Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[C:19]([N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[N:18]2[N:38]=[CH:39][CH:40]=[C:17]2[N:16]=1.[NH4+].[Cl-]>CN(C=O)C>[CH3:35][Si:34]([CH3:37])([CH3:36])[CH2:33][CH2:32][O:31][CH2:30][N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:19]1[N:18]2[N:38]=[CH:39][CH:40]=[C:17]2[N:16]=[C:15]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH:20]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2ccnn12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 899.4 %

Procedure:
The methyl 4-hydroxybenzoate (330 mg, 0.2 mmol) was dissolved in dry DMF (3 mL) and NaH (8 mg, 60% in oil, 0.2 mmol) was added and the mixture was stirred at room temperature for 5 min. Then, 5-chloro-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (430 mg, 0.1 mmol) was added and the resulting mixture was heated up to 130° C. with Microwave and stirred for 30 min. After cooling to room temperature, NH4Cl (aq) was added to quench the reaction and extracted with EtOAc (50 mL×3). The combined organics were washed with water and brine and dried over Na2SO4. After concentration, the residue was purified with column (silica gel, 20% EtOAc/Hexane) gave the product, methyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yloxy)benzoate (490 mg) as clear oil. HPLC-MS tR=2.84 min (UV254 nm); mass calculated for formula C26H40N4O5Si2 544.3, observed LCMS m/z 545.3 (M+H).
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:6]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[F:19])=[C:10]([F:20])[C:9]([O:21][CH3:22])=[C:8]([CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([N:30]4[CH2:39][CH2:38][C:37]5[N:36]=[C:35]([CH2:40][CH2:41][CH3:42])[C:34]([C:43]([O:45]C)=[O:44])=[CH:33][C:32]=5[C:31]4=[O:47])[CH2:26][CH2:25]3)[CH:7]=2)[CH2:5][CH2:4]1>C(O)C>[CH:3]1([C:6]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[F:19])=[C:10]([F:20])[C:9]([O:21][CH3:22])=[C:8]([CH2:23][N:24]3[CH2:25][CH2:26][CH:27]([N:30]4[CH2:39][CH2:38][C:37]5[N:36]=[C:35]([CH2:40][CH2:41][CH3:42])[C:34]([C:43]([OH:45])=[O:44])=[CH:33][C:32]=5[C:31]4=[O:47])[CH2:28][CH2:29]3)[CH:7]=2)[CH2:5][CH2:4]1
Reactant: CCCc1nc2c(cc1C(=O)OC)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4F)c(F)c3OC)CC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1nc2c(cc1C(=O)O)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4F)c(F)c3OC)CC1)CC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
A 2 M aqueous sodium hydroxide solution (1.5 mL) was added at room temperature to an ethanol (8 mL) solution of methyl 6-(1-((6-cyclopropyl-2,2′,4′-trifluoro-3-methoxybiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (244 mg), and the mixture was stirred at 80° C. for 2 hours in a nitrogen atmosphere. Then, the solvent was distilled off under reduced pressure. Water was added to the obtained residue, and the mixture was neutralized with 2 M hydrochloric acid, followed by extraction with a mixed solution of ethyl acetate and THF. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was crystallized (hexane/ethyl acetate) and further recrystallized (hexane/ethanol) to obtain the title compound (160 mg).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.Cl[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:20][N:19]=1>>[C:23]1([C:21]2[O:20][N:19]=[C:18]([CH2:17][N:7]3[C:8]4[C:4](=[C:3]([C:2]([F:14])([F:1])[F:15])[C:11]([C:12]#[N:13])=[CH:10][CH:9]=4)[CH:5]=[CH:6]3)[N:22]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Reactant: ClCc1noc(-c2ccccc2)n1
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3ccccc3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 23 using 4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-phenyl-1,2,4-oxadiazole: MS (ES) m/z 369 (M+1).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][C:20]1[CH:24]=[CH:23][O:22][N:21]=1>>[O:22]1[CH:23]=[CH:24][C:20]([NH:19][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)=[N:21]1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: Nc1ccon1
Product: O=C(Nc1ccon1)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 73 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 3-aminoisoxazole as the starting materials.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:7]([CH2:18]O)=[N:8][CH:9]=[CH:10][C:11]=1[N:12]([CH3:17])[CH2:13][CH2:14][CH2:15][OH:16]>ClCCl>[Cl:5][C:6]1[C:7]([CH2:18][Cl:3])=[N:8][CH:9]=[CH:10][C:11]=1[N:12]([CH3:17])[CH2:13][CH2:14][CH2:15][OH:16]
Reactant: O=S(Cl)Cl
Reactant: CN(CCCO)c1ccnc(CO)c1Cl
Solvent: ClCCl
Product: CN(CCCO)c1ccnc(CCl)c1Cl
Reaction time: 1 h

Procedure:
Thionyl chloride (3.5 ml, 47.6 mmol), dissolved in dichloromethane (25 ml), is added dropwise at 4° C. to a solution of 3-[(3-chloro-2-hydroxymethyl-pyridin-4-yl)-methyl-amino]-propanol (5.0 g, 21.6 mmol) in dichloromethane (75 ml). The solution is stirred for 1 h at this temperature, triturated with ice water and neutralized with saturated sodium bicarbonate solution. After separation of the organic layer the aqueous phase is extracted with dichloromethane. The combined organic extracts are washed with water, dried over magnesium sulfate and evaporated in vacua. The residue is employed without additional purification for the synthesis described in step b).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:27])[C@H:9]([CH2:18][O:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:10][C:11]([F:17])([F:16])[C:12](OC)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+]>C1COCC1>[C:23]([O:22][C:20]([O:19][CH2:18][C@@H:9]([N:8]([CH3:27])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][C:11]([F:17])([F:16])[CH2:12][OH:13])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: COC(=O)C(F)(F)C[C@@H](COC(=O)OC(C)(C)C)N(C)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@H](COC(=O)OC(C)(C)C)CC(F)(F)CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a solution of (S)-methyl 4-(tert-butoxycarbonyl(methyl)amino)-5-(tert-butoxycarbonyloxy)-2,2-difluoropentanoate (42.0 g, 0.106 mol) in THF (300 mL) was added Lithium borohydride (79.3 mL, 2 M, 0.159 mol) in THF at 0° C. The reaction mixture was stirred at 0° C. for 1 h and at RT for 2 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated and partitioned between EtOAc and H2O. After separating layers, the aqueous layer was extracted further with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated, and the resulting residue was purified by silica gel column (hexanes/EtOAc) to give (S)-tert-butyl 1-(tert-butoxycarbonyloxy)-4,4-difluoro-5-hydroxypentan-2-yl(methyl)carbamate (35.3 g, 90%). LRMS (M+Na+) m/z 392.4.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][N:11]([C:19]2[N:28]=[C:27]([NH:29][CH2:30][CH2:31][NH:32]C(=O)OC(C)(C)C)[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([CH3:40])[CH:25]=3)[N:20]=2)[CH2:10][CH2:9]1>ClCCl>[S:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][N:11]([C:19]2[N:28]=[C:27]([NH:29][CH2:30][CH2:31][NH2:32])[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([CH3:40])[CH:25]=3)[N:20]=2)[CH2:10][CH2:9]1
Reactant: Cc1ccc2nc(N3CCSc4ccccc4C3)nc(NCCNC(=O)OC(C)(C)C)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2nc(N3CCSc4ccccc4C3)nc(NCCN)c2c1
Reaction time: 3 h
Yield: 72.1 %

Procedure:
To a cooled solution of trifluoroacetic acid in dichloromethane (2 mL, V/V=1/4) was added tert-butyl {2-[2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]aminoethyl}carbamate (120 mg, 0.258 mmol) in an ice bath. The mixture was stirred for 3 hours whilst allowing the temperature of the mixture rising naturally to room temperature, and then concentrated in vacuo. The residue was dissolved in water (10 mL), and washed with dichloromethane (10 mL). The aqueous layer was adjusted to pH 10 with a saturated aqueous solution of sodium carbonate and extracted with ethyl acetate (20 mL×2). The organic extracts were dried with sodium sulfate, concentrated in vacuo to afford 68 mg of the product as a white solid (yield was 72%). MS obsd. (ESI+) [(M+H)+] 366, 1H NMR (400 MHz, CD3OD) δ ppm 7.67-7.64 (t, J=12.0 Hz, 2 H), 7.49-7.47 (d, J=8.4 Hz, 1 H), 7.38-7.30 (m, 2 H), 7.23-7.19 (dd, J=8.4, 7.6 Hz, 2 H), 7.13-7.09 (dd, J=8.8 Hz, 1 H), 5.04 (s, 2 H), 4.38 (s, 2 H), 3.75-3.72 (m, 2 H), 2.98-2.92 (m, 4 H), 2.39 (s, 3 H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([NH:11][S:12]([C:15]1[C:16]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[C:32]([CH2:33][OH:34])=[C:31]([Cl:35])[N:30]=[C:29]3[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:23][CH:22]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:13])=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]([NH:11][S:12]([C:15]1[C:16]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[C:32]([CH2:33][OH:34])=[C:31]([Cl:35])[N:30]=[C:29]3[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:23][CH:22]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:13])=[O:14])=[O:10]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)CNC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)CN)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a DCM (500 μL) solution of intermediate (1d) (600 mg, 1.0 mmol) was added TFA (500 μL, 6.4 mmol). The mixture was stirred at room temperature for 30 minutes. Volatiles were removed under vacuum and the TFA salt of the product was lyophilized in 50/50 water/acetonitrile to give the title compound as a white solid (418 mg). Anal. HPLC: retention time=1.2 minutes. Gradient conditions: 25% solvent B/75% solvent A to 95% solvent B/5% solvent B over 6 minutes. MS m/z: [M+H]+ calcd for C23H27ClN4O4S, 491.15. found 473.1 [M+H]+-18.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:11]2[N:12]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13](=[O:15])[NH:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].N(C(C)(C)C#N)=NC(C)(C)C#N.[Cl:36]N1C(=O)CCC1=O>ClC1C=CC=CC=1>[Cl:36][C:9]1[C:10]2[NH:14][C:13](=[O:15])[N:12]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11]=2[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCCn1c(=O)[nH]c2cccc(C(CC)CC)c21
Reactant: O=C1CCC(=O)N1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: CCOC(=O)CCCn1c(=O)[nH]c2c(Cl)ccc(C(CC)CC)c21
Temperature: 85 °C
Reaction time: 48 h
Yield: 63.2 %

Procedure:
To a solution of ethyl 4-[7-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]butanoate (9.7 g, 30.5 mmol) and 2,2′-azobisisobutyronitrile (AIBN; 0.5 g, 3.05 mmol) in chlorobenzene (100 mL) was added N-chlorosuccinimide (NCS; 4.35 g, 32.6 mmol) in portions at 65° C., and the mixture was stirred at 80-90° C. for 2 days. After cooled to room temperature, the reaction mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous phase was extracted with ethyl acetate (100 ml×3), washed with brine (100 mL), dried over anhydrous sodium sulfate and purified by silica gel column (petroleum ether/ethyl acetate, 50/1) to afford the title compound (6.8 g, 61%) as yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)=[C:6]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23]([CH:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[N:5]=[C:4]([NH:29][C:30]2[CH:35]=[C:34]([CH3:36])[C:33]([CH:37]3[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][O:45][CH3:46])[CH2:39][CH2:38]3)=[CH:32][C:31]=2[O:47][CH:48]([CH3:50])[CH3:49])[N:3]=1.[NH2:51][NH2:52]>C1COCC1>[CH:48]([O:47][C:31]1[CH:32]=[C:33]([CH:37]2[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][O:45][CH3:46])[CH2:39][CH2:38]2)[C:34]([CH3:36])=[CH:35][C:30]=1[NH:29][C:4]1[N:3]=[C:2]2[NH:51][N:52]=[C:8]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:7]2=[C:6]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23]([CH:26]([CH3:28])[CH3:27])(=[O:24])=[O:25])[N:5]=1)([CH3:50])[CH3:49]
Reactant: NN
Reactant: COCCN1CCC(c2cc(OC(C)C)c(Nc3nc(Cl)c(C(=O)c4ccccc4)c(Nc4ccccc4S(=O)(=O)C(C)C)n3)cc2C)CC1
Solvent: C1CCOC1
Product: COCCN1CCC(c2cc(OC(C)C)c(Nc3nc(Nc4ccccc4S(=O)(=O)C(C)C)c4c(-c5ccccc5)n[nH]c4n3)cc2C)CC1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
To a 10 mL microwave reaction tube was added (4-chloro-2-(2-isopropoxy-4-(1-(2-methoxyethyl)piperidin-4-yl)-5-methylphenylamino)-6-(2-(isopropylsulfonyl)phenylamino)pyrimidin-5-yl)(phenyl)methanone (0.0548 mmol), THF (4 mL) and H2NNH2 (0.4 mL). The resulting mixture was stirred at 120° C. for 30 minutes by using a microwave machine. The reaction solution was concentrated in vacuo and the residue was purified by reverse phase HPLC to afford N6-(2-isopropoxy-4-(1-(2-methoxyethyl)piperidin-4-yl)-5-methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine as a slightly yellow solid. MS (ES+): 698.30 (MH+).
Reaction SMILES: COCCOC.Br[CH2:8][C:9]1[O:13][N:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[CH2:8][C:9]1[O:13][N:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=1
Reactant: OB(O)c1cc(F)ccc1F
Reactant: CCOC(=O)c1cc(CBr)on1
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: COCCOC
Solvent: O
Product: CCOC(=O)c1cc(Cc2cc(F)ccc2F)on1
Yield: 58.7 %

Procedure:
1,2-Dimethoxyethane (8 mL) and water (2 mL) were added to the mixture of ethyl 5-(bromomethyl)isoxazole-3-carboxylate (1.00 g; 4.27 mmol), 2,5-difluorophenylboronic acid (0.773 g; 4.70 mmol), tetrakis(triphenylphosphine)palladium(0) (0.248 g; 0.640 mmol) and sodium carbonate (0.911 g; 8.55 mmol). The mixture was irradiated in a microwave oven at 130° C. for 20 minutes. After cooling, the reaction mixture was extracted with ethyl acetate and water. The organic layer was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (eluent: 5 to 40% of ethyl acetate in heptane) to give 0.67 g (59%) of ethyl 5-(2,5-difluorobenzyl)isoxazole-3-carboxylate as a yellow oil.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[C:13]([CH:14]=[C:15]4[C:20]=2[CH:19]=[CH:18][CH:17]=[CH:16]4)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[I:25]N1C(C)(C)C(=O)N(I)C1=O.O>C(Cl)(Cl)Cl>[I:25][C:14]1[C:15]2[C:20]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:8]3[C:13]=1[CH:12]=[CH:11][CH:10]=[CH:9]3)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: CC1(C)C(=O)N(I)C(=O)N1I
Reactant: c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Ic1c2ccccc2c(-c2ccccc2)c2ccccc12
Temperature: 70 °C
Reaction time: 3 h
Yield: 117.3 %

Procedure:
Into a 500 mL Erlenmeyer flask was put 4.5 g (18 mmol) of 9-phenylanthracene. Then 200 mL of acetic acid was added to the flask, followed by heating to 70° C., and 9-phenylanthracene was dissolved therein. Into this solution, 5.2 g (13 mmol) of 1,3-diiodo-5,5-dimethylimidazolidine-2,4-dione (abbreviation: DIH) was added. This solution was stirred in air at 70° C. for 3 hours. After the stirring, about 100 mL of water and about 200 mL of chloroform were added to this solution. This mixture was washed with water twice, and the aqueous layer was extracted with chloroform. The extracted solution was combined with the organic layer and washed with a saturated saline, and then the organic layer was dried with magnesium sulfate. This mixture was gravity filtered, and the obtained filtrate was concentrated to give a brown solid. This solid was washed with hexane to give 5.8 g of a yellow solid, which was the object of the synthesis, in a yield of 86%.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:7][C:6](=[N:21]OC(NCCC)=O)[C:5]1=[O:29].[ClH:30].O1CCOCC1>CO.CCOCC.[C].[Pd]>[ClH:30].[CH3:1][O:2][CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:7][CH:6]([NH2:21])[C:5]1=[O:29]
Reactant: CCCNC(=O)ON=C1CN(c2ccccc2)c2ccccc2N(COC)C1=O
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CO
Product: COCN1C(=O)C(N)CN(c2ccccc2)c2ccccc21
Yield: 69.3 %

Procedure:
10% Palladium carbon (2.0 g) was added to 1-methoxymethyl-2-oxo-3-propylaminocarbonyloxyimino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (14.2 g) suspended in methanol (200 ml), and the resultant mixture was stirred for two hours under hydrogen atmosphere (3 kg/cm2) at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1), to thereby obtain a yellow oily substance. The substance was dissolved in ether, and 4N hydrochloric acid-dioxane (10 ml) was added thereto. Crystals so precipitated were collected by filtration, to thereby obtain 8.28 g of the title compound as a white solid (yield: 69.3%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([Li])CCC.[C:22](=[O:24])=[O:23].Cl>C(OCC)C.CCCCCC>[F:10][C:4]1[C:5]([C:22]([OH:24])=[O:23])=[C:6]([F:9])[C:7]([F:8])=[C:2]([F:1])[C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C=O
Reactant: Fc1cc(F)c(-c2ccccc2)c(F)c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C(O)c1c(F)c(F)c(F)c(-c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under a dry argon atmosphere, a stirred solution of 2,3,4,6-tetrafluoro-[1,1'-biphenyl] (23.0 g, 0.102 mole) in 400 ml of diethyl ether was cooled to -65°. During a 11/4 hour period 63.4 ml of a 1.6 M solution of n-butyl lithium in hexane was added to the reaction mixture, which was then stirred at -65° for 23/4 hours. During a one hour period, freshly crushed dry ice (750 g) was added to the mixture. The stirred reaction mixture was then allowed to warm to room temperature. The mixture was cooled; 400 ml of 6 N aqueous hydrochloric acid was added and the resultant mixture stirred vigorously for two hours. The mixture was poured into a separatory funnel, the aqueous phase separated and extracted with three 300 ml portions of diethyl ether. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a solid residue. The solid was recrystallized from toluene:n-heptane (1:1) to give 2,4,5,6-tetrafluoro-[1,1'-biphenyl]-3-carboxylic acid (mp, 189°-190.5°).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:15]C)(=[O:14])[CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].[CH3:17][C:18]([CH3:22])([CH3:21])[CH:19]=O>C(O)(C)(C)C>[CH3:13][O:12][C:10](=[O:11])[C:9](=[CH:17][C:18]([CH3:22])([CH3:21])[CH3:19])[CH2:8][C:7]([OH:15])=[O:14]
Reactant: COC(=O)CCC(=O)OC
Reactant: CC(C)(C)C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)C(=CC(C)(C)C)CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
To a solution of 11.2 g (0.1 mol) potassium tert-butoxide in 100 ml tert-butanol was added a mixture of 14.6 g (0.1 mol) dimethyl succinate and 8.6 g (0.1 mol) trirnethylacetaldehyde over a period of 30 min. The mixture was allowed to stir at room temperature for one hour and heated to 50° C. for an additional hour. The solvent was removed under reduced pressure, the residue was dissolved in 100 ml water and transferred into a separation funnel. The solution was extracted twice with 50 ml ethyl acetate to remove neutral impurities, acidified with 6M HCl and extracted again twice with 20 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure, to give 14.9 g (75%) of a light yellow creamy solid. 1H-NMR:>95% E-isomer.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[CH3:10][O-:11].[Na+]>CO>[CH3:10][O:11][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CCCCBr
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCCCCC(=O)OC
Yield: 97.7 %

Procedure:
A solution of methyl 5-bromovalerate (10.0 g, 51.3 mmol), NaOMe (12.3 ml of 25% solution, 53.8 mmol) in 100 ml of MeOH was refluxed for 5 hrs. The MeOH was removed in vacuo and residue was partitioned between CHCl3 (200 ml) and water (50 ml). The organic layer was separated and washed with water (100 ml). After drying (Na2SO4) and evaporation of solvent, methyl 5-methoxyvalerate (7.33 g, 97.8%) was obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[F:9].[Li]CCCC.[CH2:15]=[CH:16][CH2:17][CH2:18][C:19](=[O:24])[CH2:20][CH2:21][CH:22]=[CH2:23]>C1COCC1>[F:9][C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[C:19]([OH:24])([CH2:20][CH2:21][CH:22]=[CH2:23])[CH2:18][CH2:17][CH:16]=[CH2:15]
Reactant: Fc1cccc(Br)c1F
Reactant: C=CCCC(=O)CCC=C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCCC(O)(CCC=C)c1cccc(F)c1F
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
In an oven-dried 250 mL round-bottomed flask (t=g) was added 1-Bromo-2,3-difluorobenzene (2.304 mL, 20.58 mmol) in THF (60 mL) to give a colorless solution. After cooling to −78° C., BuLi (8.23 mL, 20.58 mmol) was added dropwise via syringe. The mixture was stirred at −78° C. for 20 minutes, and nona-1,8-dien-5-one (2.37 g, 17.15 mmol) (azeotroped with dry benzene) was added dropwise via canuula (plus 6 ml THF rinse). The mixture was warmed up to room temperature over 1 hour. Quenched with water and the THF solvent was stripped off. The remaining mixture was extracted with EtOAc. The layers were separated and the organic layer was washed with brine, dried with Na2SO4, and concentrated to a yellow oil. The residue was purified by FCC up to 35% Et2O/hexane. The desired fractions were pooled and concentrated to the product as a colorless oil (2.39 g, 55.3%). 1H NMR (400 MHz, CDCl3) δ 7.30-7.22 (m, 1H), 7.10-7.03 (m, 2H), 5.82-5.70 (m, 2H), 4.97-4.85 (m, 4H), 2.20-2.00 (m, 4H), 2.00-1.75 (m, 4H).