Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:8]=[N:9][C:10]([Br:13])=[CH:11][CH:12]=1)[C:3]([NH2:5])=[O:4].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]1[C:27](O)=[O:28])=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[NH2:5][C:3](=[O:4])[C@@H:2]([NH:1][C:27]([C@@H:22]1[CH2:23][CH2:24][CH2:25][CH2:26][N:21]1[C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])=[O:28])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([Br:13])=[CH:11][CH:12]=1
Reactant: NC(=O)[C@@H](N)Cc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@@H](Cc1ccc(Br)nc1)C(N)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
(S)-2-Amino-3-(6-bromopyridin-3-yl)propanamide (1 g), (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (0.939 g) and triethylamine (2.86 mL) in DMF (3 mL) were stirred under nitrogen at 0° C. 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosorinan-2,4,6-trioxide (3.13 g) was added and stirring at 0° C. was continued for 1 h. The reaction mixture was allowed to reach RT then it was diluted with ethyl acetate, washed with water and brine sequentially, dried over magnesium sulfate, filtered and concentrated in vacuo to give the sub-title compound (1.740 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([Mg]Br)C.CCN(CC)CC.[CH2:20]=[O:21].Cl>C1COCC1.CCOC(C)=O.C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:20]=[O:21])=[C:4]([OH:8])[CH:3]=1
Reactant: C=O
Reactant: Oc1cccc(F)c1
Agent: CC[Mg]Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: O=Cc1ccc(F)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.3 %

Procedure:
To a solution of 3-fluorophenol (1 ml, 11 mmol) in THF (20 ml) in a three-neck flask was added ethylmagnesium bromide (5.5 ml, 5.5 mmol, 1M in THF). After stirring at room temperature for 2 hours, benzene was added to the reaction mixture and THF was removed by distillation at 80° C. Additional benzene (50 ml) was added to the reaction, followed by NEt3 (2.3 ml, 16.5 mmol) and paraformaldehyde (1 g, 33.3 mmol). After heating at reflux for 3 hours, the reaction mixture was allowed to cool to room temperature and was poured into 250 ml of 10% HCl. EtOAc was added and the organic layer was separated and washed with H2O. After drying over MgSO4, the solvent was removed under reduced pressure. The resulting residue was purified by flash chromatography to give 4-fluoro-2-hydroxy-benzaldehyde as a white solid (560 mg, 36%), 1H NMR (CDCl3, 300 MHz) δ: 6.71 (m, 2H), 7.56 (dd, 1H, J=6.3 Hz, 8.6 Hz), 9.84 (s, 1H), 11.36 (s, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].O.NN.[OH-].[K+].Cl>O>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(C(=O)CCC(=O)O)cc1
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: O
Product: CC(C)c1ccc(CCCC(=O)O)cc1
Temperature: 127 °C
Yield: 58.7 %

Procedure:
A solution of compound 76 (0.5 g, 2.27 mmol) and 2 mL of 80% hydrazine hydrate was stirred at 45° C. for 1 hour. To the mixture, KOH (1 g, 17.8 mmol) was added and the reaction mixture was heated to 104-150° C. for 2 hours. After cooling to ambient temperature, the reaction mixture was diluted with 10 mL of water and acidified to pH 2 with aqueous HCl (1 M) and extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica-gel (2×15 cm, petroleum ether:ethyl acetate=8:1 elution) to give 275 mg of compound 77. MS m/z 207 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[S:30])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>>[CH3:20][O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([S:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:29]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[C:23]([C:31]([F:34])([F:32])[F:33])[CH:24]=3)=[S:30])=[CH:7][CH:6]=1)[CH:18]=[CH:17]2
Reactant: COc1ccc2nc(Sc3ccc(N)cc3)ccc2c1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Product: COc1ccc2nc(Sc3ccc(NC(=S)Nc4ccc(Cl)c(C(F)(F)F)c4)cc3)ccc2c1
Yield: 71.8 %

Procedure:
2-(4-aminophenylthio)-6-methoxyquinoline (15.0 moles, 4.2 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (15.0 mmoles, 3.6 g) were reacted according to procedure C to yield 5.6 g, 72% of the title compound. Mass Spec (FD) 519. Calculated for C24H17ClF3N3OS2 : C, 55.44; H, 3.30; N, 8.08. Found: C, 55.62; H, 3.43; N, 8.27.
Reaction SMILES: C(N(C(C)C)C(=O)[O:6][CH:7]([CH3:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])(C)C.[H-].C([Al+]CC(C)C)C(C)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][CH:7]([OH:6])[CH3:16]
Reactant: CC(Cc1ccccc1F)OC(=O)N(C(C)C)C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(O)Cc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
Under a nitrogen atmosphere, to a solution of 5.11 g (18.2 mmol) of 2-(2-fluorophenyl)-1-methylethyl diisopropylcarbamate in THF, a 1.0M solution of 182 ml (182 mmol) of diisobutylaluminum hydride in THF was added dropwise. The reaction mixture was stirred overnight at room temperature and sodium sulfate 10-hydrate was slowly added until no effervescence was observed. After addition of the sodium sulfate, the mixture was filtered, the filtrate was distilled off and purified by silica gel column chromatography, giving 2.15 g of the title compound. (Yield: 77% yield, 97% ee)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH:6]=[CH:7][CH:8]=O)#[N:2].[NH2:13][NH:14][C:15]([NH2:17])=[S:16]>>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH:6]=[CH:7][CH:8]=[N:13][NH:14][C:15]([NH2:17])=[S:16])#[N:2]
Reactant: NNC(N)=S
Reactant: N#Cc1cccc(C=CC=O)c1
Product: N#Cc1cccc(C=CC=NNC(N)=S)c1
Yield: 46 %

Procedure:
The compound is prepared according to the method described in Example 1A from 3-cyanocinnamaldehyde (2.54 mmol) and from thiosemicarbazide (2.54 mmol). Yield 46%.
Reaction SMILES: [N+:1](=[CH:3][C:4](=[O:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N-].B(F)(F)F.CCOCC.[Cl:22][CH2:23][C:24]#N>ClCCl>[Cl:22][CH2:23][C:24]1[O:12][C:4]([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:3][N:1]=1
Reactant: N#CCCl
Reactant: [N-]=[N+]=CC(=O)Cc1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: ClCc1ncc(Cc2ccccc2)o1
Yield: 61.6 %

Procedure:
1-Diazo-3-phenyl-2-propanone (0.8 g, 5 mmol) in dichloromethane (5 ml) was added to a mixture of boron trifluoride diethyl etherate (1.2 ml, 10 mmol), chloroacetonitrile (6.4 ml, 100 mmol) and dichloromethane (5 ml) at 20° C. After 0.5 h at 20° C. the solution was washed with cold aqueous 20% sodium hydroxide, dried (MgSO4), and evaporated under reduced pressure to give an oil which was purified by chromatography (10 g silica, dichloromethane) to give 2-chloromethyl-5-benzyl oxazole as a yellow oil (0.64 g, 62%); δH (CDCl3) 7.2 (5H, S, aryl), 6.7 (1H, S, het-H), 4.5 (2H, S, CH2Cl), 4.2 (2H, S, CH2Ar), 2-Chloromethyl-5-benzyloxazole (0.6 g, 3 mmol) and triethyl phosphite (0.7 ml, 4.5 mmol) were heated together for 1 h at 160° C. and then cooled. Direct chromatography (10 g silica, 0 to 5% methanol in dichloromethane) then gave diethyl 5-benzyl-2-oxazolylmethyl phosphonate as a light brown oil (0.65 g, 70%); δH (CDCl3) 7.2 (5H, S, aryl), 6.7 (1H, S, het-H), 4.1 (4H, m, OCH2), 3.9 (2H, S, CH2Ar), 3.3 (2H, d, CH2P), 1.3 (6H, t, Me).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=3[O-])[C:7]=2[CH:22]=1)#[N:2].CC1(C)CC(C2C=CC=CN=2)C2C=C(C(O)=O)C=CC=2O1.C(#N)C.OO>CO.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH3:12][C:10]1([CH3:13])[CH:9]2[O:14][C:8]2([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:7]2[CH:22]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:11]1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](c2cccc[n+]2[O-])[C@@H]1O
Agent: O=[W](=O)([O-])[O-]
Agent: CC1(C)CC(c2ccccn2)c2cc(C(=O)O)ccc2O1
Agent: OO
Solvent: CO
Solvent: CC#N
Product: CC1(C)Oc2ccc(C#N)cc2C2(c3ccccn3)OC12

Procedure:
The rac-trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carbonitrile used as the starting material was prepared as follows: (A) 3 g of 2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carbonitrile and 420 mg of sodium tungstate were heated in 30 ml of methanol and 30 ml of acetonitrile at 50° C. and 12 ml of 30% (w/v) hydrogen peroxide were added. After heating overnight the mixture was evaporated and the residue was taken up in dichloromethane and water. The organic phase was separated, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:3 and 1:2) for the elution to give 440 mg of la,7b-dihydro-2,2-dimethyl-7b-(2-pyridyl)-2H-oxireno[c][1]benzopyran-6-carbonitrile which was used without further purification. (B) 646 mg of la,7b-dihydro-2,2-dimethyl-7b-(2-pyridyl)-2H-oxireno[c][1]benzopyran-6-carbonitrile were dissolved in 100 ml of ethanol and 100 mg of 10% palladium-on-charcoal were added. The mixture was shaken under a hydrogen atmosphere overnight and then filtered. The filtrate was evaporated and the resulting oil was chromatographed twice on silica gel, with the elution being carried out initially using ethyl acetate/petroleum ether (1:3) and then 1% to 2% (v/v) methanol/dichloromethane. There were obtained 66 mg of rac-cis-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carbonitrile of melting point 186°-188° C. (from acetonitrile) and 340 mg of rac-trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6carbonitrile of melting point 175°-176° C. (from t-butyl methyl ether).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4](=[O:10])[NH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH:17](I)([CH3:19])[CH3:18]>CN(C=O)C>[CH:17]([N:3]1[C:4](=[O:10])[C:5]2[CH:9]=[CH:8][NH:7][C:6]=2[N:1]=[CH:2]1)([CH3:19])[CH3:18]
Reactant: O=c1[nH]cnc2[nH]ccc12
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1cnc2[nH]ccc2c1=O
Temperature: 55 °C
Reaction time: 13 h

Procedure:
Under argon gas, 7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (1.0 g) was dissolved in DMF (35 ml) with warming. Then, anhydrous potassium carbonate (1.02 g) and isopropyl iodide (1.1 ml) were added and the mixture was stirred at 55° C. for 13 hours. The insoluble matter was filtered off and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography (silica gel; hexane: ethyl acetate=4:1→1:1) to provide the title compound (110 mg). 1 H-NMR (CDCl3) δ: 1.48(6H,d,J=7.OHz), 5.31(1H,m), 6.74(1H,dd,J=2.2&3.4Hz), 6.96(1H,dd,J=2.2&3.4Hz), 7.95(1H,s), 9.20(1H,brs).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:18])=[CH:12][CH:11]=2)=[N:7][CH:8]=1)#[N:2].[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[C:1]([C:3]1[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:5][C:6]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][O:18][S:31]([C:28]3[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=3)(=[O:33])=[O:32])=[CH:14][CH:15]=2)=[N:7][CH:8]=1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1cnc(Nc2ccc(CCO)cc2)nc1-c1ccccc1
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(Nc3ncc(C#N)c(-c4ccccc4)n3)cc2)cc1

Procedure:
5-Cyano-4-phenyl-N-[4-(2-p-toluenesulphonyloxyethyl)phenyl]pyrimidine-2-amine was prepared from 5-cyano-4-phenyl-N-[4-(2-hydroxyethyl)phenyl]pyrimidine-2-amine (3.30 g, 10.43 mmol) and 4-toluenesulphonylchloride (2.19 g, 11.47 mmol) as a pale yellow solid (3.91 g) m.p. 134-135°. δH (d6 DMSO) 8.69 (1H, s), 8.05 (2H, dd, J 6.0, 2.0 Hz), 7.72 (2H, d, J 8.3 Hz), 7.61-7.51 (6H, m), 7.29 (2H, d, J 8.1 Hz), 7.14 (2H, d, J 8.5 Hz), 4.21(2H, t, J 7.0 Hz), 2.95 (2H, t, J 7.0 Hz) and 2.41 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][C:11]([N+:14]([O-])=[O:15])([CH3:13])[CH3:12].C(O)(=O)C>C(O)C.[Zn]>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[N+:14]([C:11]([CH3:13])([CH3:12])[CH3:10])[O-:15])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(F)c1
Reactant: CC(C)(C)[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)[N+]([O-])=Cc1cccc(F)c1

Procedure:
To a suspension of 3-fluorobenzaldehyde (327.5 mg, 2.64 mmol), 1,1-dimethylnitroethane (542.3 mg, 5.26 mmol) and zinc (517.9 mg, 7.92 mmol) in ethanol (3.0 ml) was added acetic acid (946.2 mg, 15.8 mmol) dropwise at 5° C. while stirring. The mixture was stirred at room temperature for 5 hours. Zinc acetate in the mixture was filtered off and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=2/1).
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=1)[C:10]([N:12]([CH:14]([CH:39]([CH3:41])[CH3:40])[C:15]([NH:17][CH:18]([C:31]1[NH:36][C:35](=[O:37])[CH:34]=[C:33]([CH3:38])[N:32]=1)[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:21]=1)=[O:16])[CH3:13])=[O:11])=O)CCC>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:8][CH:9]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=1)[C:10]([N:12]([CH:14]([CH:39]([CH3:41])[CH3:40])[C:15]([NH:17][CH:18]([C:31]1[NH:36][C:35](=[O:37])[CH:34]=[C:33]([CH3:38])[N:32]=1)[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:21]=1)=[O:16])[CH3:13])=[O:11]
Reactant: CCCCOC(=O)NC(Cc1ccc(F)cc1)C(=O)N(C)C(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1nc(C)cc(=O)[nH]1)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(=O)[nH]c(C(Cc2ccc(O)c(C(C)(C)C)c2)NC(=O)C(C(C)C)N(C)C(=O)C(N)Cc2ccc(F)cc2)n1
Yield: 94.6 %

Procedure:
To a solution of 2-(1-(2-((2-butoxycarbonylamino-3-(4-fluorophenyl)propionyl)-N-methylamino)-3-methyl-butyrylamino)-2-(3-tert-butyl-4-hydroxyphenyl)ethyl)-6-methyl-4-pyrimidinone (A) (279 mg) in methylene chloride (8 ml), TFA (1.3 ml) was added under cooling with ice. The resultant mixture was stirred at room temperature for 1 hour and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: methylene chloride:methanol=15:1), giving the titled compound (225 mg, 95%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:12][CH:11]1[CH2:13][CH2:14]O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:35]Br.C(=O)([O-])O.[Na+]>CN(C)C=O>[Si:1]([O:8][CH2:9][CH:10]1[CH2:12][CH:11]1[CH2:13][CH2:14][Br:35])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC1CC1CCO
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC1CC1CCBr
Temperature: -20 °C
Reaction time: 0.08 h
Yield: 14.2 %

Procedure:
2-(2-hydroxyethyl)cyclopropylmethyl t-butyldimethylsilyl ether (15.0 g, 65 mmol) was dissolved in N,N-dimethylformamide (120 ml), and triphenylphosphine (17.3 g, 66 mmol) was added thereto at room temperature. Twenty minutes later, the mixture was cooled to -20° C. Bromine (10.5 g, 66 mmol) was added thereto over a period of 5 minutes, and the temperature was gradually raised to 0° C. The mixture was poured into a saturated sodium hydrogen carbonate aqueous solution, and the product was extracted with ethyl ether. Then, it was dried over anhydrous magnesium sulfate and purified by silica gel column chromatography to obtain 2-(2-bromoethyl)cyclopropylmethyl t-butyldimethylsilyl ether (2.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:26]1([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])[CH:30]=[CH:29][N:28]=[CH:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][N:26]1[CH:30]=[CH:29][N:28]=[CH:27]1)=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: NCCCCCCn1ccnc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(NCCCCCCn1ccnc1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
When 5-chloroindole-2-carboxylic acid is reacted with 1,1'-carbonyldiimidazole and 1H-imidazole-1-hexanamine by the procedure of Example 29, the compound of the Example is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]=O>>[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2/[CH:26]=[CH:14]/[C:13]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:15]
Reactant: O=Cc1c[nH]c2ccc(Br)cc12
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Product: COc1cc(C(=O)/C=C/c2c[nH]c3ccc(Br)cc23)cc(OC)c1OC
Yield: 65.7 %

Procedure:
Substantially the same procedure as in Example 12 was repeated using 3',4',5'-trimethoxyacetophenone (2.1 g) and 5-bromoindole-3-carboxaldehyde (2.24 g) except that the obtained crystals were recrystallized from ethyl acetate, to give Compound 31 (2.73 g).
Reaction SMILES: [C:1]([C:3]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)([CH2:10][CH2:11][C:12]([O:14]C)=O)[CH2:4][CH2:5][C:6]([O:8]C)=O)#[N:2].C[O:27]C1C=C(CC#N)C=CC=1OC>>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:24][CH3:25])[C:3]1([CH2:10][CH2:11][C:12](=[O:14])[NH:2][C:1]1=[O:27])[CH2:4][CH2:5][C:6]2=[O:8]
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(OC)c(OC)c1
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1cc2c(cc1OC)C1(CCC(=O)NC1=O)CCC2=O
Temperature: 110 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
Unpurified dimethyl γ-cyano-γ-(3,4-dimethoxyphenyl)pimelate, prepared from 334 grams of 3,4-dimethoxyphenylacetonitrile as described by Horning et al., J. Am. Chem. Soc., 74, 773 (1942), was added with stirring to 3.0 kg of polyphosphoric acid. This reaction mixture was stirred at 110° C. for 2 hours and poured into 6.0 liters of crushed ice with stirring. The resulting solid was filtered and recrystallized from isopropyl alcohol-water to give 65.8 grams (18%) of 2,3-dihydro-6,7-dimethoxyspiro-[naphthalene-1(4H),3'-piperidine]-2',4,6'-trione, melting point 269°-271° C.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[OH:25]>>[OH:25][C:17]1[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:16]=1[NH:15][C:7]([C:6]1[CH:5]=[C:4]([CH3:10])[S:3][C:2]=1[Br:1])=[O:9]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: Cc1cc(C(=O)O)c(Br)s1
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)Nc2cc([N+](=O)[O-])ccc2O)c(Br)s1

Procedure:
In the same manner as in Starting Material Synthesis Example 67 and using 2-bromo-5-methyl-3-thiophenecarboxylic acid, thionyl chloride and 2-amino-4-nitrophenol, N-(2-hydroxy-5-nitrophenyl)-2-bromo-5-methyl-3-thiophenecarboxamide is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=1I)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([O:22][C:23](=[O:42])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=1)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.ClCCl.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:20]([O:22][C:23](=[O:42])[CH2:24][C:25]1[CH:26]=[C:27]([C:12]2[CH:13]=[CH:14][C:15]([Br:17])=[CH:16][C:11]=2[CH2:10][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:19])[CH2:8][CH3:9])[C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)[CH3:21]
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCN(Cc1cc(Br)ccc1I)C(=O)OC(C)(C)C
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: [K+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(Br)cc2CN(CC)C(=O)OC(C)(C)C)c1
Temperature: 80 °C

Procedure:
(5-Bromo-2-iodo-benzyl)-ethyl-carbamic acid tert-butyl ester (2.0 g, 4.54 mmol), [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (1.67 g, 5.21 mmol), and potassium carbonate (1.57 g, 11.4 mmol) were combined in DME:H2O (2:1) under nitrogen. The mixture was purged with nitrogen, and then tetrakis(triphenylphosphine)palladium(0) (0.150 g, 0.13 mmol) was added, and the reaction was heated to 80° C. for 36 hours. Once no starting material was seen by analytical LCMS, the mixture was cooled to room temperature and diluted with dichloromethane and water. The aqueous layer was separated and extracted with dichloromethane, and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate in hexanes) to give the title compound.
Reaction SMILES: CC1C=CC=C(C#CC=C2CCN(C3C=CC=CN=3)CC2)N=1.FC1C=CC=CN=1.[F:30][C:31]1[CH:32]=[C:33]([C:38]#[C:39][CH:40]=[C:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:34]=[C:35]([F:37])[CH:36]=1.Cl[C:48]1[N:55]=[C:54]([CH3:56])[CH:53]=[CH:52][C:49]=1[C:50]#[N:51].C(=O)([O-])[O-].[K+].[K+]>>[F:30][C:31]1[CH:32]=[C:33]([C:38]#[C:39][CH:40]=[C:41]2[CH2:42][CH2:43][N:44]([C:48]3[N:55]=[C:54]([CH3:56])[CH:53]=[CH:52][C:49]=3[C:50]#[N:51])[CH2:45][CH2:46]2)[CH:34]=[C:35]([F:37])[CH:36]=1
Reactant: Fc1cc(F)cc(C#CC=C2CCNCC2)c1
Reactant: Cc1ccc(C#N)c(Cl)n1
Agent: Cc1cccc(C#CC=C2CCN(c3ccccn3)CC2)n1
Agent: Fc1ccccn1
Agent: O=C([O-])[O-]
Product: Cc1ccc(C#N)c(N2CCC(=CC#Cc3cc(F)cc(F)c3)CC2)n1
Yield: 61 %

Procedure:
The title compound was synthesized following the procedure reported for the compound of Example 59 replacing the compound of Example 3, 2-fluoropyridine and TEA respectively with Compound 228b, 2-chloro-6-methylnicotinonitrile and potassium carbonate. Purification by automated flash chromatography (Horizon™-Biotage) eluting with PE-EtOAc 95:5. Yellow solid. Yield: 61%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(O)C.[C:27]1([C:33]([N:35]=[C:36]=[S:37])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[C:33]([NH:35][C:36]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][C:18]=1[F:23])=[S:37])(=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (76 mg, yield 80%).