Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][S:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1)(=[O:14])=[O:13].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:61]([O:63][C:64](=[O:67])[CH2:65][NH2:66])[CH3:62]>CN(C)C=O>[CH2:61]([O:63][C:64](=[O:67])[CH2:65][NH:66][C:19](=[O:21])[C:18]1[CH:17]=[CH:16][C:15]([S:12](=[O:13])(=[O:14])[NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]2[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:2]=2[Cl:1])=[CH:23][CH:22]=1)[CH3:62]
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(Cl)cc2Cl)cc1
Reactant: CCOC(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
The solution of 4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-benzoic acid (8.207 g, 18.7 mmol), triethylamine (5.2 mL, 37.4 mmol) and HBTU (8.24 g, 21.7 mmol) in dry dimethyl formamide (150 mL) was stirred at room temperature for five minutes before glycine ethyl ester hydrochloride (Aldrich) (2.614 g, 18.7 mmol) was added. The pH of the reaction mixture was adjusted to 8 by the addition of triethylamine, the so obtained mixture was stirred at room temperature overnight, then concentrated in vacuo. The residue was treated with saturated sodium hydrogencarbonate solution (300 mL), the precipitated crystals were filtered off, washed with water and dried. The crude product was purified by column chromatography using Kieselgel 60 (0.040-0.063 mm) (Merck) as adsorbent, and n-hexane:ethyl acetate=2:1 as eluent to yield 7.68 g (78%) of the title compound. MS (EI) 524 (MH+).
Reaction SMILES: [C:1]1([CH:11]=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][C:15]=1O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>CCO>[C:1]1([C:11]2[O:12][C:15]3[CH:16]=[C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:19][C:14]=3[N:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)Cc1ccc(N)c(O)c1
Reactant: O=Cc1cccc2ccccc12
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Solvent: CCO
Product: COC(=O)Cc1ccc2nc(-c3cccc4ccccc34)oc2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 41.8 %

Procedure:
In EtOH (8 ml), 1-naphthaldehyde (263 mg, 1.68 mmol) and methyl 4-amino-3-hydroxyphenylacetate (305 mg, 1.68 mmol) were stirred at room temperature for 12 hours. Iodobenzene diacetate (651 mg, 2.02 mmol) was added to the reaction mixture, followed by stirring at room temperature for 5 minutes. After removal of the solvent by distilling the reaction mixture under reduced pressure, the residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (6:1, v/v) eluate fractions, methyl (2-(1-naphthyl)-6-benzoxazolyl)acetate (223 mg, 42%) was obtained as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C@@H:22]3[F:27])([CH3:20])[C:18](=[O:28])[CH2:17][CH2:16]4)[C@H:13]([CH2:29][CH2:30][CH2:31][CH2:32]Cl)[CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Na+].[CH2:36]([NH2:41])[CH2:37][CH2:38][CH2:39][CH3:40]>CN(C)C=O>[CH2:29]([C@@H:13]1[CH2:12][C:11]2[CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:26]=[CH:25][C:24]=2[C@@H:23]2[C@@H:14]1[C@H:15]1[C@@:19]([CH2:21][C@@H:22]2[F:27])([CH3:20])[C:18](=[O:28])[CH2:17][CH2:16]1)[CH2:30][CH2:31][CH2:32][NH:41][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(OCc5ccccc5)cc4C[C@@H](CCCCCl)[C@H]3[C@@H]1CCC2=O
Reactant: CCCCCN
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCNCCCC[C@@H]1Cc2cc(OCc3ccccc3)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Temperature: 0 °C

Procedure:
A solution of 273 mg of 3-benzyloxy-7α-(4-chlorobutyl)-11β-fluor-estra-1,3,5(10)-trien-17-one in 7 ml of dimethylformamide is stirred with 262 mg of sodium iodide and 0.5 ml of n-pentylamine for 24 hours at 80° C. Then, the reaction mixture is added to ice water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated by evaporation in a vacuum. After the crude product is chromatographed on silica gel with a methylene chloride-methanol gradient, 275 mg of 7α-(5-azadecyl)-3-benzyloxy-11β-fluor-estra-1,3,5(10)-trien-17-one is obtained.
Reaction SMILES: [CH2:1]([S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH2:2][CH3:3].C1(C)C(C)=CC=CC=1.[CH2:20]([SH:23])[CH2:21][CH3:22]>ClC1C=CC=CC=1Cl.C1(C)C=CC=CC=1>[CH2:1]([S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH2:2][CH3:3].[CH2:1]([S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:23][CH2:20][CH2:21][CH3:22])[CH2:2][CH3:3]
Reactant: CCCS
Agent: CCCSc1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: Clc1ccccc1Cl
Solvent: Cc1ccccc1C
Product: CCCSc1ccccc1SCCC
Reaction time: 64 h
Yield: 56.4 %

Procedure:
A solution of 215 g of 61.5 weight % of o-chlorophenyl propyl sulfide in o-dichlorobenzene (ODCB) was combined with 222.8 g of 85% potassium propyl mercaptide, 200 ml of xylene, 45 g of Carbowax® 350, polyethyleneglycol (Union Carbide), and 20 ml of propyl mercaptan, and heated at reflux for 96 hours. The liquid temperature of the refluxing mixture, initially at 137° C., rose to 168° after 64 hours, and to 198° C. after 86 hours. The dark solution was cooled, diluted with 300 ml of toluene, and washed with water to remove inorganic salts. The organic phase was dried (MgSO4) and fractionally distilled to give 48.6 g of recovered o-chlorophenyl propyl sulfide and 129.6 g (56.4%) of ortho-bis-propylthiobenzene, b.p. 100°-105° C. (0.06 mmHg).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH2:13])[N:10]=[CH:9]2)=[C:5]([CH3:14])[O:4][N:3]=1.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24](Cl)=[O:25])=[CH:23][C:18]=2[O:17][CH2:16]1.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH:13][C:24]([C:22]3[CH:21]=[CH:20][C:19]4[O:15][CH2:16][O:17][C:18]=4[CH:23]=3)=[O:25])[N:10]=[CH:9]2)=[C:5]([CH3:14])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cnc(N)c1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1noc(C)c1Cn1cnc(NC(=O)c2ccc3c(c2)OCO3)c1
Yield: 16.5 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-imidazol-4-amine (example 10-40a) (110 mg, 0.57 mmol), benzo[d][1,3]dioxole-5-carbonyl chloride (105 mg, 0.57 mmol), and triethylamine (90 μL, 0.69 mmol) in dichloromethane was stirred for 16 hours. The reaction was diluted with dichloromethane (30 mL) and washed consecutively with brine and water. The organics were dried over sodium sulfate and concentrated by rotary evaporation. The crude product was purified by reverse phase HPLC (Solvent system: acetonitrile/water, 10% to 100% gradient, 25 minute run) to afford N-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-imidazol-4-yl)benzo[d][1,3]dioxole-5-carboxamide as a white crystalline solid (32 mg, 15% yield). MS M+H calculated 341.3, found 341.3. 1H NMR (400 MHz, DMSO-d6): δ 2.08 (s, 3H), 2.41 (s, 3H), 5.02 (s, 2H), 6.07 (s, 2H), 6.95 (d, J=8.4 Hz, 1H), 7.27 (d, J=1.6 Hz, 1H), 7.54 (m, 3H), 10.6 (s, 1H). The compound had an IC50 on hT2R8 bitter receptor of 12.1 μM.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[C:8]=1[CH3:14])=[O:5].[C:19]([O-])(O)=[O:20].[Na+]>C1COCC1>[Br:13][C:9]1[C:8]([CH3:14])=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:1][C:19]2=[O:20])[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1c(Br)cccc1NC(=O)c1ccccc1N
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1-n1c(=O)[nH]c2ccccc2c1=O
Yield: 97 %

Procedure:
A solution of 2-amino-N-(3-bromo-2-methylphenyl)benzamide (2.00 g, 6.55 mmol) in THF (50 mL) was treated with bis(trichloromethyl)carbonate[triphosgene] (2.92 g, 9.83 mmol) and heated at reflux for 60 min. The cooled mixture was treated with saturated aqueous NaHCO3, extracted with EtOAc, and the combined organic phases were washed twice with saturated NaHCO3, then with water, dried and concentrated. The residue was triturated with DCM to give a white solid which was collected by filtration. The residue from concentration of the filtrate was triturated with DCM to give additional white solid which was collected by filtration. The two solids were combined to give 3-(3-bromo-2-methylphenyl)quinazoline-2,4(1H,3H)-dione as a white solid (2.10 g, 97% yield). Mass spectrum m/z 331, 333 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ 8.07 (dd, J=7.92, 1.32 Hz, 1H), 7.65-7.75 (m, 2H), 7.21-7.32 (m, 4H), 2.20 (s, 3H). 1H NMR (400 MHz, chloroform-d) δ 9.38 (br. s., 1H), 8.19 (dd, J=7.9, 1.1 Hz, 1H), 7.76-7.69 (m, 1H), 7.69-7.60 (m, 1H), 7.35-7.17 (m, 3H), 7.04-6.97 (m, 1H), 2.28 (s, 3H).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[F-].[K+].[NH:7]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C@H:8]([C:10]([NH:12][C@H:13]([C:17]([N:19]1[CH2:27][CH2:26][CH2:25][C@H:20]1[C:21]([CH2:23]Br)=[O:22])=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])[CH3:9]>>[NH:7]([C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:29])[C@H:8]([C:10]([NH:12][C@H:13]([C:17]([N:19]1[CH2:27][CH2:26][CH2:25][C@H:20]1[C:21]([CH2:23][O:3][C:1]([CH3:2])=[O:4])=[O:22])=[O:18])[CH:14]([CH3:15])[CH3:16])=[O:11])[CH3:9]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)CBr
Reactant: CC(=O)O
Agent: [F-]
Agent: [K+]
Product: CC(=O)OCC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(C)C

Procedure:
Acetic acid (230 μl, 4.02 mmol), KF (0.234 g, 4.02 mmol), 13 (1.00 g, 2.01 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:22])[CH2:10][C:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1.[CH2:23](O)[CH2:24][OH:25].CC1C=CC(S(O)(=O)=O)=CC=1>CC1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:10][C:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH:12]=3)[O:25][CH2:24][CH2:23][O:22]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)N1CC=C(CC(=O)c2cccc(OC)c2)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC=C(CC2(c3cccc(OC)c3)OCCO2)CC1

Procedure:
A mixture of 30 parts of ethyl 2,3-dihydro-4-[2-(3-methoxyphenyl)-2-oxoethyl]-1(6H)-pyridinecarboxylate, 15 parts of 1,2-ethanediol, 0.1 parts of 4-methylbenzenesulfonic acid and 135 parts of methylbenzene is stirred and refluxed overnight. The reaction mixture is cooled and evaporated, yielding 30 parts of ethyl 2,3-dihydro-4-[2-(3-methoxyphenyl)-1,3-dioxolan-2-ylmethyl]-1(6H)-pyridinecarboxylate as a residue.
Reaction SMILES: [CH:1]1[C:17]2[CH2:16][C@H:15]3[N:18]([CH2:20][CH2:21][C@@:7]45[C@H:14]3[CH:13]=[CH:12][C@H:10]([OH:11])[C@@H:8]4[O:9][C:5]([C:6]=25)=[C:3]([OH:4])[CH:2]=1)[CH3:19].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[Na+]>C1COCC1.C(Cl)Cl>[CH2:22]([C:3]1([OH:4])[C:5]2[O:9][C@@H:8]3[C@@:7]45[CH2:21][CH2:20][N:18]([CH3:19])[C@@H:15]([C@@H:14]4[CH:13]=[CH:12][C@@H:10]3[OH:11])[CH2:16][C:17]([C:6]5=2)=[CH:1][CH2:2]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN1CC[C@]23C4=C5O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1CC4=CCC5(O)Cc1ccccc1
Reaction time: 8 h
Yield: 59.6 %

Procedure:
To a suspension of morphine (10.0 g, 35.1 mmol) in THF (200 ml), was added benzyi bromide (5.5 ml, 98%, 45.3 mmol) and sodium hydroxide (1.48 g, 37.0 mmol) at 0° C. The reaction mixture was stirred overnight. The reaction temperature rose gradually to rt. during the process. THF in the reaction mixture was removed on a rotary evaporator. The residue was dissolved in CH2Cl2 (150 ml) and water (50 ml). The organic layer was separated. The aqueous layer was extracted with CH2Cl2 (3×50 ml). The combined organic layer was dried over anhydrous sodium sulfate, evaporated in vacuo to obtain a crude product (13 g), which was dissolved in CH2Cl2 and loaded onto a silica gel column (3×30 cm). The column was first eluted with 3% methanol in CH2Cl2, followed by 5% methanol in CH2Cl2. Pure fractions were combined to obtain 3-benzylmorphine (7.9 g, 60% yield). IR (KBr)(v, cm-1): 3540 (m, sharp, --OH), 3020 (m, sharp), 2900 (s, sharp), 1600 (m, sharp); NMR (δH)(CDCl3): 7.50-7.20 (5, m, --C6H5), 6.70 (1, d, J, 8.1, 2-H), 6.51 (1, dd, J, 8.1 & 0.9, 1-H), 5.65 (1, drn, J, 9.9, 7-H), 5.26 (1, dt, J, 9.9 & 2.5, 8-H), 5.12 (2, AB, OCH2Ph), 4.85 (1, dd, J, 6.6 & 1.2, 5-H), 4.22-4.05 (1, m, 6-H), 3.32 (1, dd, J, 6.2 & 3.3, 9-H), 3.02 (1, d, J, 18.6, 10-Hβ), 2.75-2.65 (1, m, 14-H), 2.75-2.65 (1, b, --OH), 2.58 (1, dm, J, 12.0, 16-He), 2.5-2.3 (1, m, 16-Ha), 2.42 (3, s, N--CH3), 2.27 (1, dd, J, 18.6 & 6.6, 10-Hα), 2.05 (1, td, J, 12.1 & 5.3, 15-Ha), 1.85 (1, dm, J, 12.5, 15-He).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[NH2:9][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)[CH2:15][CH2:16][CH2:17][CH2:18]Cl.[Na].Cl>C(O)C>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[NH2:9][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)[CH2:15][CH2:16][CH2:17][CH2:18][O:5][CH2:4][CH3:3]
Reactant: O=C(O)/C=C\C(=O)O
Reactant: NCCON=C(CCCCCl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOCCCCC(=NOCCN)c1ccc(C(F)(F)F)cc1
Product: O=C(O)/C=C/C(=O)O
Temperature: 70 °C

Procedure:
12 Mmol (5.1 g) of 5-chloro-4'-trifluoromethylvalerophenone O-(2-aminoethyl) oxime maleate (1:1) (melting point 121.5°-122.5° C) were added to a solution of 240 mgat. (5.5 g) of sodium in 100 ml of absolute ethanol. The mixture was heated at 70° C for 8 hours followed by neutralization at 0° C with alcoholic hydrochloric acid and the sodium chloride was filtered off. The alcohol was distilled off in vacuo and the residue was dissolved in water. 5 Ml of 50% sodium hydroxide solution were added to this solution and three extractions with 40 ml of ether were then carried out. The ether extract was washed with 5% sodium bicarbonate solution (1x) and with water (1x), followed by drying on sodium sulphate. The ether was distilled off in vacuo and the residue was dissolved in absolute ethanol. The solution was acidified with an equimolar quantity of fumaric acid. The title compound crystallized from the solution. Melting point 105°-105.5° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[CH3:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=1[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-]>O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:13]1[CH:14]=[CH:15][C:16]([CH3:17])=[C:11]([CH3:10])[CH:12]=1)=[O:8]
Reactant: Cc1ccccc1C
Reactant: O=C(Cl)CCCCCBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Cc1ccc(C(=O)CCCCCBr)cc1C
Reaction time: 0.5 h

Procedure:
6-Bromohexanoyl chloride (2.0 g) was added to o-xylene (20 ml), and aluminum chloride (1.4 g) was added at -20° C., which was followed by stirring for 30 min. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure to give 2.6 g of 6-bromo-1-(3,4-dimethylphenyl)-1-hexanone.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[O:22][CH3:23])=[CH:9][CH:8]=[C:7]([S:24]([N:27](CC1C=CC(OC)=CC=1)[C:28]1[S:29][CH:30]=[CH:31][N:32]=1)(=[O:26])=[O:25])[CH:6]=2.C(Cl)Cl.C(O)(C(F)(F)F)=O>CO>[NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=1[O:22][CH3:23])=[CH:9][CH:8]=[C:7]([S:24]([NH:27][C:28]1[S:29][CH:30]=[CH:31][N:32]=1)(=[O:26])=[O:25])[CH:6]=2
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4OC)c(N)cnc3c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1cc(C(F)(F)F)ccc1-c1c(N)cnc2cc(S(=O)(=O)Nc3nccs3)ccc12
Reaction time: 1 h
Yield: 87.3 %

Procedure:
A round-bottom flask was charged with 3-amino-4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)quinoline-7-sulfonamide (Intermediate NNNN; 42.59 mg, 0.071 mmol), DCM (1 mL) and TFA (0.5 mL). The mixture was stirred for 1 h, then diluted with MeOH and concentrated. The residue was taken up in DCM and loaded onto a 500-mg SCX-2 ion exchange column (Biotage, LLC). The column was eluted with MeOH, then with 2N ammonia in methanol. The basic fractions were combined and concentrated. The residue was concentrated from DCM to give 3-amino-4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)quinoline-7-sulfonamide (30 mg, 0.062 mmol, 88% yield) as a light-yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=12.72 (br. s., 1H), 8.65 (s, 1H), 8.22 (d, J=2.0 Hz, 1H), 7.59 (dd, J=2.0, 8.9 Hz, 1H), 7.52-7.44 (m, 2H), 7.42-7.35 (m, 1H), 7.24 (d, J=4.7 Hz, 1H), 7.08 (d, J=8.9 Hz, 1H), 6.81 (d, J=4.6 Hz, 1H), 5.62 (s, 2H), 3.75 (s, 3H); m/z (ESI) 481.2 (M+H)+.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Si:11]([O:18][C@@H:19]1[C@@H:24]([N:25]2[C:34](=[O:35])[C:33]3[C:28](=[C:29]4[CH:48]=[CH:47][CH:46]=[CH:45][C:30]4=[C:31]([CH2:36][C:37]4[CH:38]=[N:39][C:40]([CH2:43][OH:44])=[CH:41][CH:42]=4)[CH:32]=3)[N:27]=[CH:26]2)[CH2:23][CH2:22][O:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[Si:11]([O:18][C@@H:19]1[C@@H:24]([N:25]2[C:34](=[O:35])[C:33]3[C:28](=[C:29]4[CH:48]=[CH:47][CH:46]=[CH:45][C:30]4=[C:31]([CH2:36][C:37]4[CH:42]=[CH:41][C:40]([CH:43]=[O:44])=[N:39][CH:38]=4)[CH:32]=3)[N:27]=[CH:26]2)[CH2:23][CH2:22][O:21][CH2:20]1)([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:12])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1COCC[C@@H]1n1cnc2c(cc(Cc3ccc(CO)nc3)c3ccccc32)c1=O
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@H]1COCC[C@@H]1n1cnc2c(cc(Cc3ccc(C=O)nc3)c3ccccc32)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of dimethylsulfoxide (0.040 mL, 0.56 mmol) in 2 mL of dichloromethane at −78° C. was added oxalyl chloride (0.025 mL, 0.28 mmol). After 30 min, a solution of 3-((3R,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}tetrahydro-2H-pyran-4-yl)-6-{[6-(hydroxymethyl)pyridine-3-yl]methyl}benzo[h]quinazolin-4(3H)-one (Example 21, 0.075 g, 0.14 mmol) in 1 mL of dichloromethane. After 30 min, triethylamine (0.157 mL, 1.13 mmol) was added, and the reaction was warmed to rt. After 30 min, the mixture was treated with saturated aqueous ammonium chloride and extracted 2× with diethyl ether. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo to provide 5-{[3-((3R,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}tetrahydro-2H-pyran-4-yl)-4-oxo-3,4-dihydrobenzo[h]quinazolin-6-yl]methyl}pyridine-2-carbaldehyde that gave proton NMR spectra consistent with theory.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18]1[O:20][C@H:19]1[CH2:21][OH:22]>CC(C)=O>[OH:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:18][C@@H:19]([OH:20])[CH2:21][OH:22])=[CH:7][CH:6]=1
Reactant: OC[C@H]1CO1
Reactant: OCCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCCCc1ccc(OC[C@@H](O)CO)cc1
Temperature: 25 °C

Procedure:
To 3-(4-hydroxyphenyl)-1-propanol (10.0 g, 66.0 mmol) and potassium carbonate (13.5 g, 100 mmol) in acetone (200 mL) is added (S)-glycidol (6.5 mL, 100 mmol). The mixture is heated at reflux for 18 h. After cooling to RT the solvent is removed in vacuo and the residue partitioned between EtOAc and water. The aqueous layer is further extracted twice with EtOAc and the combined organic portions are washed with water, brine, then dried (MgSO4), filtered and concentrated in vacuo. The crude residue is purified by flash chromatography (SiO2, EtOAc:iso-hexane, 1:1) to afford the title compound as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7]C(N)=[CH:4][C:3]=1[CH3:9].C([O-])(O)=O.[Na+].IC.[CH3:17][N:18]([CH:20]=O)[CH3:19]>C(OCC)(=O)C.O>[I:1][C:2]1[CH:8]=[CH:7][C:20]([N:18]([CH3:19])[CH3:17])=[CH:4][C:3]=1[CH3:9]
Reactant: CN(C)C=O
Reactant: Cc1cc(N)ccc1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(N(C)C)ccc1I

Procedure:
To a solution of 4-iodo-3-methylaniline (commercially available) (1 eq), NaHCO3 (2.5 eq), and iodomethane (2.5 eq), in DMF ((0.2M) was stirred at ambient temperature overnight. The reaction mixture was then diluted with ethyl acetate and water. The two phases were separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane and 4-iodo-N,N,3-trimethylaniline was isolated as a yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7](=[O:8])[C:5]1=[O:6].[CH:15]([NH2:18])([CH3:17])[CH3:16]>CN(C)C=O>[CH:15]([NH:18][CH2:2][CH2:3][N:4]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7](=[O:8])[C:5]1=[O:6])([CH3:17])[CH3:16]
Reactant: O=C1C(=O)N(CCBr)c2ccccc21
Reactant: CC(C)N
Solvent: CN(C)C=O
Product: CC(C)NCCN1C(=O)C(=O)c2ccccc21

Procedure:
A solution of 4.00 g of 1-(2-bromoethyl)isatin and 13.5 ml of isopropylamine in 160 ml of dry N,N-dimethylformamide was stirred for 1 hour at 80° C. The solution was concentrated under reduced pressure and the residue was dissolved in 50 ml of a 2N-hydrochloric acid. The solution was washed with ethyl acetate, neutralized by adding an aqueous sodium bicarbonate solution, and extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (eluent: chloroform/methanol=10/1) to obtain 3.11 g of 1-(2-isopropylaminoethyl)isatin in an oil.
Reaction SMILES: [C:1]([O:4][CH3:5])(=[O:3])[CH3:2].O1CCCOO1.[C:12]([OH:15])(=[O:14])[CH3:13].I.[C]=O>>[C:1]([O:4][CH2:5][O:15][C:12](=[O:14])[CH3:13])(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: COC(C)=O
Agent: C1COOOC1
Agent: I
Agent: [C]=O
Product: CC(=O)OCOC(C)=O
Temperature: 200 °C
Reaction time: 16 h

Procedure:
A 1-liter, magnetically stirred autoclave was charged with 0.001 mol of Rh(CO)2Cl, sealed and flushed with nitrogen followed by carbon monoxide. The autoclave was then charged with 1 mol of methyl acetate, 1 mol of trioxane, 0.5 mol of acetic acid and 0.056 mol of hydrogen iodide. The autoclave was sealed, pressured to 1000 psig with carbon monoxide, and rapidly heated to 200° C. After 16 hours at 200° C., the reaction was terminated, the autoclave was opened and the reaction mixture analyzed by nuclear magnetic resonance spectroscopy, infrared spectroscopy and gas-liquid chromatography. The conversion of methyl acetate was 49% and the yield of methylene bis-acetate, ##STR9## based on converted methyl acetate, was 28%.