Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])=[C:5]([C:16]([NH2:18])=[O:17])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]1)#[N:2].CO[CH:29](OC)[N:30]([CH3:32])[CH3:31]>>[C:1]([C:3]1[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])=[C:5]([C:16](/[N:18]=[CH:29]/[N:30]([CH3:32])[CH3:31])=[O:17])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]1)#[N:2]
Reactant: COC(OC)N(C)C
Reactant: N#Cc1c(N2CCOC(CO)C2)sc(C(N)=O)c1-c1ccc(Cl)cc1Cl
Product: CN(C)/C=N/C(=O)c1sc(N2CCOC(CO)C2)c(C#N)c1-c1ccc(Cl)cc1Cl
Yield: 99.7 %

Procedure:
A mixture of 4-cyano-3-(2,4-dichlorophenyl)-5-[2-(hydroxymethyl)morpholin-4-yl]thiophene-2-carboxamide (115 mg, 0.279 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (3.44 mL, 0.025 mol) was flushed with argon and then irradiated in microwave at 160° C. for 60 min. The reaction mixture was concentrated to give 4-cyano-3-(2,4-dichlorophenyl)-N-[(1E)-(dimethylamino)methylene]-5-[2-(hydroxymethyl)morpholin-4-yl]thiophene-2-carboxamide (130 mg, 99%). LCMS: (FA) ES+ 467. To the above intermediate in AcOH (4.3 mL, 0.076 mol) was added hydrazine hydrate (100 mg, 0.003 mol). The mixture was flushed with argon and then irradiated in microwave at 120° C. for 20 min. The mixture was concentrated to remove the solvent. The residue was purified using ISCO chromatography on silica gel, elution 1:1 hexane-ethyl acetate to ethylacetate to afford 4-(2,4-dichlorophenyl)-2-[2-(hydroxymethyl)morpholin-4-yl]-5-(4H-1,2,4-triazol-3-yl)thiophene-3-carbonitrile (90 mg, 70%). LCMS: (FA) ES+ 436, 1H NMR (400 MHz, d4-methanol) δ: 8.28 (s, 1H), 7.55 (d, 1H), 7.41 (dd, 1H), 7.34 (d, 1H), 4.12-3.72 (m, 5H), 3.68-3.61 (m, 2H), 3.30-3.20 (m, 1H), 3.12-3.02 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]([OH:16])=[O:15])[C@H:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=O)[CH3:32])=[CH:27][CH:26]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Li].[NH2:45][NH2:46]>C1COCC1.CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]([OH:16])=[O:15])[C@H:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3].[F:23][C:20]1[CH:21]=[CH:22][C:17]([C@H:10]2[C@H:11]([C:14]3[CH:32]=[C:31]([C:28]4[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=4)[NH:46][N:45]=3)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]2)=[CH:18][CH:19]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: NN
Agent: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)O)[C@H](c2ccc(F)cc2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2cc(-c3ccc(F)cc3)[nH]n2)[C@H](c2ccc(F)cc2)C1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
The starting material (3R,4R)-1-tert-butoxycarbonyl-3-(4-fluorophenyl)piperidine-4-carboxylic acid was prepared as an enantiomeric mixture according to the procedure disclosed in WO 2002/068387. The resulting enantiomers were separated via SFC (Instrument: Berger MG II preparative SFC; Column: ChiralPak AD-H, 250×30 mm I.D.; Mobile phase: CO2: Methanol (with 0.01% DEA), 95:5; Flow rate: 70 mL/min; Sample preparation: dissolved in Methanol, 20 mg/ml; Injection: 2 ml per injection.). The faster eluting enantiomer of (3R,4R)-1-tert-butoxycarbonyl-3-(4-fluorophenyl)piperidine-4-carboxylic acid (300 mg, 0.928 mmol) in THF (4.0 ml) was treated with CDT (165 mg, 1.021 mmol) and heated at 60° C. for 20 min. A solution of 4′-fluoroacetophenone (513 mg, 3.71 mmol) in a separate vial was treated at rt with solid lithium bis(trimethylsilyl)amide (621 mg, 3.71 mmol) and the mixture was stirred at rt for 10 min. This lithium mixture was then treated dropwise with the CDT-activated carboxylic acid solution. The combined mixture was stirred for 30 min at rt and then quenched with saturated aqueous NaHCO3. The mixture was diluted with water and extracted with MTBE. The combined organic layers were dried with anhydrous Na2SO4, and then filtered. The filtrate was concentrated to give a residue. The residue was dissolved in EtOH, and treated with hydrazine (0.25 ml, 7.97 mmol). The reaction was heated at 60° C. for 1 h, then cooled to rt and concentrated. Purification of the resulting residue by chromatography on SiO2 (0 to 10% MeOH/DCM) afforded tert-butyl (3R,4R)-3-(4-fluorophenyl)-4-[5-(4-fluorophenyl)-1H-pyrazol-3-yl]piperidine-1-carboxylate, which was dissolved in DCM (1 mL) and treated with TFA (1 mL), followed by stirring at rt for 12 h and concentrating under vacuum. Purification of the resulting residue by RP-HPLC(C18, 15% to 100% water/acetonitrile over 12 min, 0.1% TFA) afforded the title compound. HPLC/MS: 340.1 (M+1), R=1.45 min (LC-4 HPLC conditions). Racemic material can be obtained in a similar manner by using racemic starting material.
Reaction SMILES: Cl.[F:2][C:3]1[NH:4][CH:5]=[CH:6][N:7]=1.[OH-].[K+].[CH2:10](Br)/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(C)=O>[CH2:10]([N:4]1[CH:5]=[CH:6][N:7]=[C:3]1[F:2])/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Fc1ncc[nH]1
Reactant: BrC/C=C/c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Fc1nccn1C/C=C/c1ccccc1
Reaction time: 0.17 h

Procedure:
2-Fluoroimidazole hydrochloride was added to a suspension of powdered KOH in acetone, stirred for 10 minutes, and E-cinnamyl bromide added. After stirring 1 hour, the mixture was worked up by extraction and chromatography to give E-1-cinnamyl-2-fluoro-imidazole, having the following n.m.r. in CDCl3 : 4.6 (d, 2H); 6.1-6.4 (d of t, 1H); 6.6 (d, 1H); 6.6-6.8 (m, 2H); 7.2-7.5 (m, 5H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][CH:10]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14]([CH2:16][C:17]([N-:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([OH:28])[CH:22]=1)=[O:18])#[N:15]>>[OH:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[OH:27])[CH2:20][NH:19][C:17](/[C:16](=[CH:10]/[CH:9]=[CH:8]/[C:7]1[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)/[C:14]#[N:15])=[O:18]
Reactant: O=CC=Cc1ccc([N+](=O)[O-])cc1
Reactant: N#CCC(=O)[N-]Cc1ccc(O)c(O)c1
Product: N#C/C(=C\C=C\c1ccc([N+](=O)[O-])cc1)C(=O)NCc1ccc(O)c(O)c1

Procedure:
The compound was prepared as described in Example 3 by adding 4-nitrocinnamaldehyde (0.009 g, 0.05 mmol) to N-(cyanoacetyl)3,4-dihydroxybenzylamide (Example 2, 0.010 g, 0.05 mmol). After refluxing for 2 h and recrystallization from ethanol a yellow solid was obtained (0.007 g, 39%). The product gave the following analytical data:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:13]4[C:18]([C:19]=3[CH:20]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[B:38]([O:43]C)(OC)[O:39]C.Cl>O1CCCC1>[C:21]1([N:12]2[C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([B:38]([OH:43])[OH:39])=[CH:7][CH:6]=4)=[CH:20][C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Brc1ccc(-c2ccc3c(c2)c2ccccc2n3-c2ccccc2)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc(-c2ccc3c(c2)c2ccccc2n3-c2ccccc2)cc1
Reaction time: 2 h
Yield: 88 %

Procedure:
In a 300-mL three-neck flask was put 8.0 g (20 mmol) of the 3-(4-bromophenyl)-9-phenyl-9H-carbazole obtained in Reaction Scheme (b-1), the atmosphere in the flask was replaced with nitrogen, 100 mL of dehydrated tetrahydrofuran (abbreviation: THF) was then added to the flask, and the temperature was lowered to −78° C. Into this mixture solution, 15 mL (24 mmol) of a 1.65 mol/L n-butyllithium hexane solution was dropped, and the mixture solution with the n-butyllithium hexane solution added was stirred for 2 hours. To this mixture, 3.4 mL (30 mmol) of trimethyl borate was added, and the mixture with the trimethyl borate added was stirred at −78° C. for 2 hours and at room temperature for 18 hours. After the reaction, 1M diluted hydrochloric acid was added to this reaction solution until the solution became acid, and the solution with the diluted hydrochloric acid added was stirred for 7 hours. This solution was subjected to ethyl acetate extraction, and the obtained organic layer was washed with a saturated saline. After the washing, magnesium sulfate was added to the organic layer to adsorb moisture. This suspension was filtered, and the obtained filtrate was concentrated, and hexane was added thereto. The mixture was irradiated with supersonic waves and then recrystallized, so that 6.4 g of a target substance was obtained as a white powder in a yield of 88%. A reaction scheme of Step 2 is shown in (b-2) given below.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[C:46]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[C:46]=3[Cl:52])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1cccc(CBr)c1Cl
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3cccc(Cl)c3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2,3-dichlorobenzene and isolated as white solid (5.5 mg, 30%). MS (m/e): 441.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20]CC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1>CN(C)C(=O)C.[Pd]>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[N:3]=1
Reactant: Nc1nc(N)c2c(Oc3ccc(OCc4ccccc4)cc3)cccc2n1
Agent: [Pd]
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2c(Oc3ccc(O)cc3)cccc2n1
Yield: 85.7 %

Procedure:
2,4-Diamino-5-(4-benzyloxyphenoxy)quinazoline (3.6 g, 10 mmol) was hydrogenated under 4 atm of H2 in the presence of 0.36 g of 10% Pd/C in 80 ml of N,N-dimethylacetamide at 50-60° C. After 4 hours the reaction mixture was filtered through a glass filter of silica gel, concentrated, dissolved in 50 ml of 2-propanol and crystallized at 4° C. The precipitate was collected by filtration, washed with 2-propanol and dried at 50° C. in vacuo to give 2,4-diamino-5-(4-hydroxyphenoxy)quinazoline (2.3 g, 85.2%, m.p. 330-341° C. (dec)).
Reaction SMILES: BrC1C=C(OC)C=C2C=1CCC(=O)N2C1C(Cl)=CC=CC=1Cl.[H-].[Na+].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=1[N:33]1[C:42]2[C:37](=[C:38]([C:45]3[CH:50]=[CH:49][C:48]([F:51])=[CH:47][C:46]=3[F:52])[CH:39]=[C:40]([O:43]C)[CH:41]=2)[CH2:36][CH2:35][C:34]1=[O:53].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=1[N:33]1[C:42]2[C:37](=[C:38]([C:45]3[CH:50]=[CH:49][C:48]([F:51])=[CH:47][C:46]=3[F:52])[CH:39]=[C:40]([OH:43])[CH:41]=2)[CH2:36][CH2:35][C:34]1=[O:53]
Reactant: COc1cc(-c2ccc(F)cc2F)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Agent: COc1cc(Br)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: CN(C)C=O
Product: O=C1CCc2c(-c3ccc(F)cc3F)cc(O)cc2N1c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of compound 1 (126 mg, 0.3 mmol) and sodium hydride (60%) (12 mg, 0.3 mmol) in 6 mL of DMF was stirred for 1 h at rt. Then the compound 2 (78 mg, 0.33 mmol) was added and stirred for 12 h at 135° C. Potassium carbonate (83 mg, 0.6 mmol) and compound 2 (78 mg, 0.33 mmol) was again added to the reaction mixture and stirred for another 24 h at 135° C. After removal of solvent, it was poured in to 30 mL of ethyl acetate and 10 mL of aq Na2CO3, and it was extracted with ethyl acetate (15 mL×3). The combined organic layer was dried over Na2CO3 and concentrated. After removal of solvent, the residue was purified by TLC with hexane/ethyl acetate/2N NH3 in MeOH to afford compound 3 (white solid). Mass spectrum (ESI) for 3, 555 (M+1) and 557 (M+3).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](I)[CH3:8].[F:10][C:11]1[C:12]([O:25][CH3:26])=[C:13]([CH:21]=[CH:22][C:23]=1[F:24])[NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17]>CN(C)C=O>[F:10][C:11]1[C:12]([O:25][CH3:26])=[C:13]([CH:21]=[CH:22][C:23]=1[F:24])[N:14]([CH2:7][CH3:8])[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17]
Reactant: CCI
Reactant: COc1c(NC(=O)C(F)(F)F)ccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(C(=O)C(F)(F)F)c1ccc(F)c(F)c1OC
Temperature: 70 °C
Reaction time: 5 h
Yield: 99.4 %

Procedure:
5.66 g (0.041 mole) of potassium carbonate and 6.39 g (0.041 mole) of ethyl iodide were added to a solution of 7.0 g (0.027 mole) of 3,4-difluoro-2-methoxy-N-(trifluoroacetyl)aniline (XI) [prepared as described in Preparation 15 (C1)] dissolved in 130 ml of dimethylformamide. The mixture was then stirred at 70° C. for 5 hours, after which the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate, and then subjected to column chromatography through silica gel eluted with toluene, to give 7.6 g of 3,4-difluoro-N-ethyl-2-methoxy-N-(trifluoroacetyl)aniline (XII, R9' =ethyl) as a reddish-brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:42]([F:45])([F:44])[F:43])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[N:7]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26]N(S(C4C=CC(C)=CC=4)(=O)=O)C(=O)[O-])=[CH:21][CH:20]=3)[C:6]=2[CH:41]=1.[OH-:46].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([C:42]([F:43])([F:44])[F:45])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[N:7]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][OH:46])=[CH:21][CH:20]=3)[C:6]=2[CH:41]=1
Reactant: Cc1ccc(S(=O)(=O)N(CCc2ccc(-n3c(CCCc4ccncc4)nc4cc(C(F)(F)F)c(Cl)cc43)cc2)C(=O)[O-])cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: OCCc1ccc(-n2c(CCCc3ccncc3)nc3cc(C(F)(F)F)c(Cl)cc32)cc1
Temperature: 40 °C
Reaction time: 7 h
Yield: 54 %

Procedure:
A mixture of 2-(4-{[5-chloro-2-{[4-(4-pyridinyl)butanoyl]amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate (step 3, 220 mg, 0.42 mmol) and 2N NaOH (15 ml) in ethanol (20 ml) was stirred at 40° C. for 7 h. The solvent was removed and the residue was added water (50 ml). The mixture was extracted with ethyl acetate(100 ml). The organic layer was washed with brine (50 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with dichloromethane:methanol (20:1) to afford 105 mg (54%) of the title compound as pale brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:5]=[C:4]([CH3:17])[C:3]=1[N+:18]([O-])=O>CO.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:5]=[C:4]([CH3:17])[C:3]=1[NH2:18]
Reactant: CCCCCCCCOc1cc(C)c([N+](=O)[O-])c(C)c1
Agent: [Pd]
Solvent: CO
Product: CCCCCCCCOc1cc(C)c(N)c(C)c1
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere in a Parr bottle, 2,6-dimethyl-4-(octyloxy)-nitrobenzene (7.89 mmoles) was dissolved in methanol (100 mL). To this was added 0.5 grams of 10% Pd/C, and shaken under a hydrogen atmosphere (30 PSI) for 18 hours. The catalyst was filtered off over Millipore filter paper, and rinsed with methanol. The filtrate was concentrated to yield 2,6-dimethyl-4-(octyloxy)-aniline as a thick oil (1.8 grams; 91%). The product was characterized by NMR (DMSO).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])=[C:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:10]2[C:5](=[CH:6][C:7]([O:31][CH3:32])=[C:8]([O:29][CH3:30])[CH:9]=2)[N:4]=1.[NH:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:31][CH3:32])=[C:8]([O:29][CH3:30])[CH:9]=3)[N:4]=[C:3]([CH2:2][C:34]3[NH:33][CH:37]=[CH:36][N:35]=3)[C:12]=2[C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: c1c[nH]cn1
Reactant: CCCCC(=O)c1c(CBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Product: CCCCC(=O)c1c(Cc2ncc[nH]2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1

Procedure:
According to the same manner as that described in Example 3, 2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-3-valerylquinoline was reacted with imidazole to give 4-(3,4-dimethoxyphenyl)-2-(1-imidazolylmethyl)-6,7-dimethoxy-3-valerylquinoline. This compound was recrystallized from ethanol to give colorless prisms. mp. 156°-157° C.
Reaction SMILES: C(O[C@@H:5]1[O:22][C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.[Al+3].[Cl-:29].[Cl-].[Cl-].C1(C)C=CC=CC=1.[Si](O)(O)(O)O>C(Cl)(Cl)Cl>[CH3:26][C:25]([O:24][CH2:23][C@H:21]1[O:22][C@@H:5]([Cl:29])[C@H:6]([O:7][C:8]([CH3:9])=[O:10])[C@@H:11]([O:12][C:13]([CH3:14])=[O:15])[C@@H:16]1[O:17][C:18]([CH3:19])=[O:20])=[O:27]
Reactant: [Cl-]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O[Si](O)(O)O
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(=O)OC[C@H]1O[C@@H](Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C

Procedure:
To a solution of β-D-glucose pentaacetate (20 g) in CHCl3 (100 mL) was added AlCl3 (3.6 g). After stirring at room temperature, toluene (100 mL) was added, followed by silicic acid (2 g). The mixture was stirred for a few minutes and the precipitate was removed by filtration. The solution was partially concentrated under vacuum and extracted with ice cold water (25 mL). The organic phase was concentrated to a syrupy mixture and ether was added to precipitate acetochloro-β-D-glucose as a powder (12 g).
Reaction SMILES: C(OC([N:8]1[C:16]2[CH:15]=[C:14]([N+]([O-])=O)[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[C:11]=2[CH:10](CCl)[CH2:9]1)=O)(C)(C)C.CCN=C=NCCCN(C)C.Cl.COC1C=C2C(=C(OC)C=1OC)NC(C(O)=O)=C2.CN(C=O)C>Cl.O>[CH2:10]1[C:11]2[C:12]3[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=3[CH:14]=[CH:15][C:16]=2[NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc([N+](=O)[O-])c1ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: COc1cc2cc(C(=O)O)[nH]c2c(OC)c1OC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2c3c(ccc2c1)NCC3
Temperature: 20 °C
Reaction time: 2 h
Yield: 196.1 %

Procedure:
A solution of 13 (170 mg, 0.47 mmol) in HCl-saturated dioxane (10 mL) was stirred at 20° C. for 2 h, then evaporated under reduced pressure below 30° C. EDCI-HCl (270 mg, 1.41 mmol), 5,6,7-trimethoxyindole-2-carboxylic acid (118 mg, 0.47 mmol) and DMF (2.5 mL) were then added, and the mixture was stirred at 20° C. for 2 h. Addition of water precipitated a crude product, which was recrystallised twice from CH2Cl2 /iPr2O to give 1-chloromethyl-5-nitro-3-[5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H-benz[e]indole (14a) (156 mg, 67%), mp 243-245° C. 1H NMR (CDCl3) δ9.44 (s, 1 H, NH), 9.24 (s, 1 H, H-9), 8.43 (dd, J=7.9, 1.2 Hz, 1 H, H-7), 7.87 (dd, J=7.7, 1.5 Hz, 1 H, H-4), 7.70-7.60 (m, 2 H, H-5,6), 7.03 (d, J=2.5 Hz, 1 H, H-3'), 6.87 (s, 1 H, H-4'), 4.88 (dd, J=10.8, 2.1 Hz, 1 H, H-2), 4.74 (dd, J=10.4, 8.9 Hz, 1 H, H-2), 4.36-4.26 (m, 1 H, H-3), 4.10 (s, 3 H, OCH3), 3.99 (dd, J=11.4, 3.1 Hz, 1 H, CHHCl), 3.95 (s, 3 H, OCH3), 3.92 (s, 3 H, OCH3), 3.58 (dd, J=11.4, 9.9 Hz, 1 H, CHHCl).
Reaction SMILES: [CH:1]1([C:4]2[N:5](COCC[Si](C)(C)C)[C:6]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH3:28])[N:22]=3)=[C:7]([C:9]3[C:10]([F:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=3)[N:8]=2)[CH2:3][CH2:2]1.Cl>CCO>[CH:1]1([C:4]2[NH:5][C:6]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH3:28])[N:22]=3)=[C:7]([C:9]3[C:10]([F:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[CH:12]=[CH:13][CH:14]=3)[N:8]=2)[CH2:2][CH2:3]1
Reactant: CNc1nccc(-c2c(-c3cccc(NS(C)(=O)=O)c3F)nc(C3CC3)n2COCC[Si](C)(C)C)n1
Agent: Cl
Solvent: CCO
Product: CNc1nccc(-c2[nH]c(C3CC3)nc2-c2cccc(NS(C)(=O)=O)c2F)n1
Temperature: 60 °C
Yield: 40.8 %

Procedure:
A solution of N-(3-(2-cyclopropyl-5-(2-(methylamino)pyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-2-fluorophenyl)methanesulfonamide (78 mg, 0.14 mmol) in EtOH (2 mL) was treated with aqueous 6.0 N HCl solution and the resulting reaction was heated at 60° C. for 1 hour. LCMS indicated complete reaction, and the reaction was allowed to cool to room temperature. The volatiles were removed in vacuo, and the resulting residue was dissolved in DMSO and purified by reverse phase HPLC. Product fractions were combined, neutralized with saturated aqueous NaHCO3 solution (pH=6), and extracted with DCM (2×). The combined organic portions were dried (Na2SO4), and concentrated. The resulting free base (3A-1) was dissolved in ACN, treated with aqueous 1.0 N HCl solution, frozen, and lypholized to provide N-(3-(2-cyclopropyl-5-(2-(methylamino)pyrimidin-4-yl)-1H-imidazol-4-yl)-2-fluorophenyl)methanesulfonamide (23 mg) as the HCl salt (3A-2): LCMS(m/z) 402.9, (MH+), tR=0.44 minute; 1H NMR (300 MHz, CD3CO2D) δ 1.26-1.38 (m, 2H) 1.37-1.52 (m, 2H) 2.41-2.60 (m, 1H) 2.84 (br s, 3H) 3.12 (s, 3H) 7.03 (d, J=6.5 Hz, 1H) 7.29-7.41 (m, 1H) 7.44-7.59 (m, 1H) 7.69-7.84 (m, 1H) 8.29 (d, J=6.5 Hz, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][N:6]1[C:15](=[O:16])[CH2:14][C:9]2([CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:8][C:7]1=[O:17].[CH3:18][S:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.C(N(C(C)C)CC)(C)C>CC#N>[CH3:18][S:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][O:5][N:6]3[C:15](=[O:16])[CH2:14][C:9]4([CH2:13][CH2:12][CH2:11][CH2:10]4)[CH2:8][C:7]3=[O:17])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1
Reactant: CSc1cccc(N2CCNCC2)c1
Reactant: O=C1CC2(CCCC2)CC(=O)N1OCCCBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CSc1cccc(N2CCN(CCCON3C(=O)CC4(CCCC4)CC3=O)CC2)c1

Procedure:
A mixture of 8-(3-bromopropyloxy)-8-azaspiro[4.5]decan-7,9-dione (4.0 g), 1-(3-methylthiophenyl)piperazine (2.75 g) and diisopropylethylamine (4.6 ml) was stirred in 100 ml of dry CH3CN at room temperature under N2.
Reaction SMILES: [CH2:1]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][CH2:4][CH3:5].[Br-].[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[C:26]([CH:27]=1)=[S+:25][C:24]1[C:19](=[CH:20][CH:21]=[C:22](Br)[CH:23]=1)[N:18]=2>C(Cl)(Cl)Cl>[Br-:13].[CH2:7]([N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]1[CH:15]=[CH:16][C:17]2[C:26]([CH:27]=1)=[S+:25][C:24]1[C:19](=[CH:20][CH:21]=[C:22]([N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH:23]=1)[N:18]=2)[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: Brc1ccc2nc3ccc(Br)cc3[s+]c2c1
Reactant: CCCCCNCCCCC
Agent: [Br-]
Solvent: ClC(Cl)Cl
Product: CCCCCN(CCCCC)c1ccc2nc3ccc(N(CCCCC)CCCCC)cc3[s+]c2c1
Reaction time: 2 h

Procedure:
To a solution of 3.2 g (20.1 mmol) of dipentylamine in 60 mL of CHCl3 was added 4.37 g (10.03 mmol) of 22. The reaction mixture was stirred at r.t for 2 h under argon and concentrated under reduced pressure to give 3,7-bis(dipentylamino)phenothiazin-5-ium bromide (CPD-15): mass spectrum (MALDI-TOF), m/z 509.38 (M+H)+.