Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH:16](=O)[CH:17]([CH3:19])[CH3:18].CNC>C(O)(C)C>[CH3:18][C:17]([CH3:19])=[CH:16][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:15])=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: CC(C)C=O
Agent: CNC
Solvent: CC(C)O
Product: CC(C)=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Yield: 71 %

Procedure:
2,6-di-tertiary-butyl phenol (4.1 g; 20 mmol), isobutyraldehyde (3 ml; 33 mmol), dimethylamine (1.5 g; 34 mmol) dissolved in isopropanol (7.5 g) were charged to a 100 ml glass vessel and refluxed at ambient pressure under nitrogen for 48 hours. The resultant reaction mixture was allowed to cool to ambient temperature and concentrated to a yellow oil which was recrystallized from a mixture of ethanol and water (90:10) to give yellow crystals (3.7 g; 71% yield) of 1,1-dimethyl-2-(3',5'-di-t-butyl-4'-hydroxyphenyl)ethene as characterized by VPC, mass spectroscopy and NMR.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.Cl.ON1C2N=CC=CC=2N=N1.ClCCl.[Br:46][C:47]1[CH:53]=[CH:52][C:50]([NH2:51])=[CH:49][CH:48]=1.C(N(CC)C(C)C)(C)C>>[Br:46][C:47]1[CH:53]=[CH:52][C:50]([NH:51][C:16](=[O:17])[C:15]2[CH:14]=[CH:13][C:12]([N:9]3[CH2:10][CH2:11][N:6]([C:4]([CH:1]4[CH2:2][CH2:3]4)=[O:5])[CH2:7][CH2:8]3)=[CH:20][CH:19]=2)=[CH:49][CH:48]=1
Reactant: O=C(O)c1ccc(N2CCN(C(=O)C3CC3)CC2)cc1
Reactant: Nc1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(Br)cc1)c1ccc(N2CCN(C(=O)C3CC3)CC2)cc1
Reaction time: 48 h

Procedure:
A solution of 4-(4-cyclopropanecarbonyl-piperazin-1-yl)-benzoic acid (1.0 g, 3.6 mmol) and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.70 g, 3.6 mmol) and 1-hydroxy-7-azabenzotriazole (0.50 g, 3.6 mmol) in dichloromethane (39 mL, 610 mmol) was stirred for 20 min at room temperature and then p-bromoaniline (0.52 g, 3.0 mmol) and N,N-diisopropylethylamine (2.6 mL, 15 mmol) were added and the reaction mixture was stirred for 2 days. The reaction mixture was filtered; the filtrate was dissolved in 1:1 acetic acid:water (8 mL). A precipitate formed. This material was filtered to provide the title product as the acetic acid salt (225 mg). (m/z): [M+H]+ calcd for C21H22BrN3O2 428.09 found 428.0.
Reaction SMILES: Cl[C:2]1[CH:34]=[CH:33][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([CH3:25])[CH3:24])[C:10]=3[OH:32])[N:8]=[C:4]2[CH:3]=1.CN1CCCC1=O.[OH-].[K+].[C:44]1([SH:50])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O>[C:44]1([S:50][C:2]2[CH:34]=[CH:33][C:5]3=[N:6][N:7]([C:9]4[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)([CH3:25])[CH3:24])[C:10]=4[OH:32])[N:8]=[C:4]3[CH:3]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: Sc1ccccc1
Reactant: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(Sc4ccccc4)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Temperature: 90 °C
Yield: 94.7 %

Procedure:
To a stirred mixture of 75 g of 5-chloro-2-(2-hydroxy-3-α-cumyl-5-tert-octylphenyl)-2H-benzotriazole and 105 g of N-methylpyrrolidone heated at 90° C. is added first 44.3 g of 45% aqueous potassium hydroxide solution over a 15-minute period then 20.4 g of thiophenol over another 15 minutes. The reaction mixture is then heated at 170-175° C. for four hours with water being removed by distillation. After cooling to 100° C., xylene and water are added and the resultant mixture is made acidic with 15% aqueous hydrogen chloride solution. The organic layer is separated and washed with water and then concentrated. The crude product residue is recrystallized from methanol to yield 82 g of the title compound as a pale yellow solid melting at 124-125° C.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:17])[NH:15][NH2:16])=[N:6]1.[F:22][C:23]([CH3:36])([C:29](=O)[C:30](OCC)=[O:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(O)C>[F:22][C:23]([C:29]1[N:16]=[N:15][C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=3[F:1])[N:6]=2)=[N:17][C:30]=1[OH:31])([CH3:36])[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C(=O)C(C)(F)C(=O)OCC
Reactant: N=C(NN)c1nn(Cc2ccccc2F)c2ncccc12
Solvent: CCO
Product: CCOC(=O)C(C)(F)c1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.000 g (purity 67%, approx. 2.357 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidohydrazide in 15 ml of absolute ethanol were initially introduced and admixed with 1.557 g (7.070 mmol) of diethyl 2-fluoro-2-methyl-3-oxobutanedioate (described in J. Med. Chem. 1966, 9, 149-151). The mixture was stirred at RT overnight and then concentrated. The residue was purified by preparative HPLC (mobile phase: methanol/water, gradient 30:70→95:5). This gave 230 mg of the target compound (purity 95%; 21% of theory).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:19][NH:20][CH3:21].Cl>>[CH3:19][N:20]([CH3:21])[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCCOc1ccccc1C=Cc1ccccc1
Reactant: CNC
Agent: Cl
Product: CN(C)CCOc1ccccc1C=Cc1ccccc1

Procedure:
2-(β-Dimethylamino-ethoxy)-stilbene was prepared from 2-(β-chloro-ethoxy)-stilbene and dimethylamine, and the free base was converted into its hydrochloride, yielding 45% of theory of the compound of the formula ##STR14## which had a melting point of 199° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4](I)[CH:3]=1.[Cu](C#N)[C:11]#[N:12]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:3]=1)[C:11]#[N:12]
Reactant: N#C[Cu]C#N
Reactant: Oc1ccc(Cl)cc1I
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)ccc1O
Yield: 79.7 %

Procedure:
2-Amino-4-chlorophenol (50 g, 0.35 mol) was dissolved in 500 ml of 2.5N HCl. The resulting solution was cooled to 0° C., at which a solution of 25.25 g (0.37 mol) of sodium nitrite in 50 ml of water was added slowly. After stirring for 30 minutes, a chilled solution of 70 g (0.42 mol) of potassium iodide in 100 ml of water was added slowly. The temperature of the reaction mixture was allowed to rise to room temperature, at which the reaction mixture was stirred overnight. The reaction mixture was extracted with ethyl acetate and the solvent was distilled off under reduced pressure, whereby 89.7 g of 4-chloro-2-iodophenol were obtained (yield: 99%). Next, 85 g (0.33 mol) of the 4-chloro-2-iodophenol and 32.5 g (0.36 mol) of copper cyanide were dissolved in 150 ml of DMF. After the resultant solution was heated under reflux for 2 hours, the DMF was distilled off under reduced pressure. The residue was extracted with ethyl acetate and the extract was then washed with water. An insoluble matter was filtered off. The solvent was then distilled off under reduced pressure, whereby 40.4 g of 5-chloro-2-hydroxybenzonitrile were obtained (yield: 80%) (melting point: 150.3-152.6° C.).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)[N:10]=[N:9][C:8]=1[C:23]([NH:25][CH:26]1[CH2:28][CH2:27]1)=[O:24])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[F:35][CH:36]([F:39])[CH2:37]O>C(#N)C.C(OCC)(=O)C>[CH:26]1([NH:25][C:23]([C:8]2[N:9]=[N:10][N:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=3)[C:7]=2[CH2:6][O:5][CH2:37][CH:36]([F:39])[F:35])=[O:24])[CH2:28][CH2:27]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COS(C)(=O)=O)cc1
Reactant: OCC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COCC(F)F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
(4-[(Cyclopropylamino)carbonyl]-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazol-5-yl)methyl methanesulfonate (204 mg, 0.5 mmol) obtained in Example 126a), potassium carbonate (69 mg, 0.5 mmol, 1.0 eq.) and 2,2-difluoroethanol (0.5 ml) were suspended in acetonitrile (3 ml), and the suspension was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (30 ml), washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated. Diethyl ether was added and the precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (160 mg, 83%).
Reaction SMILES: [N:1]1([CH2:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=2)[O:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:21]1[S:25][C:24]([NH2:26])=[N:23][N:22]=1>>[N:1]1([CH2:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=2)[O:12][CH2:13][CH2:14][CH2:15][NH:16][C:21]2[S:25][C:24]([NH2:26])=[N:23][N:22]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCCC2)c1
Reactant: Nc1nnc(Br)s1
Product: Nc1nnc(NCCCOc2cccc(CN3CCCCCC3)c2)s1

Procedure:
The compound is prepared by a method analogous to that of Example 51 from 3-[3-[(hexahydro-1H-azepin-1-yl) methyl]phenoxy]-1-propanamine and 5-bromo-1,3,4-thiadiazole-2-amine.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:22][CH:21]=1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: OB(O)c1ccc(Cl)cc1
Product: Cc1c2n(c3c(-c4ccc(Cl)cc4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, light grey solid (78 mg, 93%), MS (ISP) m/z=336.5 [(M+H)+], mp 298° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 4-chloro-phenylboronic acid (50.8 mg, 0.325 mmol).
Reaction SMILES: F[C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].CCO[C:13]([S-:15])=[S:14].[K+]>CN(C)C=O.O.Cl>[I:9][C:7]1[CH:6]=[CH:5][C:3]2[N:4]=[C:13]([SH:15])[S:14][C:2]=2[CH:8]=1
Reactant: Nc1ccc(I)cc1F
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Sc1nc2ccc(I)cc2s1
Temperature: 95 °C
Reaction time: 5 h

Procedure:
A mixture of 2-fluoro-4-iodoaniline (24.19 g, 0.100 mole) and potassium ethylxanthogenate (35.27 g, 0.220 mole) in N,N-dimethylformamide (80 mL) was stirred at 95° C. for 5 hours. The reaction mixture was cooled to room temperature then diluted with water (150 mL) and 1 N aqueous HCl (200 mL). The mixture was stirred at room temperature overnight. The resulting precipitate was collected by filtration and rinsed with water. The solid was dried overnight at 85° C. in a vacuum oven to provide 6-iodobenzo[d]thiazole-2-thiol. 1H NMR (300 MHz, CD3OD) δ ppm 7.09 (d, J=8 Hz, 1H), 7.70 (dd, J=2, 8 Hz, 1H), 8.10 (d, J=2 Hz, 1H), 13.82 (sbroad, 1H); MS (DCI/NH3) m/z 294 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[NH:20][CH2:19][C:17]2=[C:18]3[C:13](=[C:14]([CH2:21][C:22](=[O:24])[NH2:23])[CH:15]=[CH:16]2)[CH:12]=[CH:11][N:10]3[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O:26][C:27](=O)[C:28]([C:30]1[C:40]2=[C:41]3[C:36](=[CH:37][C:38]([F:42])=[CH:39]2)[C:35]([CH3:44])([CH3:43])[CH2:34][CH2:33][N:32]3[CH:31]=1)=O>>[C:1]([O:5][C:6]([CH:8]1[NH:20][CH2:19][C:17]2=[C:18]3[C:13](=[C:14]([C:21]4[C:22](=[O:24])[NH:23][C:27](=[O:26])[C:28]=4[C:30]4[C:40]5=[C:41]6[C:36](=[CH:37][C:38]([F:42])=[CH:39]5)[C:35]([CH3:43])([CH3:44])[CH2:34][CH2:33][N:32]6[CH:31]=4)[CH:15]=[CH:16]2)[CH:12]=[CH:11][N:10]3[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(=O)c1cn2c3c(cc(F)cc13)C(C)(C)CC2
Reactant: CC(C)(C)OC(=O)C1Cn2ccc3c(CC(N)=O)ccc(c32)CN1
Product: CC(C)(C)OC(=O)C1Cn2ccc3c(C4=C(c5cn6c7c(cc(F)cc57)C(C)(C)CC6)C(=O)NC4=O)ccc(c32)CN1

Procedure:
Beginning with 7-Carbamoylmethyl-3,4-dihydro-1H-[1,4]diazepino[6,7,1-hi]indole-2-carboxylic acid tert-butyl ester and (8-Fluoro-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-oxo-acetic acid methyl ester, the title compound was prepared essentially as Example 1.
Reaction SMILES: C[Al](C)C.[N:5]([Si](C)(C)C)=[N+:6]=[N-:7].[Si:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:30]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:29]3[CH:37]=[CH:38][C:39]([C:41]#[N:42])=[CH:40][C:28]=3[N:27]=2)=[CH:22][CH:21]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Si:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[N:30]([CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)[C:29]3[CH:37]=[CH:38][C:39]([C:41]4[NH:7][N:6]=[N:5][N:42]=4)=[CH:40][C:28]=3[N:27]=2)=[CH:24][CH:25]=1)([C:15]([CH3:18])([CH3:16])[CH3:17])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2nc3cc(C#N)ccc3n2C2CCCCC2)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: C[Al](C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2nc3cc(-c4nnn[nH]4)ccc3n2C2CCCCC2)cc1
Temperature: 95 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
Trimethylaluminum (20 mL of a 2.0 M solution in toluene, 0.040 mol) was added to a dry flask. Azidotrimethylsilane (5.3 mL, 0.040 mol) and compound 20 were added. The solution was stirred for 18 h at an oil bath temperature of 95° C. The solution was cooled and poured into a mixture of ethyl acetate and ice. The mixture was carefully acidified with dilute hydrochloric acid (caution-done in hood, hydrazoic acid liberated) to precipitate compound 21. The compound was crystallized from ethyl acetate—hexanes to afford 21 as a pinkish solid (4.13 g, 87%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2[N:17]=[C:18]([NH2:20])[S:19][C:13]=2[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2[N:17]=[C:18]([NH:20][C:42](=[O:44])[CH3:43])[S:19][C:13]=2[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: CCOC(=O)COc1ccc(Cl)cc1C1c2sc(N)nc2CCN1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1ccc(Cl)cc1C1c2sc(NC(C)=O)nc2CCN1C(=O)OCc1ccccc1

Procedure:
To an-ice cooled solution of (±)-2-amino-4-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester (50 mg, 100 μmol, 1 eq.) and NEt3 (69 μL, 500 μmol, 5 eq.) in DCM (1 mL), acetyl chloride (14 μL, 200 μmol, 2 eq.)
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:23]=[CH:22][C:9]([C:10]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20]O)[CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:7]=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[F:5][C:6]1[CH:23]=[CH:22][C:9]([C:10]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][Cl:3])[CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCCO)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(F)cc1)C1CCN(CCCCl)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
Thionyl chloride (38.7 g., 0.376 mole) was added dropwise to a stirring solution of 4-(p-fluorobenzoyl)-1-(3-hydroxypropyl) piperidine (43.1 g., 0.163 mole) in 400 ml. chloroform at room temperature. After the addition was complete the reaction mixture was stirred at room temperature an additional 16 hours. The mixture was then chilled and 125 ml. 6N sodium hydroxide solution was added dropwise. The chloroform solution was separated, washed with water, and dried over magnesium sulfate. Removal of the solvent gave 42.7 g. crude product (92% yield) with crystallized on cooling. Recrystallization from isooctane gave 25.3 g. pure product, m.p. 66.5°-68.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:11][C:10](=[O:12])[CH2:9][C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: O=C(O)Cc1cc(Cl)ccc1Br
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cc(Cl)ccc1Br
Temperature: 25 °C

Procedure:
A solution of (2-bromo-5-chlorophenyl)acetic acid (1-1) (15.0 g, 60.1 mmol) and concentrated sulfuric acid (0.150 mL of a 36N solution) in methanol (120 mL) was heated at reflux for approximately 15 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the residue partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The organic layer was separated and the aqueous phase re-extracted twice with methylene chloride. The combined organic extracts were washed with water, brine, dried (MgSO4) and the volatiles evaporated. The residual colorless liquid (15.9 g) was used without further purification in the Step C below.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:12][CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH2:21][NH2:22])[CH2:16][CH2:17][OH:18].C(=O)([O-])[O-].[Na+].[Na+].C(O)(C)C>C(Cl)(Cl)Cl>[OH:18][CH2:17][CH2:16][N:15]([CH2:14][CH2:13][OH:12])[CH2:19][CH2:20][CH2:21][NH:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: NCCCN(CCO)CCO
Reactant: Clc1ccnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: OCCN(CCO)CCCNc1ccnc2ccccc12

Procedure:
A mixture of 5.0 g. of 4-chloroquinoline, 7.2 g. of bis(2-hydroxyethyl)aminopropylamine, 3.0 g. of sodium carbonate and 25 ml. of isopropanol is heated in a pressure vessel at 150° C. for 17 hours. The resulting mixture is diluted with chloroform, filtered and purified by filtering over silica gel to obtain an oil of 4-[3-bis(2-hydroxyethyl)aminopropyl]amino-quinoline.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[Br:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([N+:29]([O-:31])=[O:30])[CH:28]=1)[C:23]([OH:25])=O.[CH3:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][NH2:42].CCN(CC)CC>CCOC(C)=O>[Br:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([N+:29]([O-:31])=[O:30])[CH:28]=1)[C:23]([NH:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][O:33][CH3:32])=[O:25]
Reactant: COCCOCCOCCN
Reactant: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCCOCCOCCNC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
T3P, 50 wt % in EtOAc (25 mL, 42.0 mmol) was slowly added to a solution of 3-bromo-5-nitrobenzoic acid (7.05 g, 28.7 mmol), 2-(2-(2-methoxyethoxy)ethoxy)ethanamine (4 g, 24.25 mmol) and Et3N (12 mL, 86 mmol) in EtOAc (50 mL) whilst immersed in an ice-bath. Once the addition was complete, the ice bath was removed and the reaction allowed to stir at rt for 2 h. The mixture was partitioned between sat. aq. NaHCO3 solution (100 mL) and EtOAc (100 mL). The organic layer was washed with aq K2CO3 solution (10 g in 100 mL) and brine (100 mL), before being dried (MgSO4), filtered and concentrated in vacuo to afford the sub-title compound (8.23 g) as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:11]3[NH:12][NH:13][CH2:14][CH2:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:29]([O:32][CH2:33][C:34](Cl)=[O:35])(=[O:31])[CH3:30]>CN1CCCC1=O.C(=O)(O)[O-].[Na+]>[C:29]([O:32][CH2:33][C:34]([N:12]1[C:11]2=[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][N:10]2[CH2:15][CH2:14][NH:13]1)=[O:35])(=[O:31])[CH3:30]
Reactant: Fc1ccc(-c2nn3c(c2-c2ccncc2)NNCC3)cc1
Reactant: CC(=O)OCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)N1NCCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c21
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
To a mixture of 7-(4-fluorophenyl)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (100 mg, 0.339 mmol) and pyridine (54 mg, 0.678 mmol) in N-methyl-2-pyrrolidone (1.5 ml) was added acetoxyacetyl chloride (60 mg, 0.441 mmol) in N-methyl-2-pyrrolidone (0.5 ml) under nitrogen atmosphere with ice cooling. After stirring for 30 minutes, the reaction mixture was diluted with an aqueous saturated sodium bicarbonate solution, then extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluent:dichloromethane/methanol; 100/1~20/1) and the obtained amorphous product was crystallized from diisopropyl ether to give 2-acetoxyacetyl-7-(4-fluorophenyl)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo-[5,1-c][1,2,4]triazine (76 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:22]1[C:27]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)(=[O:30])=[O:29])=[CH:26][N:25]=[C:24]([CH3:39])[N:23]=1>C1COCC1>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([S:28]([C:27]2[C:26]([NH:4][C:3]3[C:5]([CH3:10])=[CH:6][C:7]([CH3:9])=[CH:8][C:2]=3[CH3:1])=[N:25][C:24]([CH3:39])=[N:23][CH:22]=2)(=[O:29])=[O:30])=[CH:36][CH:35]=1
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: COc1ccc(S(=O)(=O)c2cnc(C)nc2Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)c2cnc(C)nc2Nc2c(C)cc(C)cc2C)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 45.1 %

Procedure:
To a solution of 2,4,6-trimethylaniline (0.089 mL, 0.64 mmol) in THF (2 mL), NaHMDS (1.0 M in THF, 0.64 mL, 0.64 mmol) was added dropwise at 0° C. The mixture was stirred under N2 at 0° C. for 10 min, and then 4-chloro-5-(4-methoxy-benzenesulfonyl)-2-methyl-pyrimidine (158 mg, 0.53 mmol) in THF (3 mL) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 h, and then quenched with saturated ammonium chloride. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (1:2 ethyl acetate/hexanes) to provide the target compound (95 mg, 45%) as a light yellow solid: mp 153–155° C.; 1H NMR (300 MHz, CDCl3) δ 8.74 (s 1H), 8.22 (br s, 1H), 7.88 (d, J=7.0 Hz, 2H), 6.98 (d, J=7.0 Hz, 1H), 6.91 (s, 2H), 3.86 (s, 3H), 2.38 (s, 3H), 2.30 (s, 3H), 2.01 (s, 6H); ESI MS m/z 398 [(M+H)+, calcd for C21H24N3O3S, 398.2].
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[NH:6][C:5](=[O:7])[CH2:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].[Br:15][CH2:16][C:17](Br)=[O:18]>O>[Br:15][CH2:16][C:17]([N:3]1[CH2:4][C:5](=[O:7])[NH:6][C:2]1([CH3:8])[CH3:1])=[O:18]
Reactant: O=C(Br)CBr
Reactant: CC1(C)NCC(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC1(C)NC(=O)CN1C(=O)CBr
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(1) To an ice-cold stirred solution of 2,2-dimethyl-4-imidazolidinone (7 g) and potassium carbonate (12.8 g) in water (80 ml), bromoacetyl bromide (5.4 ml) was added dropwise. The reaction mixture was stirred at the same temperature for 1 hour, then at room temperature for 2 hours. The obtained suspension was extracted three times with ethyl acetate and the organic phase was washed with 3% hydrochloric acid, dried and evaporated under reduced pressure to give a residue which was crystallized from xylene to afford 1-(2-bromoacetyl)-2,2-dimethyl-4-imidazolidinone as a white crystalline powder, m.p. 137°-138° C.