Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=[O:14])[CH2:12][NH3+:13])=[CH:3]1.C(N(C(C)C)C(C)C)C.[C:24]1([N:34]=[C:35]=[O:36])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>C1COCC1>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=[O:14])[CH2:12][NH:13][C:35]([NH:34][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)=[O:36])=[CH:3]1
Reactant: O=C=Nc1cccc2ccccc12
Reactant: [NH3+]CC(=O)c1c[nH]c2ccccc12
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)c1c[nH]c2ccccc12)Nc1cccc2ccccc12
Reaction time: 1 h
Yield: 87 %

Procedure:
[2-(3-indolyl)-2-oxoethyl]ammonium bromide (2.00 g, 7.84) was suspended in dry THF (20 ml). Ethyldiisopropylamine (1.40 ml, 7.84 mmol) was added followed by 1-naphthyl-isocyanate (1.13 ml, 7.84 ml). After stirring for 1 hour the formed precipitate was removed by filtration and washed with THF followed by water to give the sub-title product (2.33 g, 87%) as a white solid after drying.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].[CH2:10]([O:12][C:13](OCC)([O:19]CC)[C:14](OCC)=O)[CH3:11]>>[CH2:10]([O:12][C:13]([C:14]1[S:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[N:1]=1)=[O:19])[CH3:11]
Reactant: CCOC(=O)C(OCC)(OCC)OCC
Reactant: Nc1cc(Cl)ccc1S
Product: CCOC(=O)c1nc2cc(Cl)ccc2s1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To 2-amino-4-chloro-benzenethiol (1 g) was added ethyl triethoxyacetate (3 eq). The mixture was stirred at 110° C. overnight. The reaction mixture was cooled and triturated with hexane. Filtration gave 392 mg of 5-chloro-benzothiazole-2-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.CC(C)=[O:14]>>[OH:14][N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: CC(C)=O
Product: CC1(C)CC(O)CC(C)(C)N1O
Reaction time: 2 h

Procedure:
In a 100 ml flask, a solution of 0.047 M DMD in acetone (21.2 ml, 1 mmol) was added to a cold stirred solution of 2,2,6,6-tetramethyl-4-piperidinol (0.1572 g, 1 mmol) in acetone (10 ml). The reaction mixture was stirred for two hours in an ice bath. Solvent was removed on a rotary evaporator to give a white crystalline solid (0.1727 g, 99% yield, mp 161-163). Sublimation on the Kugelrohr (110-120°, 1×10-4 mmHg) gave white needles (0.170 g). Measured mp was 162-163; reported mp is 155-159 (Lee et al 1975 and Rozantsey et al 1966).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=O)O[C:8](=O)[C:4]=2[CH:3]=1.[CH:13]([NH2:16])([CH3:15])[CH3:14].[ClH:17].O1CCOCC1>C1(C)C=CC=CC=1>[ClH:17].[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][CH:12]=1)[CH2:6][N:16]([CH:13]([CH3:15])[CH3:14])[CH2:8]2
Reactant: CC(C)N
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CC(C)N1Cc2ccc(Br)cc2C1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
5-bromo-2-benzofuran-1,3-dione (1 wt) was suspended in toluene (5 vol) with stirring under nitrogen. Isopropylamine (1.1 eq, 0.416 vol) was then added dropwise over 10-30 mins at such a rate as to maintain the temperature between 15-25° C. (exothermic addition). The batch was stirred for a further 30 mins at 15-25° C. once the addition was complete, before heating to reflux under Dean-Stark conditions. The batch was held at reflux for 5-8 hrs until residual 5-bromo-2-benzofuran-1,3-dione by HPLC is <1% a/a uncorrected, then the batch was concentrated atmospherically to ca 2.5 vols2. Added toluene (3 vols) and reconcentrated atmospherically to ca 2.5 vols. Batch then cooled to 55-60° C., diluted with THF (1.5 vols), and then further cooled to 15-25° C. This was added to a solution of borane-THF complex (1.0M, 4 eq, 14.1 vol) and the resultant solution was stirred at 20-30° C. for ca 30 mins. The batch was then heated to 48-52° C., and held thus for 16-24 hrs until complete by HPLC, before cooling back to 15-25° C. The reaction was quenched inversely into aqueous hydrochloric acid (2N, 9 vol) over at least 30 mins maintaining an internal temp of 15-30° C. (initially effervescent, evolves hydrogen). Once the addition was complete, the batch was heated to 60-63° C., and held thus for 1-1.5 hrs before cooling to 15-25° C. Ethyl acetate (6 vols) was added and the resultant biphase was shaken, settled and separated1. Organics back-extracted with 2N HCl (3 vols) before being discarded. The combined aqueous liquors were then neutralized to pH>12 with 40% w/v aq NaOH (approx 3.9 vols). Overlain with ethyl acetate (6 vols) then the resultant biphase was shaken, settled and separated. Aqueous back extracted with ethyl acetate (3 vols) before being discarded. The organics were combined and washed with saturated brine (2×2 vols) before being concentrated in vacuo to ca 4 vols. Ethyl acetate (8 vols) was added and the batch was reconcentrated in vacuo to ca 4 vols. Ethyl acetate (9 vols) was added and the batch was adjusted to 0±3° C. 4M HCl in dioxane (0.89 eq, 0.98 vol) was then added slowly maintaining the batch temp within the range 0±3° C. The batch was then aged within this range for 30 min before product was collected by vacuum filtration. Washed with chilled ethyl acetate (<5° C., 2×2 vols) and dried o/n in vacuo at 30° C. to constant weight.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1.[Br:10]Br>P([O-])([O-])(O)=O.[Na+].[Na+]>[Br:10][C:6]1[C:5]([CH3:9])=[N:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: COc1cccc(C)n1
Reactant: BrBr
Agent: O=P([O-])([O-])O
Agent: [Na+]
Product: COc1ccc(Br)c(C)n1
Yield: 57.9 %

Procedure:
2-Methoxy-6-methylpyridine (10 mL, 81 mmol) was suspended in a 0.15 mol//L disodium hydrogen phosphate aqueous solution (160 mL). Thereafter, a solution prepared by suspending bromine (4.15 mL, 81 mmol) in a 0.15 mol//L disodium hydrogen phosphate aqueous solution (160 mL) was added dropwise to the suspension at room temperature over 1 hour. The reaction solution was stirred at the same temperature as described above overnight. Thereafter, the reaction solution was extracted with methylene chloride (300 mL) three times. Organic layers were gathered. The resultant was dried over anhydrous magnesium sulfate and was then filtrated, followed by vacuum concentration. The obtained residue was distilled away under reduced pressure (91° C.-96° C./16 mmHg), so as to obtain 9.47 g of 3-bromo-6-methoxy-2-methyl-pyridine.
Reaction SMILES: Cl.[CH2:2]([O:4]N)[CH3:3].[OH-].[Na+].O1CCOCC1.[Cl:14][C:15]1[CH:16]=[C:17]([C:22]2([C:41]([F:44])([F:43])[F:42])[O:26][N:25]=[C:24]([C:27]3[CH:39]=[CH:38][C:30]([C:31]([N:33]=[CH:34][N:35](C)C)=[O:32])=[C:29]([CH3:40])[CH:28]=3)[CH2:23]2)[CH:18]=[C:19]([Cl:21])[CH:20]=1>O.C(O)(=O)C>[Cl:14][C:15]1[CH:16]=[C:17]([C:22]2([C:41]([F:44])([F:43])[F:42])[O:26][N:25]=[C:24]([C:27]3[CH:39]=[CH:38][C:30]([C:31]([NH:33][CH:34]=[N:35][O:4][CH2:2][CH3:3])=[O:32])=[C:29]([CH3:40])[CH:28]=3)[CH2:23]2)[CH:18]=[C:19]([Cl:21])[CH:20]=1
Reactant: CCON
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)N=CN(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: CCON=CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Yield: 68.6 %

Procedure:
in a solution of 0.25 g of ethoxyamine hydrochloride in 4 mL of water and 8 mL of acetic acid, a solution of 0.20 g of sodium hydroxide in 4 mL of water was added, and then 5 mL of 1,4-dioxane solution of 0.62 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-N-(dimethyl-aminomethylidene)-2-methyl benzamide synthesized in Synthetic Example 30 was added dropwise at room temperature with stirring. After the completion of the addition dropwise, it was continued to stir at the same temperature further for 2 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, 50 mL of ethyl acetate was added in the residue, and washed with water. The organic phase was dehydrated with and dried over saturated sodium chloride and then anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (2:3) to obtain 0.44 g of the aimed product as white crystal. Melting point 143.0 to 146.0° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[O:16][C:17]([CH2:20]I)=[CH:18][N:19]=4)=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>>[CH2:25]([N:27]([CH2:20][C:17]1[O:16][C:15]([C:14]2[N:13]=[CH:12][N:11]3[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:24][C:6]=4[C:7](=[O:23])[N:8]([CH3:22])[CH2:9][C:10]=23)=[N:19][CH:18]=1)[CH2:28][CH3:29])[CH3:26]
Reactant: CCNCC
Reactant: CN1Cc2c(-c3ncc(CI)o3)ncn2-c2ccc(F)cc2C1=O
Product: CCN(CC)Cc1cnc(-c2ncn3c2CN(C)C(=O)c2cc(F)ccc2-3)o1
Temperature: 25 °C
Reaction time: 20 h
Yield: 16 %

Procedure:
125 ml of this crude solution of 8-fluoro-3-(5-iodomethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were treated with 11.3 ml (0.109 mol) of diethylamine and stirred at room temperature for 20 hrs. The suspension obtained was completely freed from the solvents, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated, the orange-brownish product was chromatographed over silica gel with ethyl acetate/methanol 17:3 as the eluent and recrystallized from hot ethyl acetate. There was obtained 0.75 g (16%) of 3-(5-diethylaminomethyloxazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as light beige crystals; m.p. 182°-184°. A further 0.39 g of yellowish crystals was obtained from the mother liquor.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH2:14][CH3:15])[C:10]([O:12]C)=[O:11])[CH:5]=[N:6][CH:7]=1.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH2:14][CH3:15])[C:10]([OH:12])=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: CCC(Oc1cncc(Cl)c1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(Oc1cncc(Cl)c1)C(=O)O
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
The product from Stage 1 (27.4 g) was treated with a solution of sodium hydroxide (9.6 g) in water (50 ml) then stirred at 90° C. for 1.5 hours. The mixture was cooled to ambient temperature, diluted with water then washed with ethyl acetate. The aqueous phase was separated, acidified with concentrated hydrochloric acid and extracted with ethyl acetate (three times). The extracts were combined, washed with brine and dried over magnesium sulphate. The solvent was evaporated under reduced pressure to give the required product as a pale brown solid, 24.8 g, m.p. 98–101° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[S:23][C:14]=2[N:15]=[C:16]([C:18]2[O:22][N:21]=[CH:20][CH:19]=2)[N:17]=1>>[O:22]1[C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[S:23][C:14]=3[N:15]=2)=[CH:19][CH:20]=[N:21]1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: FC(F)(F)c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(isoxazol-5-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-dichlorobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=[N:3][CH:2]=1>C(O)C.[Pd]>[N:1]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=[N:3][CH:2]=1
Reactant: CCOC(=O)C=Cc1cncnc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1cncnc1
Yield: 47.9 %

Procedure:
To a solution of ethyl 3-(5-pyrimidyl)acrylate (4.75 g) in ethanol (90 ml) was added 5% palladium on charcoal (0.2 g). The mixture was hydrogenated at an initial pressure of 50 psi, then filtered to remove catalyst and the solvent evaporated. Water was added, and the product extracted into ether. Drying, charcoaling and evaporation gave ethyl 3-(5-pyrimidyl)propionate (2.3 g) as a yellow oil. 1H-NMR (CDCl3) δ 1.23 (3H, t), 2.69 (2H, t), 2.96 (2H, t), 4.14 (2H, q), 8.635 (2H, s) and 9.09 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.[N+](C1C=CC([O:33][S:34]([C:37]([F:40])([F:39])[F:38])(=O)=[O:35])=CC=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:35])=[O:33])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2cc1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.4 %

Procedure:
After dissolving 6-methoxy-4-(4-nitrophenoxy)quinolin-7-ol (1.0 g) in dimethylformamide (10 ml), there were added trifluoromethanesulfonic acid 4-nitrophenyl ester (640 mg) and potassium carbonate (1.3 g), and the mixture was stirred at room temperature for 5 hours. Water was added, extraction was performed with ethyl acetate, the organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate was used for recrystallization to obtain the title compound (1.0 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[CH2:11][CH2:12][CH2:13][CH:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]1=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH3:37])=[C:31]([O:38][CH2:39][CH3:40])[CH:30]=1>CC(N(C)C)=O>[CH2:39]([O:38][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][C:32]=1[O:35][CH2:36][CH3:37])[CH2:28][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[CH2:11][CH2:12][CH2:13][CH:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]1=[CH:5]2)[CH3:40]
Reactant: CCOc1ccc(CCl)cc1OCC
Reactant: CCOC(=O)CC1CCCn2c1cc1cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CC1CCCn2c1cc1cc(OCc3ccc(OCC)c(OCC)c3)ccc12
Temperature: 60 °C
Yield: 62.3 %

Procedure:
Ethyl 2-(2-hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (0.100 g, 0.366 mmol), cesium carbonate (0.179 g, 0.549 mmol) and 4-(chloromethyl)-1,2-diethoxybenzene (0.118 g, 0.549 mmol) were taken up in DMA (2 mL) and heated to 60° C. for 16 h in a 20 mL sealed scintillation vial. The reaction was cooled down to room temperature and filtered by vacuum filtration through a glass fiber paper. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.103 g) as an off-white solid. LCMS m/z=452.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH2:9][OH:10])[CH:3]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH:9]=[O:10])[CH:3]=1
Reactant: Cc1cc(C)nc(CO)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)nc(C=O)c1
Temperature: 0 °C
Yield: 50.7 %

Procedure:
Manganese dioxide (3.17 g, 36.5 mmol) was added to a solution of (4,6-dimethyl-pyridin-2-yl)-methanol (1.0 g, 7.30 mmol) in chloroform (30 mL) and heated at reflux overnight. The reaction mixture was cooled to 0° C. and filtered over celite, washing with further chloroform. The filtrate was evaporated to give a residue which was purified by column chromatography over silica gel (60-120 mesh) using 10% ethyl acetate in hexane as eluent to afford 4,6-dimethyl-pyridine-2-carbaldehyde (0.5 g, 51%) as a light brown liquid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:30][C:31]([F:34])([F:33])[F:32])[CH:29]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]1[CH2:17][CH2:18][CH2:19][CH:20]([CH2:21][C:22]([O:24]CC)=[O:23])[C:12]1=[CH:11]2)#[N:2].[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:30][C:31]([F:34])([F:32])[F:33])[CH:29]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]1[CH2:17][CH2:18][CH2:19][CH:20]([CH2:21][C:22]([OH:24])=[O:23])[C:12]1=[CH:11]2)#[N:2]
Reactant: CCOC(=O)CC1CCCn2c1cc1cc(OCc3cc(C#N)cc(OC(F)(F)F)c3)ccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cc(COc2ccc3c(c2)cc2n3CCCC2CC(=O)O)cc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a solution of ethyl 2-(2-(3-cyano-5-(trifluoromethoxy)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (108 mg, 0.229 mmol) in dioxane (1 mL) was added 1 M LiOH aqueous solution (0.914 mL, 0.914 mmol). The reaction was stirred at room temperature for 8 h, diluted with water, and acidified to pH 4 with 0.5 M aqueous citric acid. The solid precipitate was collected to give the title compound (90 mg). LCMS m/z=445.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.57-1.68 (m, 1H), 2.00-2.14 (m, 1H), 2.16-2.27 (m, 2H), 2.65 (dd, J=16.1, 8.5 Hz, 1H), 3.01 (dd, J=16.1, 5.4 Hz, 1H), 3.46-3.55 (m, 1H), 3.85-3.93 (m, 1H), 4.13-4.20 (m, 1H), 5.13 (s, 2H), 6.23 (s, 1H), 6.89 (dd, J=8.8, 2.4 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 7.44 (s, 1H), 7.58 (s, 1H), 7.70 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([OH:13])=O)=[C:4]([OH:14])[CH:3]=1.[N:15]1([CH:21]2[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:18]2[CH2:19][CH2:20][N:15]([CH:21]3[CH2:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24]3)[CH2:16][CH2:17]2)=[O:13])=[C:4]([OH:14])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCNCC2)C1
Reactant: O=C(O)CNc1cc(Cl)c(Cl)cc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(N2CCN(C(=O)CNc3cc(Cl)c(Cl)cc3O)CC2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 30.8 %

Procedure:
A mixture of 2-(4,5-dichloro-2-hydroxyphenylamino)acetic acid (500 mg, 2.12 mmol), tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (565 mg, 2.34 mmol), EDCI.HCl (488 mg, 2.54 mmol), HOBt (343 mg, 2.54 mmol), Et3N (428 mg, 4.24 mmol) in DMF (20 mL) was stirred at room temperature for 15 h. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed withed saturated aqueous NaHCO3 solution and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=30:1) to afford the desired product (300 mg, 31% yield). ESI-MS m/z: 457.4 [M−H]−.
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].[O:6]=[S:7]1(=[O:14])[CH2:11][CH2:10][CH:9]([CH2:12]N)[CH2:8]1>O>[O:6]=[S:7]1(=[O:14])[CH2:11][CH2:10][CH:9]([CH2:12][NH:4][S:1](=[O:3])(=[O:2])[NH2:5])[CH2:8]1
Reactant: NS(N)(=O)=O
Reactant: NCC1CCS(=O)(=O)C1
Solvent: O
Product: NS(=O)(=O)NCC1CCS(=O)(=O)C1
Temperature: 25 °C

Procedure:
Sulfamide (2.4 mmol) was dissolved in H2O (10 mL), added (1,1-dioxothiolan-3-yl)methanamine (2 mmol) and stirred at reflux for 16 h. The obtained reaction mixture was cooled to rt and freezedried affording the title compound as an oil. Used without further purification.
Reaction SMILES: [Br-].[CH2:2]([PH3+])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CC(C)([O-])C.[K+].[OH:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[CH3:24])[CH:19]=O>O1CCCC1.COC(C)(C)C>[CH:19](/[C:18]1[CH:21]=[CH:22][C:23]([CH3:24])=[C:16]([OH:15])[CH:17]=1)=[CH:2]/[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC[PH3+]
Reactant: Cc1ccc(C=O)cc1O
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CCCCC/C=C\c1ccc(C)c(O)c1
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
Under an atmosphere of Argon, to a solution of n-hexylphosphonium bromide (1.07 g) in tetrahydrofuran (10 mL) was added potassium t-butoxide (336 mg) at room temperature and the solution was stirred for 30 minutes. After cooling in ice bath, 3-hydroxy-4-methylbenzaldehyde (136 mg) was added to the reaction solution, which was stirred at room temperature for 1.5 hours. The reaction solution was diluted with t-butyl methyl ether. The solution was washed with dilute hydrochloric acid, water and brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:4) to give the title compound (180 mg) having the following physical data.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N1C=CC=CC=1.[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>ClCCl.CN(C)C1C=CN=CC=1>[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:1](=[O:10])[CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(C=Cc1ccccc1)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
In a round-bottomed flask, a solution of the crude cinnamoyl chloride (25.2 g) in dichloromethane (50 ml) was added to a stirring mixture of pyridine (14.4 g, 182 mmol) and 4-dimethylaminopyridine (1.44 g, 11.8 mmol) in dichloromethane (100 ml) at 0° C. and stirred for 15 minutes before a solution of 4-fluoroaniline (13.2 g, 118.79 mmol) in dichloromethane (50 ml) was added over 20 min. After being stirred for 3 h at room temperature, the mixture was quenched with water (500 ml) and extracted with dichloromethane (3×150 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to give a residue. The crude material was purified by silica gel chromatography using 1-5% ethyl acetate in petroleum to elute. The product-containing fractions were combined to afford N-(4-fluorophenyl)cinnamamide as a light yellow solid (17.8 g, 61%); (ES, m/z): [M+H]+ 242; 1H NMR (300 MHz, CDCl3): δ 10.28 (s, 1H), 7.70-7.75 (m, 5H), 7.39-7.65 (m, 3H), 7.15 (t, J=9.0 Hz, 2H), 6.79 (d, J=15.6 Hz, 1H).
Reaction SMILES: [CH:1]1([N:4]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[C:45]=2[Cl:51])[C:5]([C:7]2[C@@H:8]([CH2:38][O:39]COC)[N:9](C(OC(C)(C)C)=O)[CH2:10][CH2:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:30])=[CH:15][CH:14]=2)=[O:6])[CH2:3][CH2:2]1>Cl.CO>[CH:1]1([N:4]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[C:45]=2[Cl:51])[C:5]([C:7]2[C@@H:8]([CH2:38][OH:39])[NH:9][CH2:10][CH2:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:30])=[CH:15][CH:14]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: COCOC[C@@H]1C(C(=O)N(Cc2cccc(Cl)c2Cl)C2CC2)=C(c2ccc(OCCOc3c(Cl)cccc3Cl)cc2)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: O=C(C1=C(c2ccc(OCCOc3c(Cl)cccc3Cl)cc2)CCN[C@@H]1CO)N(Cc1cccc(Cl)c1Cl)C1CC1
Temperature: 55 °C
Reaction time: 1 h
Yield: 60.4 %

Procedure:
9A (52 mg, 65 μmol) as prepared in Example 9, Step A, was dissolved in 1.25 M HCl in methanol and stirred at 55° C. for 1 hour. Solvent was removed under vacuum. The residue was purified by preparatory LCMS (water:acetonitrile, 45-60%) to give Compound 6 (25 mg, 61%). ESI-MS:m/z 635.2 (M+H)+.