Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.C(O[C@@H:12]1[C@H:18]2[C@H:19]3[C@H:28]([CH2:29][CH2:30][C@:15]2([CH2:16][CH3:17])[C:14](=[O:32])[CH2:13]1)[C@@H:27]1[C:22](=[CH:23][C:24](=[O:31])[CH2:25][CH2:26]1)[CH2:21][CH2:20]3)(=O)C.O>CCO>[CH3:17][CH2:16][C@:15]12[CH2:30][CH2:29][C@H:28]3[C@@H:19]([CH2:20][CH2:21][C:22]4[C@@H:27]3[CH2:26][CH2:25][C:24](=[O:31])[CH:23]=4)[C@@H:18]1[CH:12]=[CH:13][C:14]2=[O:32]
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1C=CC2=O
Temperature: 25 °C
Yield: 60.6 %

Procedure:
Triethylamine (4 ml, 28.7 mmol) was added to a suspension of 15α-acetoxy-18-methyl-estr-4-en-3,17-dione (4 g, 11.6 mmol) in EtOH (24 ml). The mixture was heated under reflux for 2 h. It was cooled to room temperature and water (50 ml) was added. The precipitate was filtered, washed with a 6/4 EtOH/water solution and dried under vacuum. The residue was purified by flash chromatography on silica gel to afford 18-methyl-estra-4,15-dien-3,17-dione (2 g, yield: 62%).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:26][S:27]([C:30]1[CH:37]=[CH:36][C:33](CBr)=[CH:32][CH:31]=1)(=[O:29])=[O:28].Cl>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][C:33]1[CH:36]=[CH:37][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Product: CS(=O)(=O)c1ccc(CSc2c(Cl)ccc3c2CCNCC3)cc1

Procedure:
Use a method similar to the Example 380, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 4-methylsulfonylbenzyl bromide to give, after hydrochloride formation by the General Procedure 2-2, the title compound as a white solid. MS (ES+) m/z: 382 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+].COCCOC>C(OCC)(=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Br)nc1
Reactant: OB(O)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc(Br)cc2)nc1
Yield: 91.9 %

Procedure:
To a 500 mL round bottom flask, 4-bromophenylboronic acid (25.0 g, 0.125), 2-bromo-5-methylpyridine (20.0 g, 0.114 mol), palladium(0)tetrakistriphenylphosphine (4.0 g, 0.0035 mol), potassium carbonate (47.0 g, 0.34 mol.), 1,2-dimethoxyethane (120 mL) and water (120 mL.) were added. The mixture was heated to reflux under nitrogen atmosphere for 18 hours. After the reaction was cooled down, 100 mL of water and 150 mL of ethyl acetate were added. The mixture was separated in a separatory funnel. The organic phases were collected, combined and evaporated. The mixture was distilled using a kugelrohred (spelling?) to obtain 2-(4-bromophenyl)-5-methylpyridine (26.0 g) as a white solid that was further purified by recrystallization in hexanes.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[F:15][C:16]1[CH:34]=[CH:33][C:19]([CH:20]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=1.C(O)=O.[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42]>C(O)C>[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42].[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH2:5][N:30]1[CH2:29][CH2:28][N:27]([CH:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:34][CH:33]=2)[CH2:32][CH2:31]1
Reactant: COc1ccc(C=O)c(OC)c1OC
Reactant: Fc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: O=CO
Solvent: CCO
Product: COc1ccc(CN2CCN(C(c3ccccc3)c3ccc(F)cc3)CC2)c(OC)c1OC
Temperature: 25 °C
Yield: 32.7 %

Procedure:
2,3,4-Trimethoxybenzaldehyde (7.85 g; 40.0 millimoles) and 10.8 g (39.9 millimoles) of 4-fluorobenzhydrylpiperazine (see German OLS 1929330) were melted in an oil bath at 120° C., and 2.3 ml (61.0 millimoles) of formic acid was added dropwise. The mixture was stirred under heat for 1 hour, and allowed to cool to room temperature. Then, 50 ml of an ethanol solution containing 5.0 g (43.1 millimoles) of fumaric acid was added, and the precipitated crystals were collected by filtration. Recrystallization of the crystals from ethanol gave 7.4 g (yield 32.7%) of 1-(2,3,4-trimethoxybenzyl)-4-(4-fluorobenzhydryl)piperazine fumarate as colorless crystals.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(C)=O.[F:9][C:10]([F:24])([F:23])[C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)[CH2:14]Cl>O>[N:1]([CH2:14][C:13]1[CH:16]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:18]=[C:11]([C:10]([F:9])([F:23])[F:24])[CH:12]=1)=[N+:2]=[N-:3]
Reactant: FC(F)(F)c1cc(CCl)cc(C(F)(F)F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
Sodium azide (74.3 g, 1.14 mol) is suspended in water (125 mL), then DMSO (625 mL) is added. After stirring for 30 minutes, a solution consisting of 3,5-Bis(trifluoromethyl)benzyl chloride (255.3 g, 0.97 moles) and DMSO (500 mL) is added over 30 minutes. (The 3,5-Bis(trifluoromethyl)benzyl chloride is heated to 35° C. to liquefy prior to dispensing (MP=30-32° C.)). The benzyl chloride feed vessel is rinsed with DMSO (50 mL) into the sodium azide solution, the mixture is heated to 40° C., and then maintained for an hour at 40° C., then cooled to 23° C.
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.CI.[BH4-].[Na+].[C:14](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:14][N:6]1[CH2:7][CH2:8][C:9]2[S:1][CH:2]=[N:3][C:4]=2[CH2:5]1
Reactant: c1cc2scnc2cn1
Reactant: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCc2scnc2C1
Temperature: 80 °C

Procedure:
In N,N-dimethylformamide (80 ml) was dissolved thiazolo[4,5-c]pyridine (700 mg), followed by the addition of methyl iodide (0.65 ml). The resulting mixture was stirred under heat at 80° C. for 4 hours. After concentration of the reaction mixture under reduced pressure, the residue was dissolved in water (100 ml). Sodium borohydride (583 mg) was added to the resulting solution, followed by stirring at room temperature for 1 hour. After the addition of a saturated aqueous solution of potassium carbonate, the resulting mixture was extracted with ether. The organic layer thus extracted was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (methylene chloride:methanol=25:1), whereby the title compound (596 mg) was obtained as a colorless oil.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1.[F:15][C:16]([F:28])([F:27])[O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[F:15][C:16]([O:17][C:18]1[CH:19]=[CH:20][C:21]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:22][CH:23]=1)([F:27])[F:28]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Clc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: FC(F)(F)Oc1ccc(-c2cccc(Cl)c2)cc1

Procedure:
A solution of DME (40 mL) and 2M K2CO3 (40 mL) containing 1-bromo-3-chlorobenzene (2.53 g, 13.21 mol), 4-(trifluoromethoxy)phenyl boronic acid (4 g, 19.4 mmol) and Pd(PPh3)4 (0.76 g, 0.66 mmol) was refluxed under an argon atmosphere until no starting material remained by HPLC analysis. The solution was concentrated (to remove excess DME) and partitioned between water and ethyl acetate. The organic phase was washed with 1N NaOH, water (2×) and brine. The solution was then dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. LCMS1 4.23 min.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CON(C)[C:10](=[O:28])[CH2:11][C:12]1[N:16]([CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH:15]=[N:14][CH:13]=1.S(=O)(=O)(O)[O-].[K+]>O1CCCC1.O>[CH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[CH:27][C:18]=1[CH2:17][N:16]1[C:12]([CH2:11][CH:10]=[O:28])=[CH:13][N:14]=[CH:15]1
Reactant: CON(C)C(=O)Cc1cncn1Cc1ccc2ccccc2c1
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: O=CCc1cncn1Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of lithium aluminum hydride (40.8 mg, 1.07 mmol) in tetrahydrofuran (5 ml) at -45° C. was added a solution of N-methoxy-N-methyl-1-(2-naphthylmethyl)-1H-imidazol-5-ylacetamide (243 mg, 0.895 mmol) in tetrahydrofuran (5 ml) via cannula at such a rate to maintain the temperature at <-35° C. After the addition was complete, the reaction was allowed to warm to +5° C. and then recooled to -35° C. To this solution was added a solution of potassium bisulfate (272 mg) in water (1 ml). The mixture was stirred for 30 min at room temperature and then filtered through celite. The celite pad was washed with ethyl acetate (25 ml). The combined filtrates were washed with sat. sodium bicarbonate (10 ml) and then water (10 ml). The organic layer was dried (MgSO4), filtered and evaporated in vacuo to give 30 as a clear oil. This material was used as is in the next step.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[C:7]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8](=[O:13])[O:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:34][O:35][CH2:36]Cl>CN(C)C=O>[CH3:34][O:35][CH2:36][O:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[C:7]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:8](=[O:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(O)ccc2cc(NC(=O)OCc3ccccc3)c(=O)oc12
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCOc1ccc2cc(NC(=O)OCc3ccccc3)c(=O)oc2c1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of benzyl 7-hydroxy-8-methyl-2-oxo-2H-chromen-3-ylcarbamate 7 (975 mg, 3.0 mmol) in anhydrous N,N-dimethylformamide (15 mL) was added N,N-diisopropylethylamine (1.01 mL, 7.5 mmol) over 5 minutes at room temperature. The resulting solution was stirred for 30 minutes and cooled to 0° C. To it was added methoxymethylchloride (1.25 mL, 7.5 mmol) dropwise and the resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched by water and the precipitate was filtered, washed with diethyl ether and dried under vacuum to give compound 8 as a white amorphous solid (931 mg, 82%). 1H NMR (500 MHz, acetone-d6) δ 8.26 (s, 1H), 8.10 (s, 1H), 7.42 (m, 6H), 7.15 (d, 1H, J=8.7 Hz), 5.34 (s, 2H), 5.26 (s, 2H), 3.49 (s, 3H), 2.29 (s, 3H). 13C NMR (100 MHz, acetone-d6) δ 158.8, 157.2, 154.2, 149.9, 137.4, 129.3, 129.0, 128.9, 126.2, 123.1, 112.8, 115.0, 114.9, 112.3, 95.6, 67.6, 56.4, 8.3. IR (KBr) νmax 3321, 2948, 2931, 28591, 1724, 1693, 1608, 1541, 1367, 1213, 1155, 898 cm−1. HRMS (ESI+) m/z [M+Na+] calcd for C20H19NNaO6 392.1110. found 392.1104.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]([CH:18]=[CH:19][CH2:20]Br)[CH:15]=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.CN1C=CN=C1CC=CC1C=CC(C(OC)=O)=C(C2C=CC(F)=CC=2)C=1.[C:48]([N:67]1[CH:71]=[CH:70][N:69]=[CH:68]1)([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.CN1C=CN=C1>>[C:48]([N:67]1[CH:71]=[CH:70][N:69]=[C:68]1[CH2:20]/[CH:19]=[CH:18]/[C:16]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:17]=1)([C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2ccnc2)cc1
Reactant: COC(=O)c1ccc(C=CCBr)cc1-c1ccc(F)cc1
Agent: COC(=O)c1ccc(C=CCc2nccn2C)cc1-c1ccc(F)cc1
Agent: Cn1ccnc1
Product: COC(=O)c1ccc(/C=C/Cc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc(F)cc1

Procedure:
Methyl 4-[(E)-3-(1-tritylimidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate was prepared from methyl 2-(4-fluorophenyl)-4-(3-bromoprop-1-en-1-yl)benzoate using a similar method to that described for methyl 4-[3-(1-methylimidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate in Example 21, but using N-tritylimidazole in replacement of N-methylimidazole.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][CH2:8][CH2:9][OH:10])=[CH:2]1.N1C=CC=CC=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)(Cl)Cl>[CH3:17][S:18]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)(=[O:20])=[O:19]
Reactant: OCCCCc1ccsc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)OCCCCc1ccsc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.2 %

Procedure:
To a solution of 1.05 g (6.7×10-3 mol) of 4-(3-thienyl)-butanol in 25 ml of dry, freshly distilled pyridine was added 0.85 g (1.1 equiv.) of methane-sulfonyl chloride at 25° C. The addition was gradual and carried out over a several minute period. The reaction mixture was stirred for 6 hr at room temperature and quenched by pouring into a separtory funnel containing water-HCl and ether. The layers were separated and the aqueous layer was extracted once with 10% hydrochloric acid, followed by extraction with water and drying with Na2SO4. Evaporation of the solvent afforded 1.51 g of a light brown oil (95% yield), tlc (CHCl3) showed a single spot. El. Anal. Calcd. for C9H14O3S2 : C, 46.13; H, 6.02; S, 27.36. Found: C, 45.92; H, 5.94; S, 27.15. Nmr (CDCl3, δ rel TMS) 2.0-1.5 brs, 4 H; 2.67 brt, 2 H; 2.97 s, 3 H; 4.22 t, 2 H; 7.07-6.80 d, 2 H; 7.37-7.13, 1 H.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:26]CC(C)C)[S:14]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@H:10]([NH:31]C(=O)OC(C)(C)C)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1.Cl>[NH2:31][C@@H:10]1[CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][C@H:11]1[N:13]([CH3:26])[S:14]([C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)(=[O:15])=[O:16]
Reactant: CC(C)CCN([C@@H]1CN(Cc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: C1COCCO1
Product: CN([C@@H]1CN(Cc2ccccc2)C[C@H]1N)S(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of tert-butyl [(3R,4R)-1-benzyl-4-{(3-methylbutyl)[(4-nitrophenyl)sulfonyl]amino}pyrrolidin-3-yl]carbamate in 2N HCl dioxane was stirred overnight at room temperature. The solvent was evaporated to a minimal volume, diethyl ether was added, and the formed pellet was filtered off and washed with diethyl ether giving the crude title product which was used in the next step without purification.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[C:16]3[N:17]([CH2:33][CH2:34][N:35]=3)[C:18]([NH:24][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=3)=[N:19][C:20]=2[C:21]=1[O:22][CH3:23].C(N(CC)CC)C>ClCCl.CN(C)C=O>[CH2:1]([S:3]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[C:16]3[N:17]([CH2:33][CH2:34][N:35]=3)[C:18]([NH:24][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=3)=[N:19][C:20]=2[C:21]=1[O:22][CH3:23])(=[O:5])=[O:4])[CH3:2]
Reactant: COc1c(OCCCN)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Reactant: CCS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)NCCCOc1ccc2c(c1OC)N=C(NC(=O)c1cccnc1)N1CCN=C21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Ethanesulfonyl chloride (18 mg, 0.14 mmol) was diluted in dichloromethane (5 ml) and cooled to 0° C. A solution of N-[8-(3-amino-propyloxy)-7-methoxy-2,3-dihydro-imidazo[1,2-c]quinazolin-5-yl]-nicotinamide hydrotrifluoroacetate (Step 2, 50 mg, 0.13 mmol) in dimethylformamide (5 mL) was added dropwise, and the mixture was stirred at −10° C. for 30 min. Triethylamine (0.07 mL) was added dropwise, and stirring was continued at −10° C. for another 30 min. The reaction mixture was stirred at rt overnight. Another equivalent of ethanesulfonyl chloride was added, and the mixture was stirred at rt for 12 h. The reaction mixture was quenched by the addition of water, and was extracted with dichloromethane. The combined organic extracts were concentrated to afford a white solid, which was triturated with ethyl acetate to remove residual dimethylformamide. After filtration the solid was carefully washed with water and dried in a vacuum oven. The title compound was obtained as a white solid (4.2 mg, 6.8%). HPLC MS RT=1.63 min, MH+=487.3. 1H NMR (DMSO-d6+2 drops TFA-d) δ: 1.18 (3H, t), 2.00 (2H, m), 2.99 (2H, quartet), 3.14 (2H, t), 4.01 (3H, s), 4.23-4.34 (4H, m), 4.57 (2H, m), 7.49 (1H, d), 7.91 (1H, m), 8.04 (1H, d), 8.95 (1H, m), 8.96 (1H, m), 9.49 (1H, m).
Reaction SMILES: [C:1](=[N:14][C:15]1[CH:24]=[C:23](Cl)[C:22]2[C:17](=[CH:18][C:19]([S:26][C:27]3[CH:28]=[C:29]([C:33]4([C:39]#[N:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH:30]=[CH:31][CH:32]=3)=[CH:20][CH:21]=2)[N:16]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:41]1(B(O)O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1](=[N:14][C:15]1[CH:24]=[C:23]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:22]2[C:17](=[CH:18][C:19]([S:26][C:27]3[CH:28]=[C:29]([C:33]4([C:39]#[N:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH:30]=[CH:31][CH:32]=3)=[CH:20][CH:21]=2)[N:16]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: N#CC1(c2cccc(Sc3ccc4c(Cl)cc(N=C(c5ccccc5)c5ccccc5)nc4c3)c2)CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: N#CC1(c2cccc(Sc3ccc4c(-c5ccccc5)cc(N=C(c5ccccc5)c5ccccc5)nc4c3)c2)CCOCC1
Temperature: 90 °C

Procedure:
1r (100 mg, 0.18 mmol), phenylboronic acid (26 mg, 0.21 mmol), Pd(PPh3)4 (20 mg, 0.02 mmol), and potassium carbonate (50 mg, 0.36 mmol) was dissolved in 1,4-dioxane and water and degassed with N2. The mixture was heated to 90° C. until no starting material was seen by tlc analysis. The reaction was cooled to room temperature, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography to give the desired product, 1s.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:13])[CH:12]=1.C([Li])CCC.CN([CH:22]=[O:23])C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:13])[C:12]=1[CH:22]=[O:23]
Reactant: CN(C)C=O
Reactant: Cn1cc(-c2ccccc2F)nn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nnc(-c2ccccc2F)c1C=O
Reaction time: 2 h
Yield: 67.7 %

Procedure:
To a pre cooled (−70° C. to −78° C.) solution of 4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazole 3 (51 g, 287.84 mmol) under nitrogen atmosphere in THF (1200 ml) was added n-Butyllithium (138.16 ml, 345.41 mmol, 2.5M solution in hexane) and stirred for 2 h. Then DMF (1200 ml, 14794.844 mmol) was added and stirred at −78° C. for 30 min. The reaction was monitored by TLC and UPLC. The reaction mixture was slowly quenched with ice cold water (1000 ml) and the aqueous layer was extracted with ethyl acetate (5×1000 ml). The combined organic layer was dried over sodium sulphate, filtered and concentrated to afford crude mass (50 g, 84.66% mass balance). It was purified by gravity column using 20% ethyl acetate in pet ether as an eluent to afford desired product 4-(2-Fluorophenyl)-1-methyl-1H-1,2,3-triazole-5-carbaldehyde (40 g, 67.72%) as reddish solid. Then it was triturated with methyl tert-butyl ether (1000 ml) and hexane (500 ml), the supernant layer was decanted and the solid was dried to furnish desired product 4-(2-Fluorophenyl)-1-methyl-1H-1,2,3-triazole-5-carbaldehyde (32 g, 54.18% yield) as white solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.FC(F)(F)C1C=CC(B(O)O)=CC=1.BrC1C=CC(C#[N:38])=CC=1>>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:38])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: OB(O)c1ccc(C(F)(F)F)cc1
Product: N#Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
Prepared by the method of intermediate D2 using 4-trifluoromethylbenzeneboronic acid and 4-bromobenzonitrile. 1H-NMR (DMSO) δ 7.99-7.94 (6H, m) 7.86 (2H, d); MS(APCI+) found (M+1)=248, C14H8NF3requires 247.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[N+:16]([C:19]1[CH:24]=[C:23]([Cl:25])[C:22](Cl)=[CH:21][C:20]=1[CH2:27][C:28]([N:30]([CH3:49])[C@@H:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([N+:41]([O-:43])=[O:42])[CH:39]=2)CC[C@H:32]1[N:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1)=[O:29])([O-:18])=[O:17].[N+](C1C=CC=CC=1CC(O)=O)([O-])=O.N1C=CC=CC=1.Cl.O(CC)CC.Cl>>[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:27][C:28]([N:30]([CH3:49])[C@@H:31]([C:40]1[CH:35]=[CH:36][CH:37]=[C:38]([N+:41]([O-:43])=[O:42])[CH:39]=1)[CH2:32][N:44]1[CH2:45][CH2:46][CH2:47][CH2:48]1)=[O:29])([O-:18])=[O:17].[ClH:25]
Reactant: CN(C(=O)Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-])[C@@H]1c2cc([N+](=O)[O-])ccc2CC[C@H]1N1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C(O)Cc1ccccc1[N+](=O)[O-]
Solvent: CCOCC
Solvent: c1ccncc1
Product: CN(C(=O)Cc1ccccc1[N+](=O)[O-])[C@H](CN1CCCC1)c1cccc([N+](=O)[O-])c1

Procedure:
This compound was prepared via the general DCC/pyr coupling procedure from 8 (1.4886 g, 5.97 mmol), 2-nitrophenylacetic acid (2.1619 g, 11.93 mmol), DCC(2.5402 g, 12.31 mmol), and pyridine (1.00 mL, 12.36 mmol). The crude product was converted to the HCl salt with Et2O—HCl without chromatography and crystallized from MeOH—Et2O. The first crop was recrystallized again from MeOH—Et2O to yield 10 HCl.(1.3663 g, 51%): m.p. (HCl salt) 258-259° C.; 1H NMR (HCl salt, DMSO-d6) δ1.97 (br s, 4H, —CH2CH2—), 2.91 (s, 3H, —NCH3), 3.11-4.45 (complex, 8H, 4 —CH2—), 6.17 (m, 1H, —CH—), 7.51-8.25 (complex, 8H, aromatic). MS(FAB) m/z 413. Anal. (C, H, N) C21H24N4O5.HCl.0.25H2O.