Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:17])[CH2:14][CH2:15][CH3:16])[CH2:9]1)=O)(C)(C)C.CN(C=O)C.[H-].[Na+].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](F)[C:27]=1[Cl:33].Cl.CCO>>[Cl:25][C:26]1[C:27]([Cl:33])=[CH:28][CH:29]=[CH:30][C:31]=1[O:17][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][CH2:15][CH3:16]
Reactant: Fc1cccc(Cl)c1Cl
Reactant: CCC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCC[C@H](Oc1cccc(Cl)c1Cl)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((S)-1-Hydroxybutyl)pyrrolidine-1-carboxylic acid t-butyl ester (50 mg, 0.2 mmol) was dissolved in DMF (1.0 mL, 13 mmol). NaH (5.9 mg, 246 μmol) was slowly added and the mixture was stirred at room temperature for 15 minutes. 1,2-Dichloro-3-fluorobenzene (67.8 mg, 411 μmol) was added. The mixture was stirred at 70° C. for 3 hours, then concentrated. 1.2M HCl in EtOH (1.0 mL, 1.2 mmol) was added, and the mixture was stirred overnight. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (19 mg, 100% purity). MS in/z: [M+H]+ calcd for C14H19Cl2NO, 288.08. found 288.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]=[CH:13][C:14]1[O:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)[N:6]=[C:5]2[NH:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.[F:30]C1C=C2C(=CC=1F)N=C(C)NC2=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:30])[N:8]=[C:7]([CH:12]=[CH:13][C:14]1[O:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)[N:6]=[C:5]2[NH:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2nc(Nc3ccc(O)cc3)c3cc(F)ccc3n2)o1
Reactant: Cc1nc2cc(F)c(F)cc2c(=O)[nH]1
Product: O=[N+]([O-])c1ccc(C=Cc2nc(Nc3ccc(O)cc3)c3cc(F)c(F)cc3n2)o1

Procedure:
This compound was prepared in the same manner as that described in Example I or the synthesis of 6-fluoro-2-[2-(5-nitro-2-furyl)vinyl]-4-(p-hydroxyanilino)quinazoline, by using 6,7-difluoro-2-methyl-4-(3H)quinazolinone (1 g) as a starting material.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.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>[NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([O:10][CH3:9])[CH:16]=2)=[CH:4][N:3]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Nc1cnc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cccc(-c2cnc(N)cn2)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 102.5 %

Procedure:
To a solution of 2-amino-5-bromopyrazine (642 mg) in dimethoxyethane (40 mL) was added 3-methoxyphenylboronic acid (560 mg), 1.5N aqueous sodium carbonate solution (4 mL) and tetrakis(triphenylphosphine)palladium (0) (86 mg). The mixture was stirred at 80° C. for 6 hours. To the reaction mixture was added water (20 mL) and the whole was extracted with ethyl acetate (50 mL×3). The extract was washed with saturated saline solution and then dried over anhydrous Na2SO4. The concentration of the solvent left a crystal residue, which was washed with ethyl ether (10 mL) to give the subject compound (760 mg).
Reaction SMILES: C(#N)C.[NH:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6]([C:13]#[N:14])=[N:5]1.C(=O)([O-])[O-].[K+].[K+].[F:21][C:22]([F:30])([F:29])[C:23]([F:28])([F:27])[CH2:24][CH2:25]I>CCOC(C)=O>[F:27][C:23]([F:28])([C:22]([F:30])([F:29])[F:21])[CH2:24][CH2:25][N:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6]([C:13]#[N:14])=[N:5]1
Reactant: N#Cc1n[nH]c2ncccc12
Reactant: FC(F)(F)C(F)(F)CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1nn(CCC(F)(F)C(F)(F)F)c2ncccc12
Temperature: 75 °C

Procedure:
An acetonitrile solution (150 mL) containing the intermediate from Step C above (10.5 g, 43.7 mmol), potassium carbonate (30.2 g, 219 mmol) and 1,1,1,2,2-pentafluoro-4-iodobutane (23.95 g, 87 mmol) was heated at 75° C. for 48 hours. The reaction solution was cooled to room temperature and diluted with EtOAc. The solution was washed with water, brine and concentrated in vacuo. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the title compound. 1H NMR (400 MHz, CH3CN-d3): δ 8.71 (dd, J=4.47, 1.51 Hz, 1H); 8.31 (dd, J=8.22, 1.52 Hz, 1H); 7.44 (dd, J=8.24, 4.48 Hz, 1H); 4.92 (t, J=6.98 Hz, 3H); 3.00-2.82 (m, 2H). m/z=291.0 (M+H).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([CH2:13][CH3:14])([CH2:11][CH3:12])[CH2:6][S:7]([NH2:10])(=[O:9])=[O:8].Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([N:22]=[CH:23][N:24]=2)[N:21]=1.Cl>CN(C)C=O.O>[CH2:11]([C:5]([CH2:13][CH3:14])([CH2:6][S:7](=[O:8])(=[O:9])[NH2:10])[CH2:4][O:3][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([N:22]=[CH:23][N:24]=2)[N:21]=1)[CH3:12]
Reactant: CCC(CC)(CO)CS(N)(=O)=O
Reactant: Clc1ccc2ncnn2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)(COc1ccc2ncnn2n1)CS(N)(=O)=O
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
In 20 ml of dimethylformamide was suspended 0.64 g of 60% sodium hydride in oil, followed by addition of 1.56 g of 3-hydroxy-2,2-diethyl-1-propanesulfonamide and the mixture was stirred under reduced pressure at room temperatue for 30 minutes. Then, 1.24 g of 6-chloro[1,2,4]triazolo[1,5-b]pyridazine was added and the mixture was further stirred at room temperature for 1.5 hours. Following addition of 100 ml of iced water, the reaction mixture was adjusted to pH 6 with 1N-hydrochloric acid and the resulting crystals were collected by filtration and washed with 20 ml of water and 20 ml of ethyl ether. The washed crystals were recrystallized from hot ethanol to provide 1.57 g of the title compound. m.p. 194°-197° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][CH2:23][NH:24][O:25][CH3:26])[CH:17]=[CH:18][C:19]=1[Cl:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][CH2:23][N:24]([O:25][CH3:26])[C:8](=[O:9])[CH:7]=[C:5]2[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CONCCCc1ccc(Cl)c(Cl)c1
Product: CON(CCCc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 95 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-[3-(3,4-dichlorophenyl)-propyl]-O-methyl-hydroxylamine as described in the preparation of compound 1-A gave the title amide as white crystals (95% yield): mp 105-106° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.91 (6H, s, CH3), 2.13 (2H, m, CH2), 2.77 (2H, t, J=7.9 Hz, CH2), 3.86 (2H, t, J=7.0 Hz, NCH2), 3.88 (3H, s, OCH3), 6.54 (1H, broad s, CH), 7.2 (H, broad dd, aromatic), 7.44 (1H, broad d, J=2 Hz, aromatic), 7.50 (1H, d, J=8.1 Hz, aromatic). Anal. calcd for C17H19Cl2NO5: C, 52.59; H, 4.93; N, 3.61. Found: C, 52.68; H, 5.08; N, 3.50.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[C:9]1([CH2:15][C:16](Cl)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN1C(=O)CCC1>[Cl:8][C:5]1[N:4]=[N:3][C:2]([NH:1][C:16](=[O:17])[CH2:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:6]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1ccc(Cl)nn1
Solvent: CN1CCCC1=O
Product: O=C(Cc1ccccc1)Nc1ccc(Cl)nn1
Temperature: 19 °C
Reaction time: 1.5 h
Yield: 88.3 %

Procedure:
To a solution of 3-amino-6-chloropyridazine (11.14 g, 86.0 mmol) in NMP (279 mL) at 19° C. was added phenylacetyl chloride (18.2 mL, 137.6 mmol) dropwise over 5 minutes with the internal temperature of the solution maintained Ti≦28° C. The resulting mixture was stirred at 19° C. for 90 minutes and poured into ice water (557 mL). The white precipitate was collected by suction filtration, rinsed with water (2×110 mL) and diethyl ether (110 mL). The product was dried overnight under high vacuum to afford N-(6-chloropyridazin-3-yl)-2-phenylacetamide (xxx, 18.8 g). 1H NMR (300 MHz, DMSO-d6) δ 11.57 (s, 1H), 8.40 (d, J=9.636 Hz, 1H), 7.90 (d, J=9.516 Hz, 1H), 7.36 (m, 5H) 3.82 (s, 2H)
Reaction SMILES: C([N:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH2:4][C:5]([OH:7])=[O:6])C.O.[OH-].[Li+].Cl>C1COCC1.O>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([NH:3][CH2:4][C:5]([OH:7])=[O:6])=[CH:13][CH:12]=1
Reactant: CCN(CC(=O)O)c1ccc(OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(NCC(=O)O)cc1
Reaction time: 15 h
Yield: 50.7 %

Procedure:
To a solution of 19.59 g (108 mmol) of ethyl N-(4-methoxyphenyl)glycine in 100 mL of THF under N2 was added 5.44 g (130 mmol) of lithium hydroxide monohydrate in 25 mL water. After 15 hours, the mixture was reduced to ½ the original volume in vacuo and then acidified with concentrated hydrochloric acid to ph 3 and a precipitate formed. The solid was collected and washed with 100 mL water, then dried in vacuo to give 9.92 g (51%) of the desired compound as a off-white solid. 1H NMR (CDCl3): δ6.68 (d, J=8.8, 2H); 6.49 (d, J=8.8, 2H); 3.73 (s, 2H); 3.64 (s, 3H); 2.49 (br s, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23]1>CCCCO>[Br:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:23]2)=[C:4]2[C:10]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1cccc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCCCO
Product: Cc1cccc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c23)c1
Temperature: 25 °C
Yield: 47.3 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylbenzamide (210 mg, 0.60 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (360 mg, 1.8 mmol) in n-BuOH (3 mL) was stirred at 155° C. in a sealed tube. The reaction was then cooled to room temperature and concentrated to dryness. The crude residue was purified by reverse phase HPLC to give (R)-tert-butyl 1-(5-bromo-3-(3-methylbenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (150 mg, 47% yield).
Reaction SMILES: [CH3:1][CH:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].OO>O1CCOCC1>[CH3:1][C:2](=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)O
Agent: OO
Solvent: C1COCCO1
Product: CCCCCCC(C)=O
Yield: 37 %

Procedure:
The reaction was carried out in the same manner as in Example 1, except that 2-octanol and an aqueous hydrogen peroxide solution were made into a homogenous phase by adding dioxane (10 ml) in advance, and 2-octanone was obtained in yield of 37%.
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[Br:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[C:10]([F:20])[C:9]([OH:21])=[C:8]([CH:22]=[O:23])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[C:10]([F:20])[C:9]([O:21][CH:2]([CH3:4])[CH3:3])=[C:8]([CH:22]=[O:23])[CH:7]=1
Reactant: O=Cc1cc(Br)c(-c2ccc(F)cc2F)c(F)c1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1c(C=O)cc(Br)c(-c2ccc(F)cc2F)c1F
Reaction time: 3 h
Yield: 94.5 %

Procedure:
2-Iodopropane (461 mg) was added at room temperature to a mixture of 6-bromo-2,2′,4′-trifluoro-3-hydroxybiphenyl-4-carbaldehyde (598 mg), potassium carbonate (499 mg), and DMF (10 mL), and the mixture was stirred at 60 C for 3 hours in a nitrogen atmosphere. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was separated, then 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 purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (637 mg).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:38]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:18]3[N:19]=[CH:20][N:21]=[C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH:34]5[CH2:36][CH2:35]5)=[O:32])=[C:26]([F:37])[CH:25]=4)[C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.O1CCCC1.[Pt]=O>[CH:34]1([NH:33][C:31]([NH:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][C:22]3[C:17]4[CH:16]=[C:15]([C:12]5[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=5)[N:38]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:45])([CH3:44])[CH3:46])[C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:25][C:26]=2[F:37])=[O:32])[CH2:36][CH2:35]1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Oc3ccc(NC(=O)NC4CC4)c(F)c3)ncnc21
Agent: O=[Pt]
Solvent: C1CCOC1
Solvent: CCO
Product: C[Si](C)(C)CCOCn1c(-c2ccc(O)cc2)cc2c(Oc3ccc(NC(=O)NC4CC4)c(F)c3)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
After dissolving 263 mg of 1-(4-(6-(4-benzyloxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-2-fluorophenyl)-3-cyclopropylurea in 7 ml of ethanol and 3 ml of tetrahydrofuran, 30 mg of platinum oxide was added and the mixture was stirred overnight at room temperature and ordinary pressure under a hydrogen atmosphere, after which it was filtered with celite and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate) to obtain 160 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.Br[CH2:28][C:29]([O:31][CH2:32][CH2:33][CH3:34])=[O:30]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][CH2:28][C:29]([O:31][CH2:32][CH2:33][CH3:34])=[O:30])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: CCCOC(=O)CBr
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Product: CCCOC(=O)COc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Yield: 55 %

Procedure:
The procedure of Example 3 was repeated by using 10-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (250 mg) and n-propyl bromoacetate (0.1 ml) to obtain the title compound (170 mg, 55%).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([NH:13][CH2:14][CH2:15][N:16]2[CH:21]=[C:20]([CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:35])=[O:12])[CH:6]=1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[C:23]1([CH:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:20]2[CH:19]=[CH:18][C:17](=[O:35])[N:16]([CH2:15][CH2:14][NH:13][C:11](=[O:12])[C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([OH:4])[CH:6]=3)[CH:21]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(=O)Oc1cccc(C(=O)NCCn2cc(C(c3ccccc3)c3ccccc3)ccc2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(NCCn1cc(C(c2ccccc2)c2ccccc2)ccc1=O)c1cccc(O)c1
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
To a solution of 3-[({2-[5-(diphenylmethyl)-2-oxo-1(2H)-pyridinyl]ethyl}amino)carbonyl]phenyl acetate (77.0 mg) in MeOH (2.3 mL) was added portionwise K2CO3 (68.4 mg) at ambient temperature and the mixture was stirred at the same temperature for 15 minutes. The resulting mixture was diluted with water (5.0 mL) and the aqueous solution was extracted with EtOAc (10.0 mL). The organic layer was washed successively with 1M HCl aqueous solution, saturated NaHCO3 aqueous solution and brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo to give N-{2-[5-(diphenylmethyl)-2-oxo-1(2H)-pyridinyl]ethyl}-3-hydroxybenzamide (70 mg) as a off-white amorphous powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cu][C:22]#[N:23]>CN1CCCC1=O>[C:22]([C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])#[N:23]
Reactant: CCCN(CCC)C(=O)c1cc(Br)cc(C(=O)OC)c1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: CCCN(CCC)C(=O)c1cc(C#N)cc(C(=O)OC)c1

Procedure:
Methyl 3-bromo-5-[(dipropylamino)carbonyl]benzoate (Preparation 3) (0.15 g), copper (I) cyanide, and N-methylpyrrolidinone (1 mL) was heated at 150° C. overnight, at which time the mixture was cooled and partitioned between ethyl acetate and aq. HCl (1N). The organic layer was dried (magnesium sulfate), concentrated under reduced pressure, and the residue was chromatographed on silica gel using ethyl acetate-hexane (20/80) to give 0.066 g of the desired product. ms (m+H) 289.2. See also preparation 7 for the preparation of the acid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([Br:42])[C:38]2=[N:43][C:35]3=[C:36](Br)[N:37]2[C:12]=1[N:13]1[CH2:49][CH2:48][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[C:25]([F:46])=[CH:26][CH:27]=[CH:28][C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CN(C=O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:42][C:39]1[C:38]2=[N:43][C:35]3=[CH:36][N:37]2[C:12]([N:13]2[CH2:14][CH2:15][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]4[C:25]([F:46])=[CH:26][CH:27]=[CH:28][C:29]=4[C:30]4[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=4)[CH2:48][CH2:49]2)=[C:11]([C@H:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([O:9][CH3:10])=[O:8])[C:40]=1[CH3:41]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(Br)c2nc3c(Br)n2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1c(F)cccc1-c1cccc-3c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(Br)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1c(F)cccc1-c1cccc-3c1
Temperature: 40 °C
Yield: 59.4 %

Procedure:
Methyl(2S)-2-(tert-butoxy)-2-[(22S)-5,8-dibromo-19-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (0.13 g, 0.16 mmol, 1.0 equiv) and ammonium formate (0.101 g, 1.6 mmol, 10.0 equiv) were dissolved in DMF (3.19 mL). To this solution was added tetrakis (0.018 g, 0.016 mmol, 0.1 equiv). The mixture was heated at 40° C. overnight. Then it was diluted with ethyl acetate, washed by NaHCO3, dried over MgSO4, concentrated and purified by flash column (24 g, 0-100% EtOAc[2% TEA]/Hex) to afford the product (70 mg, 59.6%). LCMS (ESI, M+1): 736.3.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:18](Br)([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:19][CH:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1)[CH3:20]
Reactant: O=S(=O)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(S(=O)(=O)c2ccc(O)cc2)cc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 44.4 %

Procedure:
30.3 g of bis(p-hydroxyphenyl)sulfone, 18.5 g of isopropylbromide, and 22.2 g of potassium carbonate as acid-binding agent were added to 200 ml of dimethylformamide, then stirred for 4 hours at about 120° C. and dimethylformamide was distilled off under reduced pressure. When this was accomplished, chloroform was added to the residue to extract crude 4-hydroxy-4'-isopropoxydiphenylsulfone. Then this crude compound was refined by using a silica gel column chromatography and 15.7 g of 4-hydroxy-4'-isopropoxydiphenylsulfone was obtained in white microfine crystals with a melting point of 129.0°~131.0° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[NH2:13].CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH2:1]([NH:13][C:12]1[CH:11]=[C:10]([Cl:9])[CH:16]=[C:15]([Cl:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1cc(Cl)cc(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Clc1cc(Cl)cc(NCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.3 h

Procedure:
A mixture of benzaldehyde (1.04 g, 9.40 mmol), 3,5-dichloroaniline (1.71 g, 10.60 mmol), and HOAc (0.20 mL) in MeOH (35 mL) was cooled to 0° C. Then a solution of NaBH3CN (28.0 mL, 28.0 mmol, 1.0 M solution in THF) was added dropwise via a syringe pump over 0.25 h. The solution was allowed to stir an additional 0.3 h at 0° C., and then room temperature for 18 h. The excess NaBH3CN was quenched with HCl and the solvent was removed under reduced pressure. The resulting oil was dissolved in EtOAc/H2O, basified with NaOH, and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent removed under reduced pressure. The resulting oil was purified by chromatography (SiO2, 15:1 hexanes/EtOAc) to provide N-benzyl-3,5-dichloroaniline as a white solid. This compound was coupled to 2-chloro-4-trifluoromethylpyrimidine-5-carbonyl chloride as described and purified by chromatography (SiO2, 9:1 hexanes/EtOAc) to provide the title compound (15% yield) as a white foam; m.p. 102°-104° C.
Reaction SMILES: C(OC(=O)C)(=O)C.NCC[N:11]1[C:15](=[O:16])[CH:14](CCCCCCCCC)[S:13][CH:12]1[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[N:28]1[CH:29]=[CH:30][CH:31]=[C:26]([CH:12]2[NH:11][C:15](=[O:16])[CH2:14][S:13]2)[CH:27]=1
Reactant: CCCCCCCCCC1SC(c2cccnc2)N(CCN)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: O=C1CSC(c2cccnc2)N1
Reaction time: 8 h
Yield: 201.8 %

Procedure:
Acetic anhydride (0.2 g) was added dropwise to a solution of 3-(2-aminoethyl)-5-(n-nonyl)-2-(3-pyridyl)thiazolidin-4-one (0.50 g, 1.43 mmol) in pyridine (2 ml) with stirring under cooling with ice. The mixture was left standing overnight at room temperature. To this solution was added saturated aqueous NaHCO3 (30 ml), and the mixture was extracted with benzene. After drying of the extract, the solvent was removed therefrom by evaporation under reduced pressure, giving the intended 3-(2-acetylam:inoethyl)-5-(n-nonyl)- ,2-(3-pyridyl)thiazolidin-4-one (0.52 g, 92% yield) in oily form.