Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:37])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=3[O:31][CH2:32][CH:33]([OH:36])[CH2:34][OH:35])[C:5]2=[CH:4][CH:3]=1.[CH3:38][Si:39]([C:42]#[CH:43])([CH3:41])[CH3:40].CCN(CC)CC>CN(C=O)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>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:37])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:43]#[C:42][Si:39]([CH3:41])([CH3:40])[CH3:38])[CH:27]=[CH:26][C:25]=3[O:31][CH2:32][CH:33]([OH:36])[CH2:34][OH:35])[C:5]2=[CH:4][CH:3]=1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2OCC(O)CO)N1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(OCC(O)CO)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Temperature: 75 °C

Procedure:
To a stirred solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2,3-dihydroxy-propoxy)-5-iodo-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′-dione (120 mg, 0.183 mmol) in DMF (2 mL) were added PdCl2(PPh3)2 (15 mg), CuI (2 mg), trimethylsilyl acetylene (Aldrich, 2 mL) and Et3N (Aldrich, 2 mL) and the mixture was purged with nitrogen and then heated at 75° C. for 3 hrs. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried, and concentrated. The residue was purified by chromatography (0-4% MeOH in EtOAc). Yield 8 mg. MS (H+), 623
Reaction SMILES: C(C1(C)N=[C:7]([CH2:9][CH3:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)C.N1C=CCNC1.C(=O)([O-])[O-:22].[Na+].[Na+]>Cl>[NH2:4][C:5]([CH3:11])([CH2:12][CH3:13])[CH2:6][C:7](=[O:22])[CH2:9][CH3:10]
Reactant: CCC1=NC(C)(CC)NC(C)(CC)C1
Reactant: O=C([O-])[O-]
Agent: C1=CNCNC1
Agent: Cl
Agent: [Na+]
Product: CCC(=O)CC(C)(N)CC

Procedure:
196.3 g of 2,4,6-triethyl-2,6-dimethyl-1,2,5,6-tetrahydropyrimidine were added dropwise to 300 ml of concentrated hydrochloric acid at 30°-40° C., with stirring. When all of the tetrahydropyrimidine had been added, the entire mixture was stirred for 4-5 hours and then neutralized with sodium carbonate and extracted with benzene. The resulting benzene solution was washed, in turn, with a 5% aqueous solution of sodium carbonate and with water, and was then dried over potassium carbonate. After removing the benzene, the residue was distilled under reduced pressure, giving 72.4 g of 5-amino-5-methyl-3-heptanone (bp 46°-48° C./2.5 mmHg).
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10]1.O.S(=O)(=O)(O)O>CC(O)C>[CH2:11]1[C:10]2[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[NH:7][C:9]=2[CH2:13][CH2:12]1
Reactant: NNc1ccccc1
Reactant: O=C1CCCC1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: c1ccc2c3c([nH]c2c1)CCC3
Temperature: 20 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
A solution of phenylhydrazine (32.44 g, 300 mmol) in 2-propanol (300 mL) was treated with cyclopentanone (27 mL, 25.7 g, 305 mmol). The solution was stirred at 20° C. for 1 h and poured onto mixture of ice (900 g) and water (300 mL). The chilled mixture was stirred until the ice had melted then filtered. The filter-cake was washed with water (2×300 mL) an the resultant damp solid (85 g) was added to water (540 mL). The stirred suspension was treated with concentrated sulfuric acid (33 mL, 61 g, 600 mmol) then heated under reflux for 30 min, cooled to 0° C. and stirred for 15 min. The dark red solid was filtered off, washed with water (2×60 mL) and air-dried for 18 h. The crude product was added to dichloromethane (300 mL), stirred for 30 min then filtered, washing with dichloromethane (100 mL). The filtrate was treated with silica (48 g), stirred for 1 h, filtered and washed with dichloromethane (400 mL). The filtrate was concentrated to give a solid, which was triturated with hexane to give 1,2,3,4-tetrahydrocyclopent[b]indole (30 g, 65%) as a pink solid. Analytical data for 1,2,3,4-tetrahydrocyclopent[b]indole are included in Table 3 below.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:60][CH:61]=[CH:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1.FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:60][CH:61]=[CH:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: N=C(OCC=Cc1ccccc1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccccc4)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (100 mg in 3 ml 33% methylene chloride in cyclohexane), cinnamyl trichloroacetimidate (54 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 30 minutes the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×8 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (45 mg).
Reaction SMILES: [CH2:1]1[CH:8]2[C:4]3([C:10]([OH:12])=[O:11])[CH2:5][CH:6]([CH2:9][CH:2]1[CH2:3]3)[CH2:7]2.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[N:28]1[CH:33]=[CH:32][CH:31]=[N:30][C:29]=1[N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][CH2:42]O)[CH2:36][CH2:35]1>C(Cl)(Cl)Cl>[N:28]1[CH:33]=[CH:32][CH:31]=[N:30][C:29]=1[N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][CH2:42][O:11][C:10]([C:4]23[CH2:5][CH:6]4[CH2:9][CH:2]([CH2:1][CH:8]2[CH2:7]4)[CH2:3]3)=[O:12])[CH2:36][CH2:35]1
Reactant: OCCCN1CCN(c2ncccn2)CC1
Reactant: O=C(O)C12CC3CC(CC1C3)C2
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: ClC(Cl)Cl
Product: O=C(OCCCN1CCN(c2ncccn2)CC1)C12CC3CC(CC1C3)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To stirred solution of hexahydro-2,5-methanopentalene-3a[1H]-carboxylic acid (0.6 g, 3.6×10-3 mol) in 25 ml of chloroform under a dry nitrogen atmosphere was added carbonyldiimidazole (0.58 g, 3.6×10-3 mol). The resulting solution was stirred at ambient temperature for three hours, during which time a gas (CO2) was evolved. A solution of 3-[1-(2-pyrimidyl)-4-piperazinyl]propanol (0.80 g, 3.6×10-3 mol) in 25 ml of chloroform was then added, and the resulting reaction mixture was stirred under nitrogen at ambient temperature for two days. The mixture was diluted to 150 ml with chloroform, washed with three-one hundred ml portions of water, dried over anhydrous sodium sulfate, and concentrated on a rotary evaporator. The desired product (TLC on silica using a 30% methanol in ethyl acetate solvent system, Rf=0.48) was isolated by gravity chromatography on silica gel and converted to the hydrochloride salt with isopropanolic HCl (0.79 g, 51% yield), mp.=231°-232° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C(N(CC)CC)C.[CH3:16][O:17][C:18](=[O:23])[CH2:19][C:20](Cl)=O>C(OCC)C>[CH3:16][O:17][C:18](=[O:23])[CH2:19][C:20]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: COC(=O)CC(=O)Cl
Reactant: Nc1ccccc1S
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)Cc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
3.2 mL (30 mmol) 2-Amino-thiophenol are dissolved in 100 mL diethylether and treated with 4.17 mL (1 eq.) triethylamine to yield a suspension, to which 3.21 mL (1 eq.) chlorocarbonyl-acetic methyl ester in 10 mL diethylether is added dropwise within 20 min. The resulting suspension is stirred and additional 2 h at room temperature, and the precipitate removed by filtration. The filtrate is evaporated and column chromatographed (silica gel, ethyl acetate/petroleum ether 1:2) to yield the desired product as a yellowish liquid (5.1 g, 82%).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[CH2:28][C:29](O)=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32]1([N:38]=C=NC2CCCCC2)CCCCC1.C1COCC1.CN>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[CH2:28][C:29]([NH:38][CH3:32])=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: COc1ccc(N2CCN(CC(=O)O)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Agent: CN
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)CN1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Reaction time: 16 h
Yield: 29.3 %

Procedure:
A solution of [(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetic acid (21.2 mg, 0.05 mmol) in CH2Cl2 (0.5 mL) at 0° C. was treated with catalytic 4-dimethylaminopyridine (DMAP) (˜1 mg) and N,N′-dicyclohexylcarbodiimide (DCC) (11.3 mg, 0.055 mmol) followed 5 min later by a 2 M THF solution of methylamine (30 μL, 0.06 mmol). The reaction mixture was stirred for 16 h, evaporated, and purified by silica gel flash chromatography with 50% EtOAc/hexane, then 100% EtOAc, then 5% MeOH/EtOAc as eluant to afford the title compound as an oil (6.4 mg, 29%). LC/MS (Method A) 5.09 min, [M+1]+ 438.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[O:19]([C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[C:22]=1[C:23](Cl)=[O:24])[CH3:20].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[O:19]([C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[C:22]=1[C:23]([N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][N:14]=2)[C:10]([C:7]2[CH2:8][CH:9]3[N:4]([CH2:3][CH2:2][CH2:1]3)[CH2:5][CH:6]=2)=[CH:11]1)=[O:24])[CH3:20]
Reactant: C1=C(c2c[nH]c3ncccc23)CC2CCCN2C1
Reactant: COc1cccc(OC)c1C(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(OC)c1C(=O)n1cc(C2=CCN3CCCC3C2)c2cccnc21

Procedure:
from 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-7-Azaindole (10 mg, 0.0418 mmol), 2,6-dimethoxylbenzoyl chloride (20 mg, 0.0997 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (1 mL) at RT.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([CH:18]=O)=[CH:13][C:12]=3[CH:20]=2)=[CH:4][CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]([NH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C>ClCCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([CH2:18][N:29]4[CH2:30][CH2:31][CH:26]([NH:25][C:23](=[O:24])[C:22]([F:21])([F:32])[F:33])[CH2:27][CH2:28]4)=[CH:13][C:12]=3[CH:20]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C=O)CCO3)cc1
Reactant: O=C(NC1CCNCC1)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(CN2CCC(NC(=O)C(F)(F)F)CC2)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carbaldehyde (2.0 g) and 4-trifluoroacetamidopiperidine (1.56 g) dissolved in 1,2-dichloroethane (50 ml) was added under ice cooling sodium triacetoxyborohydride (1.8 g), and the resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. Thereto were added triethylamine (1.1 ml) and sodium triacetoxyborohydride (0.8 g), and the resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was evaporated to remove the solvent, was neutralized with a 1 N aqueous solution of sodium hydrogen carbonate and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and then was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain crude crystals (3.0 g). A portion of the crystals was recrystallized from ethyl acetate/hexane to obtain 1-(7-(4-methylphenyl)-2,3-dihydro-1-benzooxepin-4-ylmethy)-4-trifluoroacetamidopiperidine as light yellow crystals.
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:16])[NH:10][NH:11][C:12]=1[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>O1CCCC1.C(O)(=O)C>[C:17]([N:11]1[C:12]([CH:13]([CH3:14])[CH3:15])=[C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9](=[O:16])[NH:10]1)(=[O:19])[CH3:18]
Reactant: CC(C)c1[nH][nH]c(=O)c1Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)n1[nH]c(=O)c(Cc2ccccc2)c1C(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 77 %

Procedure:
4-Benzyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one (1.50 g) was dissolved in tetrahydrofuran (6.0 g) at room temperature. Acetic anhydride (0.708 g) and acetic acid (0.0208 g) was added to the solution successively. After the reaction mixture was stirred at room temperature for 15 hours, the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (The product was eluted with dichloromethane at first, and then n-hexane/ethyl acetate=4/1) to give 1-acetyl-4-benzyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one (1.38 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:30][CH2:31][O:32][CH3:33])=[CH:4][C:5]([O:26][CH2:27][O:28][CH3:29])=[C:6]([C:8]2[N:9]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[C:10](=[S:13])[NH:11][N:12]=2)[CH:7]=1.[C:34](=O)([O-])[O-].[K+].[K+].CI>C(O)C>[Br:1][C:2]1[C:3]([O:30][CH2:31][O:32][CH3:33])=[CH:4][C:5]([O:26][CH2:27][O:28][CH3:29])=[C:6]([C:8]2[N:9]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[C:10]([S:13][CH3:34])=[N:11][N:12]=2)[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COCOc1cc(OCOC)c(-c2n[nH]c(=S)n2-c2ccc(N3CCOCC3)cc2)cc1Br
Agent: [K+]
Solvent: CCO
Solvent: CI
Product: COCOc1cc(OCOC)c(-c2nnc(SC)n2-c2ccc(N3CCOCC3)cc2)cc1Br

Procedure:
5-(5-bromo-2,4-bis-methoxymethoxy-phenyl)-4-[4-(morpholin-4-yl)-phenyl]-2,4-dihydro-[1,2,4]triazol-3-thione (Example 1-5, IM6-S-d01: 54 mg, 0.1 mmol), potassium carbonate (13.8 mg, 0.17 mmol) and ethanol (5 mL) were placed in a test tube, and then methyl iodide (14.2 mg, 0.1 mmol) was added, and the mixture was heated for 2 hours under reflux. After completing the reaction, potassium carbonate was removed by filtration, and the mother liquor was concentrated. The crude product (IM6-SMe-d01) thus obtained was subjected to the next reaction without further purification in particular.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])[CH3:4].O1CCOCC1>C(Cl)(Cl)Cl>[Br:1][CH2:4][C:3]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)=[O:5]
Reactant: BrBr
Reactant: CC(=O)c1ccco1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccco1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.3 %

Procedure:
Bromine (71.14 ml, 1.39 mol) is added dropwise over 1 hour to a solution of 117.59 g (1.07 mol) of 2-acetylfuran (1) in a mixture of 900 ml of either and 400 ml of 1,4-dioxane, at 0° C. under a nitrogen atmosphere. The reaction is warmed to ambient temperature and stirred for 18 hours, then quenched with 1.1 liter of saturated aqueous ammonium chloride and extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo to give a dark oil. Flash-chromatography on neutral silica gel using chloroform as eluent followed by distillation using a Kugelruhr apparatus gives 190.81 g (94%) of compound 2 as a light yellow oil, boiling point 85° C. (0.30 mmHg).
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH2:16][CH2:17][OH:18])[CH:13]=[C:12]([CH2:19]N(CC)CC)[C:11]=2[OH:25])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[N:26]1[N:27]([C:35]2[CH:40]=[C:39]([CH2:41][CH2:42][OH:43])[CH:38]=[CH:37][C:36]=2[OH:44])[N:28]=[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=12.CO.C[O-].[Na+]>C1(C)C(C)=CC=CC=1>[CH2:19]([C:12]1[CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[CH:15]=[C:10]([N:2]2[N:3]=[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]3=[N:1]2)[C:11]=1[OH:25])[C:37]1[CH:38]=[C:39]([CH2:41][CH2:42][OH:43])[CH:40]=[C:35]([N:27]2[N:28]=[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]3=[N:26]2)[C:36]=1[OH:44]
Reactant: OCCc1ccc(O)c(-n2nc3ccccc3n2)c1
Reactant: CCN(CC)Cc1cc(CCO)cc(-n2nc3ccccc3n2)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CO
Product: OCCc1cc(Cc2cc(CCO)cc(-n3nc4ccccc4n3)c2O)c(O)c(-n2nc3ccccc3n2)c1
Temperature: 25 °C
Yield: 54 %

Procedure:
In 100 ml of xylene were dissolved 34.7 g of crude 2-(2H-benzotriazole-2-yl)-4-(2-hydroxyethyl)-6-(N,N-diethylaminomethyl)phenol synthesized in Example 9 and 25.5 g (0.1 mols) of the purified product of 2-(2H-benzotriazole-2-yl)-4-(2-hydroxyethyl)phenol synthesized in Example 6. 5 ml of methanol solution of 28% sodium methylate was added, and the mixture was refluxed in a nitrogen stream for 10 hours. After completion of the reaction, the reaction mixture was cooled to room temperature. Precipitated yellow crystals were collected by filtration and recrystallized in chloroform, giving 28.5 g of 2,2'-methylenebis[6-(2H-benzotriazole-2-yl)-4-(2-hydroxyethyl)phenol] as white crystals (yield 54%, purity 98.9%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:20][C:21]([C:23]4([O:28][CH3:29])[CH2:27][CH2:26][NH:25][CH2:24]4)=[O:22])[CH:18]=3)[NH:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl[CH2:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[N:51]=[CH:50][CH:49]=[CH:48][N:47]=3)=[C:42]([F:52])[CH:41]=2)[CH2:36][CH2:35]1)=[O:33].C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:20][C:21]([C:23]4([O:28][CH3:29])[CH2:27][CH2:26][N:25]([CH2:31][C:32]([N:34]5[CH2:39][CH2:38][N:37]([C:40]6[CH:45]=[CH:44][C:43]([C:46]7[N:47]=[CH:48][CH:49]=[CH:50][N:51]=7)=[C:42]([F:52])[CH:41]=6)[CH2:36][CH2:35]5)=[O:33])[CH2:24]4)=[O:22])[CH:18]=3)[NH:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: O=C(CCl)N1CCN(c2ccc(-c3ncccn3)c(F)c2)CC1
Reactant: COC1(C(=O)Nc2ccc3[nH]nc(-c4ccc(OC(C)C)cc4)c3c2)CCNC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC1(C(=O)Nc2ccc3[nH]nc(-c4ccc(OC(C)C)cc4)c3c2)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)c(F)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methoxy-pyrrolidine-3-carboxylic acid [3-(4-isopropoxy-phenyl)-1H-indazol-5-yl]-amide (8AB) (40 mg, 0.086 mmol, 1 equiv) and 2-Chloro-1-[4-(3-fluoro-4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethanone (7AB) (35 mg, 0.103 mmol, 1.2 equiv) were weighed out in a flask, and to it was added N,N-dimethylformamide (3 mL) and diisopropylethylamine (22 mg, 30 uL, 0.172 mmol, 2 equiv). The reaction content was stirred at room temperature, overnight.
Reaction SMILES: I[C:2]1[C:7]([N:8]([CH3:15])[C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[C:6]([I:16])[N:5]=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:32]=[CH:31][C:21]([O:22][C:23]2[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=2)[C:26]#[N:27])=[C:20]([Cl:33])[CH:19]=1.C(=O)([O-])O.[Na+]>CN1CCCC1=O>[Cl:33][C:20]1[CH:19]=[C:18]([NH:17][C:2]2[C:7]([N:8]([CH3:15])[C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[C:6]([I:16])[N:5]=[CH:4][N:3]=2)[CH:32]=[CH:31][C:21]=1[O:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:25]([C:26]#[N:27])[CH:24]=1
Reactant: N#Cc1cccc(Oc2ccc(N)cc2Cl)c1
Reactant: CN(C(=O)C(F)(F)F)c1c(I)ncnc1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CN(C(=O)C(F)(F)F)c1c(I)ncnc1Nc1ccc(Oc2cccc(C#N)c2)c(Cl)c1
Temperature: 100 °C
Yield: 44.3 %

Procedure:
N-(4,6-Diiodopyrimidin-5-yl)-2,2,2-trifluoro-N-methylacetamide (3 g) and 3-(4-amino-2-chlorophenoxy)benzonitrile (1.69 g) were dissolved in 1-methyl-2-pyrrolidone (11.4 mL), and the mixture was stirred with heating at 100° C. for 16 hrs. To the reaction mixture was added aqueous sodium hydrogen carbonate (80 mL) and the mixture was extracted with ethyl acetate (100 mL×2). The organic layer washed with saturated brine (80 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=90:10→hexane:ethyl acetate=50:50) and crystallized from diisopropyl ether to give the title compound (1.67 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[S:10]1[CH2:16][C:14](=[O:15])[NH:13][C:11]1=S.CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:11]1[S:10][CH2:16][C:14](=[O:15])[N:13]=1
Reactant: NCc1ccccc1Cl
Reactant: O=C1CSC(=S)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1CSC(NCc2ccccc2Cl)=N1
Temperature: 0 °C
Reaction time: 72 h
Yield: 10.4 %

Procedure:
To a suspension of 2-chlorobenzylamine (7.88 g, 55 mmol) and Rhodanine (6.65 g, 50 mmol) in acetonitrile (150 mL) was added DIPEA (19.15 mL, 110 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (13.5 g, 50 mmol) was added in three portions within a period of 15 min. After addition, the suspension was allowed to warm to room temperature and stirred for 3 days. The resulting black solids were filtered through a plug of celite and washed with dichloromethane (1 L) and methanol (500 mL). The combined solvents were removed under the vacuum and the crude residue was diluted with water (150 mL) and ethyl acetate (150 mL). After shaking, lot of solids formed which was collected by filtration to obtain 1.25 g of the desired product. Then, the two layers were separated and the ethyl acetate layer was washed with brine solution and dried over anhydrous magnesium sulfate. After filtration, the ethyl acetate solution was removed partially and then it was stored in the refrigerator. The resulting solids were collected by filtration to afford 2.67 g of the desired product. Then, the aqueous layer was extracted with dichloromethane (2×150 mL). The dichloromethane extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the crude residue which was purified by using a Biotage (40 m) silica gel column chromatography to obtain 4.2 g (total product 8.12 g, 67.5% yield) of 2-(2-chlorobenzylamino)-thiazol-4-one as a white amorphous solid: EI-HRMS m/e calcd for C10H9ClN2OS (M+) 240.0124. found 240.0122.