=[C:19]([NH:23][C:24](=[O:31])[CH2:25][C:26]5[S:27][CH:28]=[CH:29][CH:30]=5)[CH:20]=[CH:21][CH:22]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)=[CH:40][C:39]=1[F:45]
Reactant: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1
Reactant: CN(C)CCCNc1ccc(N)cc1F
Agent: Cl
Solvent: CC(C)O
Product: CN(C)CCCNc1ccc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5cccs5)c4)nn4ccccc34)n2)cc1F
Temperature: 120 °C
Yield: 36.6 %

Procedure:
To a slurry of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(2-thienyl)acetamide (100 mg, 0.22 mmol.) in i-PrOH (4 mL) was added N1-[3-(dimethylamino)propyl]-2-fluoro-1,4-benzenediamine (75 mg, 0.30 mmol) and 2 drops of conc. HCl. The reaction was heated in a microwave to 120° C. for 20 min. and allowed to cool to rt. A second batch of N1-[3-(dimethylamino)propyl]-2-fluoro-1,4-benzenediamine (75 mg, 0.30 mmol) was added and the reaction microwaved to 120° C. for 1 h further. The reaction was concentrated and the crude purified by HPLC (Agilent, 50-90% gradient over 15 min.) to give the title compound (50 mg, 36% yield) as an oil which solidified to a dark green solid. 1H NMR (400 MHz, d6-DMSO) δ 10.33 (s, 1H), 9.27 (s, 1H), 8.79 (d, J=7.0 Hz, 1H), 8.42 (bd, J=6.8 Hz, 1H), 8.15-8.17 (m, 2H), 7.85 (s, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.51 (d, J=14.3 Hz, 1H), 7.35-7.43 (m, 3H), 7.23 (d, J=7.5 Hz, 1H), 7.18 (d, J=8.6 Hz, 1H), 7.08 (t, J=7.8 Hz, 1H), 6.93-6.95 (m, 2H), 6.60 (t, J=9.4 Hz, 1H), 6.38 (d, J=5.3 Hz, 1H), 3.84 (s, 2H), 3.05 (t, J=7.0 Hz, 2H), 2.37 (t, J=7.0 Hz, 2H), 2.18 (s, 6H), 1.69 (quintet, J=7.0 Hz, 2H) ppm. ES-LC/MS m/z=621 [M+H]+.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21](=[N:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=1)[C:22]1[CH:23]=[C:24]([O:32][CH3:33])[C:25]2[O:29][CH2:28][CH2:27][C:26]=2[C:30]=1[F:31]>CN(C=O)C>[F:31][C:30]1[C:26]2[CH2:27][CH2:28][O:29][C:25]=2[C:24]([O:32][CH3:33])=[CH:23][C:22]=1[CH:21]([NH:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]#[N:42])=[CH:39][CH:40]=1)[C:20]1[NH:19][C:18](=[O:17])[N:1]([C:3]2[N:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)c2c(c1F)CCO2
Reactant: NNc1ncccn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(Nc2ccc(C#N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c(F)c2c1OCC2
Temperature: 85 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
After adding 144 mg of 2-hydrazinopyrimidine and 900 μl of triethylamine to a solution of 624 mg of [2-(4-cyanophenylimino)-2-(4-fluoro-7-methoxy-2,3-dihydrobenzofuran-5-yl)-1-methylsulfanylethylidene]carbamic acid methyl ester in 12 ml of DMF, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 6.6 ml of a methanol:acetic acid=10:1 mixed solvent. After adding 1 g of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture. The organic layer was washed with dilute hydrochloric acid and saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 4-{[(4-fluoro-7-methoxy-2,3-dihydrobenzofuran-5-yl)-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]amino}benzonitrile (414 mg) as a light yellow solid.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([OH:8])[CH2:6][CH2:5][CH2:4][CH:3]1[OH:9].C(N(C(C)C)CC)(C)C.[N:19]1([C:25]([NH:27][C@@H:28]([CH2:32][S:33]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:35])=[O:34])[C:29](O)=[O:30])=[O:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[OH:9][CH:3]1[CH2:4][CH2:5][CH2:6][CH:7]([OH:8])[CH:2]1[NH:1][C:29]([C@@H:28]([NH:27][C:25]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:26])[CH2:32][S:33]([CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)(=[O:35])=[O:34])=[O:30]
Reactant: O=C(O)[C@H](CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Reactant: NC1C(O)CCCC1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1C(O)CCCC1O)[C@H](CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 10.7 %

Procedure:
A solution of 2-amino-cyclohexane-1,3-diol (0.55 g) in dimethylformamide (30 ml) was treated with diisopropylethylamine (1.6 ml, 9.2 mmol). After stirring at room temperature for 5 minutes the mixture was treated with (R)-2-[(morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionic acid (1.73 g, 4.86 mmol) followed by HATU (1.68 g, 4.42 mmol). This mixture was stirred at room temperature overnight and then evaporated. The residue was subjected to flash chromatography on silica eluting with ethyl acetate and then a mixture of ethyl acetate and methanol to give morpholine-4-carboxylic acid [(R)-1-(2,6-dihydroxy-cyclohexylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-amide as a white solid (210 mg). MS: 470 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](Cl)(=[O:18])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:18])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C=Cc1ccccc1)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
An ice-cooled solution of 4-bromophenol (69.2 g) and cinnamoyl chloride (66.8 g) in dichloromethane (150 ml) was treated with triethylamine (40.6 g). After stirring for 18 hrs at room temperature the mixture was washed with water (250 ml), 1 M aqueous HCl, and dried over anhydrous sodium sulphate. Evaporation in vacuum left solid 3-phenylacrylic acid 4-bromophenyl ester (121.0 g, 99.8% yield), m.p. 113.3° C., tlc: (1) 0.83. NMR (CDCl3) 116.85, 118.87, 123.49, 128.38, 129.06, 130.90, 132.49, 134.02, 147.07, 149.84, 165.06.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Fc1ccc(CBr)cc1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2ccc(F)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 1-(bromomethyl)-4-fluorobenzene (0.52 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.76 g, 58%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:39]=[CH:40][CH:41]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([N+:36]([O-])=O)[CH:31]=3)=[CH:25][CH:24]=2)([C:19]([F:22])([F:21])[F:20])[C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)([O-])=O.O.NN>CC(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:39]=[CH:40][CH:41]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([NH2:36])[CH:31]=3)=[CH:25][CH:24]=2)([C:19]([F:20])([F:21])[F:22])[C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(Oc2ccc(C(c3ccc(Oc4cccc([N+](=O)[O-])c4)cc3)(C(F)(F)F)C(F)(F)F)cc2)c1
Agent: NN
Solvent: O
Solvent: CC(C)O
Product: Nc1cccc(Oc2ccc(C(c3ccc(Oc4cccc(N)c4)cc3)(C(F)(F)F)C(F)(F)F)cc2)c1
Temperature: 22.5 °C
Yield: 75 %

Procedure:
In the next step, a 300 ml glass reaction vessel was charged with 20 grams (0.035 mol) of crude 2,2-bis[4-(3-nitrophenoxy)phenyl]-1,1,1,3,3,3-hexafluoropropane, 2 grams of active carbon, 0.2 gram of ferric chloride hexahydrate and 100 ml of IPA. The mixture was refluxed for 30 minutes with stirring and 7 grams (0.14 mol) of hydrazine hydrate was dropwise added at 60-70° C. during 2 hours, and refluxed for further 5 hours with stirring. The resultant reaction mixture was cooled, filtered to remove the catalyst and heated to distill off 60 ml of IPA. To the residue, 80 grams of 17.5% aqueous hydrochloric acid and 10 grams of sodium chloride were added and cooled to 20-25° C. with stirring. The separated crystals were filtered and recrystallized again from 40 ml of IPA and 80 grams of 17.5% aqueous hydrochloric acid. The resulting crystals were dissolved into 50% aqueous IPA solution and neutralized with aqueous ammonia to separate crystals. The crystals were filtered, washed with water, dried and recrystallized from the solvent mixture of benzene and n-hexane. Colorless crystals of 2,2-bis[4-(3-aminophenoxy)phenyl]-1,1,1,3,3,3-hexafluoropropane thus obtained were 13.6 grams (75% yield) and had a melting point of 137-139° C. The analytical results were as follows.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34]1([C:40]2[C:41]3[CH:51]=[CH:50][CH:49]=[CH:48][C:42]=3[S:43][C:44]=2[CH:45](O)[CH3:46])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C1(P([N:66]=[N+:67]=[N-:68])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCOCC1>[N:66]([CH:45]([C:44]1[S:43][C:42]2[CH:48]=[CH:49][CH:50]=[CH:51][C:41]=2[C:40]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:46])=[N+:67]=[N-:68]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(O)c1sc2ccccc2c1-c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(N=[N+]=[N-])c1sc2ccccc2c1-c1ccccc1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 55.1 %

Procedure:
DIAD (556 mg, 2.75 mmol) was added to a solution of triphenylphosphine (722 mg, 2.75 mmol) in dioxane (5 mL) at 0° C. under a nitrogen atmosphere. After 10 min, 1-(3-phenylbenzo[b]thiophen-2-yl)ethanol (350 mg, 1.37 mmol) was added followed by diphenylphosphoryl azide (454 mg, 1.65 mmol). The reaction mixture was stirred 20° C. for 16 h then concentrated in vacuo. The crude reaction mixture was purified by column chromatography (Si—PCC, gradient 0-20% DCM in cyclohexane) affording the title compound as a colourless oil (211 mg, 55%). 1H NMR (CDCl3, 400 MHz): δ 7.88 (1H, d, J=7.87 Hz), 7.54-7.42 (4H, m), 7.41-7.29 (4H, m), 4.97 (1H, q, J=6.80 Hz), 1.58 (3H, d, J=6.80 Hz).
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.Br[C:20]1[CH:31]=[CH:30][C:23]([CH2:24][C:25]2[NH:29][N:28]=[N:27][N:26]=2)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:20]2[CH:21]=[CH:22][C:23]([CH2:24][C:25]3[NH:29][N:28]=[N:27][N:26]=3)=[CH:30][CH:31]=2)=[CH:12][CH:11]=1
Reactant: Brc1ccc(Cc2nnn[nH]2)cc1
Reactant: C[C@@H]1CCCN1CCc1ccc(B(O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(Cc3nnn[nH]3)cc2)cc1
Temperature: 130 °C

Procedure:
A mixture of (R)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid hydrochloride (50 mg, 0.185 mmol), 5-(4-bromobenzyl)-1H-tetrazole (53.2 mg, 0.223 mmol), Na2CO3 (79 mg, 0.742 mmol), and dichlorobis(p-dimethylaminophenyldi-tert-butylphosphine)palladium (1.313 mg, 1.855 μmol) in 1,4-dioxane (1 mL) and H2O (0.2 mL) was heated under microwave irradiation at 130° C. for 120 min. The mixture was concentrated. The residue was purified by HPLC to give the title compound. LCMS m/z=348.1 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.27 (d, J=6.5 Hz, 0.4H), 1.46 (d, J=6.6 Hz, 2.6H), 1.70-1.82 (m, 1H), 2.02-2.11 (m, 2H), 2.22-2.33 (m, 1H), 3.05-3.21 (m, 4H), 3.36-3.48 (m, 1H), 3.52-3.62 (m, 1H), 3.72-3.83 (m, 1H), 4.36 (s, 2H), 7.36-7.44 (m, 4H), 7.61-7.67 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][CH:7]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11]>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:14]#[C:13][Si:10]([CH3:12])([CH3:11])[CH3:9])[CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)C#Cc1cccc(Br)c1
Temperature: 25 °C
Yield: 83.8 %

Procedure:
To a solution of m-bromoiodobenzene (25.0 g. 881.1 mmol) in diisopropylamine (500 ml), there were added bis(triphenylphosphine)palladium dichloride (1.24 g. 1.80 mmol) and copper (I) iodide (1.24 g, 2.03 mmol). The solution was degassed via a rapid stream of argon, and trimethylsilylacetylene (9.51 g, 97.0 mmol) was added over a period of 15 min. The reaction mixture was stirred at room temperature until G.C. analysis indicated the disappearance of starting material (2 h). The reaction mixture was cooled to room temperature and filtered to remove salts. The filtrate was concentrated in vacuo, and the oily residue was taken up in dichloromethane. The solution was washed with an aqueous 5% HCl solution (2×200 ml), water (2×200 ml) and brine (1×200 ml). The combined organic layers were dried (MgSO4) and the solvent removed in vacuo yielding the crude product as a yellow oil. The liquid chromatographed from silica gel in pentane. Elution with pentane gave the product (1b) (20.59 g, 91%) as a clear liquid: bp 81°-82° C., 1H NMR (200 MHz, CDCl3) c 0.30 (s), 7.23(m).