Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:27])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)[C:11]([CH3:25])([CH3:24])[CH:10]2O)=[O:4].FC(F)(F)C(O)=O>C([SiH](CC)CC)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:27])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)[C:11]([CH3:24])([CH3:25])[CH2:10]2)=[O:4]
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc([N+](=O)[O-])c1)C(C)(C)C2O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Cl)cc2c1NC(c1cccc([N+](=O)[O-])c1)C(C)(C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.3 %

Procedure:
To a mixture of 6-chloro-4-hydroxy-3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (7.8 g, 20 mmol) and triethylsilane (30 mL) at 25° C. was added trifluoroacetic acid (15 mL) dropwise. The resulting mixture was stirred at 25° C. for 1 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with saturated aqueous sodium bicarbonate solution (2×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(10% ethyl acetate/hexanes) afforded 6-chloro-3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (1 g, 13%) as a white solid: LC/MS m/e calcd for C19H19ClN2O4 (M+H)+: 375.83, observed: 375.1.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[CH3:18][O:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[NH:35][C:36](=[O:38])[CH3:37]>>[ClH:1].[ClH:1].[CH:14]1([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[N:4]=[N:3][C:2]([C:24]4[CH:23]=[CH:22][C:21]([NH:35][C:36](=[O:38])[CH3:37])=[C:20]([O:19][CH3:18])[CH:25]=4)=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)[CH2:17][CH2:16][CH2:15]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(C)=O
Reactant: Clc1ccc(N2CCN(C3CCC3)CC2)nn1
Product: COc1cc(-c2ccc(N3CCN(C4CCC4)CC3)nn2)ccc1NC(C)=O
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 57, starting from 3-chloro-6-(4-cyclobutyl-piperazin-1-yl)-pyridazine and N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1.[CH2:29]([N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[CH3:30]>CN(C)C=O>[Br-:1].[CH2:29]([N+:31]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][C:10]([N:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][C:16]([C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=5)=[CH:17][CH:18]=4)[CH2:13]3)=[O:11])=[CH:5][CH:4]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[CH3:30]
Reactant: Cc1ccc(-c2ccc3c(c2)CN(C(=O)Cc2ccc(CBr)cc2)CC3)cc1
Reactant: CCN1CCCCC1
Solvent: CN(C)C=O
Product: CC[N+]1(Cc2ccc(CC(=O)N3CCc4ccc(-c5ccc(C)cc5)cc4C3)cc2)CCCCC1
Product: [Br-]

Procedure:
A solution of 2-(4-bromomethylphenylacetyl)-7-(4-methylphenyl)-1,2,3,4-tetrahydroisoquinoline (0.2 g) and 1-ethylpiperidine (0.19 ml) in dimethylformamide (5 ml) was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was evaporated to remove the solvent and was mixed with ethyl acetate, and the precipitate was collected by filtration. The precipitate was dissolved in ethanol, and the solvent was evaporated to obtain 1-ethyl-1-(4-((7-(4-methylphenyl)-1,2,3,4-tetrahydroisoquinolin-2-yl)carbonylmethyl)benzyl)piperidinium bromide (compound 32) (0.23 g) as a colorless amorphous substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:16](=[CH:17][C:18]=1[N:19]1[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH:21]([CH3:32])[CH2:20]1)[N:15]1[C:6](=[N:7][C:8]3[C:13]([C:14]1=[O:33])=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]2=[O:34].C(Cl)(Cl)Cl>C(Cl)Cl.FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:16](=[CH:17][C:18]=1[N:19]1[CH2:24][CH2:23][NH:22][CH:21]([CH3:32])[CH2:20]1)[N:15]1[C:6](=[N:7][C:8]3[C:13]([C:14]1=[O:33])=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]2=[O:34]
Reactant: CC1CN(c2cc3c(cc2F)C(=O)c2nc4ccccc4c(=O)n2-3)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC1CN(c2cc3c(cc2F)C(=O)c2nc4ccccc4c(=O)n2-3)CCN1
Yield: 75 %

Procedure:
A solution of 8-fluoro-9-(3-methyl-4-t-butyloxycarbonylpiperazinyl)-indolo[2,1-b]quinazoline-6-12-dione (0.19 g, 0.4 mmol) (from Example 53) in methylene chloride (7 mL) and trifluoroacetic acid (7 mL) was stirred for 1 h. Chloroform was added and the chloroform/methylene chloride solution was washed with saturated sodium bicarbonate. The organic layer was separated, dried and concentrated to give a solid. Purification of the crude product by silica gel chromatography (chloroform eluent) gave the title compound in 75% yield: mp 225°-227° C.; 1H NMR (300 MHz, CDCl3) δ 8.40 (d, 1H), 8.18 (d, 1H), 8.03 (d, 1H), 7.85 (t, 1H), 7.65 (t, 1H) 7.50 (d, 1H), 4.3 (m, 1H), 3.86-3.76 (m, 2H), 3.13-3.04 (m, 4H), 2.8 (t, 1H) 1.75 (s, 3H).
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[C:7](=[N:20][CH:21]1[CH2:25][CH2:24][N:23]([CH3:26])[C:22]1=[O:27])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Br)C#C.C1(C)C=CC=CC=1>C1COCC1>[C:7](=[N:20][C:21]1([CH2:3][C:2]#[CH:1])[CH2:25][CH2:24][N:23]([CH3:26])[C:22]1=[O:27])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN1CCC(N=C(c2ccccc2)c2ccccc2)C1=O
Reactant: CC(C)(C)[O-]
Agent: C#CCBr
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C#CCC1(N=C(c2ccccc2)c2ccccc2)CCN(C)C1=O
Temperature: -65 °C
Reaction time: 1 h

Procedure:
Potassium tert-butoxide 1.7M in THF (602.08 mL, 1023.5 mmol) was added dropwise over a period of 2.5 h to a stirred solution of 3-(benzhydrylidene-amino)-1-methyl-pyrrolidin-2-one (259 g, 930.48 mmol) (which may be prepared as described in Description 101) and 80% solution of propargyl bromide in toluene (124.37 mL, 1116.6 mmol) in 3 A-molecular-sieve-dried reagent grade THF (1900 mL) at −65° C. under nitrogen, in a 5 L flask equipped with an overhead stirrer. After the addition was complete, the mixture was stirred at −65° C. for a further 1 h. The cooling bath was removed and a saturated solution of NaHCO3 (140 ml) was added over 1 minute (at −60° C.). After a further 5 mins more sat NaHCO3 solution (1.4 L) was added followed by Et2O (1.4 L). The mixture was stirred for 1 h then transferred to a separating funnel and water (1.4 L) was added to dissolve all solids. The layers were separated and the aqueous further extracted with Et2O (2×1 L). The combined organic extracts were re-washed with sat. brine (700 ml), diluted with water (700 ml). The organic layer was dried (MgSO4) and evaporated to a volume of approx. 500-600 ml whereupon crystallization started to occur. To this stirred mixture was then added iso-hexane (1.6 L). After standing for 15 mins the cream solid was filtered under suction and washed with iso-hexane (500 ml) and dried at 50° C. under vacuum for 5 h. This afforded 3-(benzhydrylidene-amino)-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one (D102) (274 g, 93%). This was pure by NMR but contains some additional water;
Reaction SMILES: C/[C:2](/[C:8]([O-:10])=O)=[C:3](\C)/[C:4]([O-:6])=[O:5].[CH3:11]O.[CH3:13][NH:14][C:15]([NH2:17])=[O:16]>C1(C)C(O)=CC=CC=1>[CH3:13][N:14]1[C:2](=[CH:3][C:4]([O:6][CH3:11])=[O:5])[C:8](=[O:10])[NH:17][C:15]1=[O:16]
Reactant: CNC(N)=O
Reactant: CO
Reactant: C/C(C(=O)[O-])=C(\C)C(=O)[O-]
Agent: Cc1ccccc1O
Product: COC(=O)C=C1C(=O)NC(=O)N1C

Procedure:
Proceeding in a similar manner to Example 3, 222 g of methyl urea were dissolved in 1000 g of cresol, and 432 g of dimethylmaleate were added. After termination of the reaction during which 92 g of methanol were liberated, and after gas chromatographic analysis showed 95% conversion of the reactants, the cresol was distilled off and the residue fractionated under vacuum. The main fraction distilling over at 140° to 143° C/0.06 Torr was recrystallised from ethyl acetate. The identity of the pure substance obtained, which melted at 100° C, could be confirmed by the IR and NMR spectra and elementary analysis.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11]C=C[C:5]=1[C:6](O)=O)([O-])=O.[H][H].[C:15]([OH:18])(=[O:17])[CH3:16]>C(O)C.[Pd]>[CH:6]1[C:16]([C:15]([OH:18])=[O:17])=[CH:11][CH:12]=[C:4]([NH2:1])[CH:5]=1
Reactant: [H][H]
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Reactant: CC(=O)O
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C(=O)O)cc1

Procedure:
10% Pd/C (1.98 g) was added to a 450 mL hydrogenation flask, and the flask was flushed with N2. A solution of nitro benzoic acid 1 (21.9 g, 118.3 mmol) in 140 mL ethanol and acetic acid (1 mL) were added to the flask. Hydrogenation was conducted at 15 psi in a carefully controlled manner, wherein after the pressure of H2 drops to zero, the shaking of the flask was continued for a couple of minutes before re-pressurizing. After the hydrogen uptake ceased, the pressure was raised to 40 psi, and continued shaking for an additional 30 minutes to insure completion of the reduction. The catalyst was filtered through Celite, and solvent was removed in vacuo to afford amino benzoic acid 2 as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:20]1[C:28]2[C:23](=[C:24]([CH2:30][S:31][CH3:32])[CH:25]=[C:26]([F:29])[CH:27]=2)[NH:22][CH:21]=1)[CH:10]1C(=O)O[C:13](C)([CH3:17])[O:12][C:11]1=[O:19]>N1C=CC=CC=1.C(O)C.[Cu]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:20]1[C:28]2[C:23](=[C:24]([CH2:30][S:31][CH3:32])[CH:25]=[C:26]([F:29])[CH:27]=2)[NH:22][CH:21]=1)[CH2:10][C:11]([O:12][CH2:13][CH3:17])=[O:19]
Reactant: CSCc1cc(F)cc2c(C(c3ccc(Cl)cc3Cl)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: [Cu]
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)CC(c1ccc(Cl)cc1Cl)c1c[nH]c2c(CSC)cc(F)cc12

Procedure:
2.8 mg (0.05 mmol) of copper powder were added to 3.10 g of the compound from Example 18A with a purity of 68% (4.23 mmol) in 34 ml of pyridine and 8 ml of ethanol. The reaction mixture was heated under reflux for 1 h. It was concentrated, and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient) to result in 1.52 g (82% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14](O)=[O:15])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:40]=[CH:39][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:32][CH:31]=1>S(Cl)(Cl)=O.CN(C)C1C=CN=CC=1.ClCCl>[CH2:37]([O:36][C:34](=[O:35])[C:33]1[CH:39]=[CH:40][C:30]([NH:29][C:14](=[O:15])[CH:13]([N:12]2[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=[C:8]2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:31][CH:32]=1)[CH3:38]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 63.6 %

Procedure:
The solution of 3.0 g (7.4 mmol) [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid in 5.4 ml thionylchloride was stirred under reflux. After 1 h the volatile components were removed at a rotary evaporator, the residue taken up in toluene and evaporated (three times). The remaining oil was dissolved in 30 ml dichloromethane, cooled to 0° C. and added dropwise on a solution of ethyl 4-aminobenzoate (1.35 g, 8.1 mmol) and 2.72 g (22.2 mmol) 4-dimethylaminopyridine dissolved in 30 ml dichloromethane. The cooling bath was removed and stirring was continued for another 4 h. The reaction was poured on 25% aqueous hydrochloric acid solution, the phases separated and the aqueous phase extracted with dichloromethane. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica gel using heptane:ethyl acetate (1:0 to 1:1 v/v) as eluant to afford the title compound as a colorless solid (2.6 g, 62%).
Reaction SMILES: [NH2:1][C@H:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4].[P:18](Cl)(Cl)(=[O:30])[O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.C(Cl)[Cl:34]>>[Cl:34][C:21]1[CH:22]=[CH:23][C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20]=1[O:19][P:18](=[N:1][C@H:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]([O:5][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)=[O:4])=[O:30]
Reactant: ClCCl
Reactant: N[C@@H](C(=O)OC1CCCCC1)c1ccccc1
Reactant: O=P(Cl)(Cl)Oc1cccc2ccccc12
Product: O=C(OC1CCCCC1)[C@H](N=[P+]([O-])Oc1c(Cl)ccc2ccccc12)c1ccccc1
Yield: 60 %

Procedure:
Using the general procedure for synthesizing naphthyl (aminoacid ester) phosphorochloridates the hydrochloride salt of (R)-cyclohexyl 2-amino-2-phenylacetate (2.00 g, 7.41 mmol), naphthalen-1-yl phosphorodichloridate (1.94 g, 7.41 mmol) and TEA (2.06 mL, 14.83 mmol) were combined in 15 mL of dry DCM, to give (2R)-cyclohexyl 2-(chloro(naphthalen-1-yloxy)phosphorylamino)-2-phenylacetate in 60% yield (2.75 g), as a clear, yellow, thick oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2(O)[C:13]1[C:14]([O:19][CH2:20][CH3:21])=[N:15][CH:16]=[CH:17][CH:18]=1)#[N:2].N1C=CC=CC=1.S(Cl)([Cl:31])=O.ClCCl.CO>ClCCl>[Cl:31][C:6]1([C:13]2[C:14]([O:19][CH2:20][CH3:21])=[N:15][CH:16]=[CH:17][CH:18]=2)[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=2)[NH:8][C:7]1=[O:12]
Reactant: CCOc1ncccc1C1(O)C(=O)Nc2ccc(C#N)cc21
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: CCOc1ncccc1C1(Cl)C(=O)Nc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
Under an atmosphere of nitrogen, 6.00 g (20.32 mmol) of the 5-cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one were suspended in 60 ml of anhydrous dichloromethane (dried over molecular sieve). 2.30 ml (28.45 mmol) of pyridine were then added. The reaction mixture was cooled to a temperature of 0° C., and 2.06 ml (28.45 mmol) of neat thionyl chloride were then added dropwise (exothermic reaction). The mixture was stirred at room temperature for one hour. The formation of a yellow suspension was observed. The course of the reaction was monitored by thin-layer chromatography (TLC) (silica gel, dichloromethane/methanol in a ratio of 95:5). The reaction mixture was carefully poured into ice-water. After 15 minutes of stirring, the organic phase was removed. The aqueous phase was extracted with dichloromethane (2×). All organic phases were combined, dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The product gave 5.70 g (18.17 mmol, 89%) of 3-chloro-3-(2-ethoxypyridin-3-yl)-2-oxoindoline-5-carbonitrile as an amorphous solid which was used without further purification for the next reaction.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.C(N(CC)CC)C.Cl.[NH:27]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[NH2:28]>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[OH:9])[N:27]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:28]=1
Reactant: CCOC(=O)CNN
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O

Procedure:
51.5 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one, 30.5 ml of triethylamine and 33.4 g of ethyl hydrazinoacetate hydrochloride are boiled under reflux for 0.5 h in 450 ml of ethanol. On cooling, the product precipitates in crystalline form. It is filtered off and washed with ethanol. After drying, ethyl [3,5-bis(2-hydroxyphenyl)-(1,2,4]triazol-1-yl]acetate remains as colorless crystals of m.p. 172-174° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Br:21])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]>ClCCl>[F:25][C:24]([F:27])([F:26])[C:22]([OH:28])=[O:23].[Br:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2Br)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1ccccc1OC1CCNCC1
Reaction time: 3 h
Yield: 96 %

Procedure:
To a stirred solution of 2-bromophenol (0.5 g, 0.00289 mole) in DMF (4 mL) was added potassium carbonate (0.478 g, 0.003468 mole), followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (0.888 g, 0.00318 mole). The reaction mixture was heated at 80° C. for 6 hours. The mixture was then diluted with water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (2% ethyl acetate in hexane) to afford 0.64 g (68%) of 4-(2-bromo-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 356.08 (M+1)+, 99.56%. A solution of 4-(2-bromo-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (0.64 g, 0.0018 mole) in dichloromethane (6.4 mL) was stirred at 0-5° C. To the cold solution was added TFA (3.2 mL) dropwise and stirring was continued at ambient temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was washed with hexane to afford 0.64 g (96%) of 4-(2-bromo-phenoxy)-piperidine trifluoroacetate. LCMS: 370.02 (M+1)+, 91.37%. 1H NMR (CDCl3-D2O): δ 7.6-7.54 (d, 1H), 7.32-7.26 (d, 1H), 6.94-6.86 (d, 2H), 4.8-4.7 (bs, 1H), 3.5-3.4 (m, 2H), 3.3-3.2 (m, 2H), 2.2-2.1 (s, 4H).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[NH:5][C:6](=[CH:10][CH2:11][CH2:12][NH2:13])[C:7](=[O:9])[N:8]=1.Cl.NC1NC=C(CCCN[C:25]([C:27]2[N:28]([CH3:34])[C:29]([Br:33])=[C:30]([Br:32])[CH:31]=2)=[O:26])N=1>>[ClH:1].[NH2:3][C:4]1[NH:5][C:6](=[CH:10][CH2:11][CH2:12][NH:13][C:25]([C:27]2[N:28]([CH3:34])[C:29]([Br:33])=[C:30]([Br:32])[CH:31]=2)=[O:26])[C:7](=[O:9])[N:8]=1
Reactant: Cn1c(C(=O)NCCCc2c[nH]c(N)n2)cc(Br)c1Br
Reactant: NCCC=C1NC(N)=NC1=O
Agent: Cl
Product: Cn1c(C(=O)NCCC=C2NC(N)=NC2=O)cc(Br)c1Br
Yield: 47 %

Procedure:
Using the same general procedure as used for 2-amino-5-(3-amino-propylidene)-1,5-dihydro-imidazol-4-one dihydrochloride, 0.100 g of dihydrosventrin hydrochloride 23 gave 0.048 g (47%) of the title compound 32 as a tan solid ((Z)-isomer exclusively). 1H NMR (300 MHz, CD3OD) δ 6.84 (s, 1H), 6.16 (t, 1H, J=7.8 Hz), 3.91 (s, 3H), 3.46 (t, 2H, J=6.9 Hz), 2.59 (dt, 2H, J=6.9, 14.7 Hz); 13C NMR (100 MHz, DMSO-d6) δ 163.80, 163.00, 157.19, 130.63, 129.04, 119.42, 115.92, 112.67, 99.09, 39.06, 36.28, 28.73; HRMS (ESI) calcd for C12H14Br2N5O2 (MH+) 417.9509, found 417.9511.
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=[O:2].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[C:24]([O:31][C@@H:32]([C@H:34]3[CH2:38][NH:37][C:36](=[O:39])[CH2:35]3)[CH3:33])[C:25]3[S:29][CH:28]=[N:27][C:26]=3[CH:30]=2)[CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.CCN(CC)CC.C(OC(=O)C)(=O)C>C(Cl)Cl>[C:1]([N:19]1[CH2:18][CH2:17][N:16]([C:15]2[CH:14]=[CH:13][C:12]([C:22]3[CH:23]=[C:24]([O:31][C@@H:32]([C@H:34]4[CH2:38][NH:37][C:36](=[O:39])[CH2:35]4)[CH3:33])[C:25]4[S:29][CH:28]=[N:27][C:26]=4[CH:30]=3)=[CH:11][C:10]=2[O:9][CH3:8])[CH2:21][CH2:20]1)(=[O:2])[CH3:3]
Reactant: COc1cc(-c2cc(O[C@H](C)[C@H]3CNC(=O)C3)c3scnc3c2)ccc1N1CCNCC1
Reactant: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COc1cc(-c2cc(O[C@H](C)[C@H]3CNC(=O)C3)c3scnc3c2)ccc1N1CCN(C(C)=O)CC1
Reaction time: 1.5 h

Procedure:
The crude TFA salt of 4.34 (0.072 mmol) was suspended in DCM (1 mL) and Et3N (72 μL, 0.51 mmol) was added followed by acetic anhydride (8.2 μL, 0.086 mmol). The resulting mixture was stirred 1.5 h and was partitioned between EtOAc, water, and brine. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography (0-15% MeOH in DCM) to afford (R)-4-((R)-1-((5-(4-(4-acetylpiperazin-1-yl)-3-methoxyphenyl)benzo[d]thiazol-7-yl)oxy)ethyl)pyrrolidin-2-one (4.35).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][C:10]2=O)=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>ClC(Cl)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[S:8][C:9]3[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][C:10]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)C1CCC(Sc2ccc(F)cc2)C(=O)C1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O
Product: CCOC(=O)C1CCc2sc3ccc(F)cc3c2C1
Temperature: 80 °C
Yield: 78.1 %

Procedure:
To a room temperature solution of ethyl 4-[(4-fluorophenyl)thio]-3-oxocyclohexanecarboxylate (3.4 g, 11.5 mmol) in dichloroethane (100 mL) was added AlCl3 (3.7 g, 27.6 mmol). The mixture was heated to 80° C. for 1 hour. After cooling to room temperature, the reaction was diluted with water and acidified with 1 N HCl. The aqueous mixture was extracted with EtOAc. The organic layer was washed with water then brine, then was dried over MgSO4 and concentrated to an oil. Purification by chromatography on silica gel afforded 2.5 g (77%) of the title compound as semi-solid: MS (+) 278 (M)+.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:19]4[C:14](=[N:15][CH:16]=[N:17][C:18]=4[NH2:20])[N:13]([CH3:21])[N:12]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[Cl:22][C:23]1[C:24]([F:34])=[C:25]([CH2:30][C:31](O)=[O:32])[CH:26]=[CH:27][C:28]=1[F:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:22][C:23]1[C:24]([F:34])=[C:25]([CH2:30][C:31]([N:2]2[C:10]3[C:5](=[CH:6][C:7]([C:11]4[C:19]5[C:14](=[N:15][CH:16]=[N:17][C:18]=5[NH2:20])[N:13]([CH3:21])[N:12]=4)=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)=[O:32])[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: O=C(O)Cc1ccc(F)c(Cl)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1nc(-c2ccc3c(c2)CCN3C(=O)Cc2ccc(F)c(Cl)c2F)c2c(N)ncnc21
Reaction time: 8 h

Procedure:
In a 20 mL vial with cap, to a solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine HCl (70 mg, 0.231 mmol), (3-chloro-2,4-difluorophenyl)acetic acid (47.8 mg 0.231 mmol), and HATU (88 mg, 0.231 mmol) in DMF (2 mL) was added Hunig's base (0.162 mL, 0.925 mmol). The mixture was stirred overnight. The reaction was poured into water (100 mL), and an off-white solid was formed. The solid was filtered, washed with water (10 mL), and dried to afford the title compound as an off-white solid. LC-MS (ES) m/z=455.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.24-3.31 (m, 2H), 3.94 (s, 3H), 4.03 (s, 2H), 4.32 (t, J=8.46 Hz, 2H), 7.30-7.36 (m, 1H), 7.39-7.46 (m, 2H), 7.54 (s, 1H), 8.14 (d, J=8.34 Hz, 1H), 8.25 (s, 1H).