Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13]N)[CH2:8][CH2:7]1.[CH2:19]([N:21](CC)CC)C.[C:26]([NH:34][S:35](Cl)(=[O:37])=[O:36])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[C:26]([NH:34][S:35]([NH:21][CH2:19][CH2:13][CH2:12][N:9]1[CH2:8][CH2:7][CH:6]([O:5][C:4]2[CH:15]=[CH:16][C:17]([Cl:18])=[C:2]([Cl:1])[CH:3]=2)[CH2:11][CH2:10]1)(=[O:37])=[O:36])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCN(CC)CC
Reactant: O=C(NS(=O)(=O)Cl)c1ccccc1
Reactant: NCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Solvent: ClCCl
Product: O=C(NS(=O)(=O)NCCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1)c1ccccc1
Reaction time: 16 h

Procedure:
4-(3,4-Dichlorophenoxy)-1-piperidineethanamine (0.16 g) was dissolved in dichloromethane (2 ml) and triethylamine (88 μl) was added. Benzoylsulfamoyl chloride (0.13 g) was added and the solution was stirred for 16 h. The solvent was evaporated and the residue was purified by HPLC (ammonium acetate: acetonitrile 95% to 5% aq) to give the title compound (6 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[N:3]=1.CC1(C)C(C)(C)OB([C:18]2[CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH:22]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:22]2[CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=2)[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)C1
Reactant: Clc1cc(I)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(Cl)nc(Cl)c2)C1
Temperature: 65 °C
Yield: 52.8 %

Procedure:
To a mixture of 2,6-dichloro-4-iodo-pyridine (500 mg, 1.826 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate (646.7 mg, 2.191 mmol, 1.2 equiv.), potassium carbonate (510 mg, 3.651 mmol, 2 equiv.), and PD(dppf)Cl2 DCM (223.6 mg, 0.274 mmol, 0.15 equiv.) in 1,4-dioxane (6 mL) and water (2 mL) was capped in a large CEM vial, de-gassed with N2, heated in oil bath @ 65° C. o/n. It was diluted with water, extracted with EtOAc (2×50 mL), dried over Na2SO4, filtered, concentrated in vacuo. Purification by column chromatography (ISCO), 40 g column, eluded with 0-10% EtOAc/Heptane to afford 304 mg (52.8%) of product as white foam. 1H NMR (400 MHz, CDCl3) δ 7.42 (s, 0.5H), 7.22 (s, 0.5H), 7.04 (s, 2H), 3.93 (s, 2H), 2.90 (s, 2H), 1.53 (s, 9H). LC-MS: m/z=316 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[C:38]([CH3:39])=[CH:37][C:36]([S:40](Cl)(=[O:42])=[O:41])=[C:35]([CH3:44])[CH:34]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:36]4[CH:37]=[C:38]([CH3:39])[C:33]([Cl:32])=[CH:34][C:35]=4[CH3:44])(=[O:41])=[O:42])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: Cc1cc(S(=O)(=O)Cl)c(C)cc1Cl
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cc(C)c(Cl)cc4C)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 4-chloro-2,5-dimethyl-benzenesulfonyl chloride. Purity (ELSD, based on MW=624.1)=93%.
Reaction SMILES: [CH2:1]([N:5]([C:34](=[O:41])[CH2:35][C:36]([O:38]CC)=[O:37])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][C@H:20]([OH:33])[C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:22]=3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].C(O)(=O)C>O.C(O)C>[CH2:1]([N:5]([C:34](=[O:41])[CH2:35][C:36]([OH:38])=[O:37])[C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][C@H:20]([OH:33])[C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:22]=3)[CH2:14][CH2:13]2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C(=O)CC(=O)OCC)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCCCN(C(=O)CC(=O)O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.2 %

Procedure:
To a stirred solution of ethyl 3-(butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-l}ethyl)amino]-1-piperidineyl}anilino)-3-oxopropanoate (which was obtained in Example 373) (0.23 g, 0.39 mmol) in distilled water (3 mL) and ethanol (2 mL) was added 1 N sodium hydroxide (2 mL). The reaction was stirred at room temperature for 1 hour. The mixture was acidified (pH 6) with glacial acetic acid, concentrated, triturated with water, ethyl acetate, ether, and dried under vacuum to give the titled compound as a tan solid (0.04 g, 19%); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.50 (m, 6H), 1.70-1.95 (m, 2H), 2.60-2.80 (m, 5H), 2.83 (s, 2H), 2.91 (s, 3H), 3.45-3.70 (m, 4H), 4.55-4.65 (m, 1H), 6.81 (d, J=8.0 Hz, 1H), 6.90 (d, J=8.7 Hz, 2H), 7.09 (d, J=8.7 Hz, 2H), 7.07 (s, 1H); MS (ES) m/z: 563.2 (MH+); HRMS Calcd. for C27H39N4O7S(MH+): 563.2461. Found: 563.2526.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]=[C:6]([NH2:11])[C:7]([F:10])([F:9])[F:8])[CH3:2].[C:13](Cl)(=[O:16])[CH:14]=[CH2:15].Cl>C1(C)C=CC=CC=1.CCCCCCC>[CH2:1]([O:3][C:4]([C:5]1[CH2:15][CH2:14][C:13](=[O:16])[NH:11][C:6]=1[C:7]([F:10])([F:8])[F:9])=[O:12])[CH3:2]
Reactant: C=CC(=O)Cl
Reactant: CCOC(=O)C=C(N)C(F)(F)F
Agent: Cl
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(C(F)(F)F)NC(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.8 %

Procedure:
To 3-amino-4,4,4-trifluoro-2-butenoic acid ethyl ester (529 mL, 3.47 mol) was added acryloylchloride (600 mL, 6.95 mol) dropwise over a period of 15 min. The suspension was stirred at RT for 1 h. The temperature was slowly raised with stirring to 80° C. (HCl gas evolution) and maintained at 80° C. for 5 h. Stirring continued overnight at 40° C. The mixture was cooled, diluted with toluene (2 L) and n-heptane (2 L) to precipitate the product and stirred for another 15 min at room temperature. The product was isoloated by filtration, the filter cake was washed with toluene/n-heptane (1:2; 4×100 mL) and dried in vacuo at 40° C. for 5 h. This procedure yielded the title compound (286 g, 35%) as a white solid, MS (ISP) 236.1 (M−H)−. Concentration of the mother liquor and addition of toluene/n-heptane (1:10) yielded a second crop of 29.8 g.
Reaction SMILES: [Na][Na].[C:3]([CH2:11][C:12]([C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=1[C:20]([OH:22])=[O:21])=O)(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.O.[NH2:25][NH2:26]>CO.O>[C:20]([C:15]1[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=1[C:12]1[CH:11]=[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:26][N:25]=1)([OH:22])=[O:21]
Reactant: O=C(O)C1=C(C(=O)CC(=O)c2ccccc2)CCCC1
Reactant: NN
Agent: Cl
Agent: [Na][Na]
Solvent: O
Solvent: CO
Product: O=C(O)C1=C(c2cc(-c3ccccc3)[nH]n2)CCCC1

Procedure:
To a slurry of 31.6 g of the disodium salt of 2-benzoylacetyl-1-cyclohexenecarboxylic acid in 150 ml of methanol is added 12 g of concentrated hydrochloric acid, followed by 12 g of hydrazine hydrate. The reaction mixture is refluxed for 2 hours, cooled to 5°, acidified to pH 3, and diluted with 150 ml of water. The solid is collected and recrystallized from acetic acid-water to give 11.4 g of 3-(2-carboxy-1-cyclohexen-1-yl)-5-phenylpyrazole, m.p. 207°-209°.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([F:42])=[C:22]([C@:24]34[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]3[CH2:28][S:27][C:26]([NH:34]C(=O)OC(C)(C)C)=[N:25]4)[CH:23]=2)=[O:16])=[N:13][CH:14]=1.C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)C>[NH2:34][C:26]1[S:27][CH2:28][C@@H:29]2[CH2:30][CH2:31][CH2:32][CH2:33][C@:24]2([C:22]2[CH:23]=[C:18]([NH:17][C:15]([C:12]3[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][N:13]=3)=[O:16])[CH:19]=[CH:20][C:21]=2[F:42])[N:25]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(NC(=O)c4ccc(Cl)cn4)ccc3F)CCCC[C@H]2CS1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1=N[C@@]2(c3cc(NC(=O)c4ccc(Cl)cn4)ccc3F)CCCC[C@H]2CS1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
Trifluoroacetic acid (200 μL) was added to a solution of the compound of Example 1 (23.0 mg) in dichloromethane (1.00 mL), and the mixture was stirred at room temperature for four hours. The reaction solution was diluted with diethyl ether and neutralized with a sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by NH-silica gel column chromatography to obtain the title compound (18.0 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][CH:12]=[N:13][CH:14]=1.N1C=CC=CC=1.[C:21]1([C:34](Cl)=[O:35])[C:33]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1>ClCCl>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:34]([C:21]2[C:33]3[CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]=3[CH:24]=[CH:23][CH:22]=2)=[O:35])=[CH:4][C:3]=1[C:9]1[CH:14]=[N:13][CH:12]=[N:11][CH:10]=1
Reactant: O=C(Cl)c1cccc2c1Cc1ccccc1-2
Reactant: Cc1ccc(N)cc1-c1cncnc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc3c2Cc2ccccc2-3)cc1-c1cncnc1
Reaction time: 2 h
Yield: 73.9 %

Procedure:
To a suspension of 4-methyl-3-(pyrimidin-5-yl)aniline (0.111 g) and pyridine (0.15 ml) in dichloromethane (2 ml) was dropwise added a solution of the fluorene-1-carbonyl chloride (0.137 g) in dichloromethane (2 ml) followed by stirring for 2 hours. The mixture was diluted with dichloromethane and washed with an aqueous solution of sodium hydrogen carbonate and brine. The separated organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was triturated with methanol. The resulting solid was collected by filtration to give N-(4-methyl-3-(pyrimidin-5-yl)-phenyl)-9H-fluorene-1-carboxamide (0.167 g, 73.9%)
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[F:39][C:40]1[CH:41]=[C:42]([CH:44]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH:46]=1)[NH2:43].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:43][C:42]1[CH:44]=[C:45]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:46]=[C:40]([F:39])[CH:41]=1
Reactant: CC1(C)OB(c2cc(N)cc(F)c2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(N)cc(F)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 53 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (250 mg, 0.42 mmol) was treated with 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (250 mg, 1.05 mmol), sodium carbonate (110 mg, 1.05 mmol) and 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (100 mg, 0.12 mmol) in a mixture of 1,2-dimethoxyethane (10.6 ml) and water (2.4 ml) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 70% n-hexane-ethyl acetate) to obtain 170 mg (53% yield, 82% purity) of the title compound.
Reaction SMILES: [Mg].Cl[CH2:3][C:4]([CH3:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:5].II.[CH:15](N1CCOCC1)=[O:16].Cl>O1CCCC1>[CH3:5][C:4]([CH3:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH:15]=[O:16]
Reactant: O=CN1CCOCC1
Reactant: CC(C)(CCl)c1ccccc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(CC=O)c1ccccc1
Temperature: 0 °C
Yield: 62 %

Procedure:
A mixture of magnesium (4.48 g, 187 mmol), 1-chloro-2-methyl-2-phenylpropane (30.0 g, 179 mmol), a small amount of iodine and tetrahydrofuran (100 ml) was stirred at 70° C. for 2.5 hours. Then, the reaction mixture was cooled to 0° C., followed by adding dropwise thereto a solution of N-formylmorpholine (24.6 g, 214 mmol) in tetrahydrofuran (45 ml), and the resulting mixture was stirred at room temperature for 2 hours. Subsequently, the reaction mixture was re-cooled to 0° C. and 3N hydrochloric acid (180 ml) was added thereto, followed by stirring at room temperature. The reaction mixture was extracted with ethyl acetate, and the extract solution was washed successively with an aqueous sodium thiosulfate solution, an aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography to obtain 18.0 g of 3,3-dimethyl-3-phenylpropionaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([OH:25])[CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2F)[C:19]#[N:20])=[CH:9][CH:8]=1.[H-].[Na+]>CN1C(=O)CCC1.COCCOCCOC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[O:25][C:23]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=3[O:15][CH2:14]2)=[CH:9][CH:8]=1
Reactant: N#Cc1ccc(F)c(OC[C@H](O)c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: COCCOCCOC
Product: N#Cc1ccc2c(c1)OC[C@@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2
Temperature: 150 °C
Reaction time: 0.03 h
Yield: 53.5 %

Procedure:
3-{(R)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-hydroxy-ethoxy}-4-fluoro-benzonitrile (10.2 g) was dissolved in 108 mL NMP-diglyme (1:9) under nitrogen and heated to 150° C. internal temperature. A suspension of sodium hydride (1130 mg of 60% NaH in mineral oil) in 10 mL NMP-diglyme (1:9) was added all at once via syringe while stirring. After 2 minutes, the reaction was removed from heating and cooled, then poured onto saturated ammonium chloride and EtOAc. The layers were separated and the organic layer washed 3 times with 1 N HCl and dried over Na2SO4. The residue was purified by silica gel flash chromatography (DCM-hexanes 1:1 to DCM). The residue was crystallized from refluxing MeOH/DCM (about 3:1), to give 5.2 g of desired product. 1H NMR (400 MHz, CDCl3): 7.53 (d, 1H), 7.45 (d, 1H), 7.34 (m, 2H), 7.27-7.24 (m, 1H), 7.22 (d, 1H) 7.18 (m, 1H), 7.0 (m, 3H), 5.12 (m, 1H), 5.04 (s, 2H), 4.37 (m, 1H), 4.03 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4]2[S:13][C:12]([CH3:14])=[CH:11][C:5]=2[NH:6][C:7]=1C(O)=O)#[N:2].O>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[C:1]([C:3]1[C:4]2[S:13][C:12]([CH3:14])=[CH:11][C:5]=2[NH:6][CH:7]=1)#[N:2]
Reactant: Cc1cc2[nH]c(C(=O)O)c(C#N)c2s1
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: Cc1cc2[nH]cc(C#N)c2s1
Temperature: 200 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a solution of 6-cyano-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (0.54 g) in quinoline (10 mL) was added Copper powder (33 mg), and the mixture was stirred at 200° C. for 30 minutes using microwave reactor. To the reaction solution was added water, and a precipitated insoluble matter was filtered through a Celite pad (registered trademark). The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with 1 mol/L hydrochloric acid, water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=76/24−53/47) to give the title compound (0.37 g).
Reaction SMILES: [C:1]([O:24][CH3:25])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[O:26]1[CH2:31][CH2:30][N:29]([CH2:32]CO)[CH2:28][CH2:27]1>C[O-].[Na+].C1(C)C=CC=CC=1>[C:1]([O:24][CH2:25][CH2:32][N:29]1[CH2:30][CH2:31][O:26][CH2:27][CH2:28]1)(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: OCCN1CCOCC1
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)OCCN1CCOCC1
Yield: 90.9 %

Procedure:
A mixture of 35.5 g of methyl behenate (18), 19.7 g of 2-morpholinoethanol (17), 270 mg of sodium methoxide and 150 g of toluene was heated under reflux for 6 hours while distilling off the methanol resulting from the reaction. The reaction solution was cooled. By standard aqueous work-up and distilling off toluene, 41.3 g of (2-morpholinoethyl) behenate (Quencher 2) was obtained (yield 91%).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[S:15]([OH:18])(=O)=[O:16].C[N:20](C)C=O>>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[S:15]([NH2:20])(=[O:18])=[O:16]
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)O)c1
Solvent: O=S(Cl)Cl
Product: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Reaction time: 2 h
Yield: 42.4 %

Procedure:
To a solution of thionyl chloride (11 mL) and 2-chloro-5-nitro-benzenesulfonic acid (4.78 g, 20.1 mmol) was added N,N-dimethylformamide (0.92 μL) and the reaction mixture was heated to reflux for 4 h. Upon cooling, the reaction mixture was azeotroped with toluene (2-3×). The sulfonyl chloride was dissolved in a minimal amount of toluene and then added to a mixture of concentrated aqueous ammonium hydroxide solution (25 mL) and tetrahydrofuran (25 mL) at −10° C. After stirring for 2 h the reaction was quenched by adding a 6.0 M aqueous hydrochloric acid solution until pH 4 was reached. The layers were separated and the organic layer was concentrated in vacuo to a slurry. Pentane was added and the product was isolated by vacuum filtration to afford the desired product, 2-chloro-5-nitrobenzenesulfonamide (2.0 g, 8.48 mmol, 42.4%) as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:21]2[C:22]([CH3:27])=[N:23][O:24][C:25]=2[CH3:26])[C:5]2[O:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:7]3[C:17](=[O:20])[NH:18][C:19]=1[C:6]=23.[CH3:28][N:29](C=O)C>CO.[C-]#N.[Zn+2].[C-]#N.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>[CH3:27][C:22]1[C:21]([C:4]2[C:5]3[O:10][CH2:9][CH:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[N:7]4[C:17](=[O:20])[NH:18][C:19]([C:6]=34)=[C:2]([C:28]#[N:29])[CH:3]=2)=[C:25]([CH3:26])[O:24][N:23]=1
Reactant: Cc1noc(C)c1-c1cc(Br)c2[nH]c(=O)n3c2c1OCC3c1ccccc1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CO
Product: Cc1noc(C)c1-c1cc(C#N)c2[nH]c(=O)n3c2c1OCC3c1ccccc1
Temperature: 150 °C

Procedure:
9-Bromo-7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (6.9 mg, 0.016 mmol), zinc cyanide (19 mg, 0.16 mmol) and tetrakis(triphenylphosphine)palladium(0) (2.8 mg, 0.0024 mmol) were dissolved in DMF (1.6 mL) and the solution was deoxygenated. The stirred reaction mixture was heated at 150° C. in a microwave for 5 min. The mixture was diluted with MeOH and purified by preparative LCMS using pH 10 buffer to give the title compound. LCMS calc. for C21H17N4O3 (M+H)+: m/z=373.1. found: 373.2.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[F:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1>O1CCCC1>[F:38][C:39]1[CH:47]=[CH:46][C:42]([C:43]([N:19]2[CH2:20][CH2:21][C:15]3[N:14]=[C:13]([C:11]4[S:12][C:8]5[C:7]([N:23]6[CH2:24][CH2:25][O:26][CH2:27][CH2:28]6)=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[C:9]=5[N:10]=4)[NH:22][C:16]=3[CH2:17][CH2:18]2)=[O:44])=[CH:41][CH:40]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNCC4)nc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCN(C(=O)c3ccc(F)cc3)CC4)nc12
Yield: 49 %

Procedure:
To a suspension of 0.037 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine hydrochloride in 3 ml tetrahydrofurane were added at 0–4° C. 0.06 ml N-ethyldiisopropylamine and 0.01 μl 4-fluorobenzoylchloride. The mixture was refluxed for 17 hours, silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with dichloromethane/methanol 96:4 to yield 0.022 g (49%) (4-fluoro-phenyl)-[2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepin-6-yl]-methanone as yellow solid; M.p.: 205–207° C.; MS (ISP): m/e=506 (M−H+).
Reaction SMILES: [C:1]([N:9]1[CH2:21][CH2:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I.O>CN(C=O)C>[C:1]([N:9]1[CH2:21][CH2:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:24])[C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=C(c1ccccc1)N1CCc2c([nH]c3ccccc23)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c2c(c3ccccc31)CCN(C(=O)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.2 %

Procedure:
To a stirred solution of 2-benzoyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole (3.0 g, 10.9 mmole) in dry DMF (75 mL) at 5° C. was added 60% NaH (0.52 g, 13.1 mmole). After 10 min, methyliodide (7.80 g, 55 mmole) was added and the reaction was allowed to warm to RT and stir for 12 hr. The reaction contents were poured into H2O (50 mL) and extracted with EtOAc (2×100 mL). The combined organic phases were washed sequentially with H2O and brine, then were dried over Na2SO4. Concentration under reduced pressure and purification on silica (hexanes/EtOAc, 1:1) afforded the title compound (3.14 g, 99%) as a white solid: MS (ES) m/e 291 (M+H)+.