Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([OH:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([N:20]([CH2:25][CH3:26])[C:21](=[O:24])[CH2:22]Cl)[CH3:19].C(=O)([O-])[O-].[Na+].[Na+]>CC(=O)CC>[CH2:18]([N:20]([CH2:25][CH3:26])[C:21](=[O:24])[CH2:22][O:17][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:16]=1)[CH3:19]
Reactant: CCN(CC)C(=O)CCl
Reactant: Oc1nc(-c2ccccc2)nc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCN(CC)C(=O)COc1nc(-c2ccccc2)nc2ccccc12
Reaction time: 22 h
Yield: 59.6 %

Procedure:
A mixture of 2-phenyl-4-quinazolinol (4.45 g), N,N-diethylchloroacetamide (3.3 g), sodium carbonate (4.25 g) and cuprous iodide (1 g) in 2-butanone (70 cc) is brought to boiling for 22 hours. The solvent is evaporated off under reduced pressure, water (100 cc) is added, the mixture is alkalinised with ammonia solution and the aqueous phase is extracted with methylene chloride (3×100 cc). The organic phase is dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue is chromatographed on silica gel with a cyclohexane/ethyl acetate (1:1 by volume) mixture as eluant. After crystatllization in isopropyl ether, N,N-diethyl-(2-phenyl-4-quinazolinyl)oxyacetamide (4 g), m.p. 113° C., is obtained.
Reaction SMILES: [NH:1]1[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][CH:2]1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH3:16][O:17][C:18]([NH:20][C@H:21]([C:25](Cl)=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19]>ClCCl.[Ag]C#N>[CH3:16][O:17][C:18]([NH:20][C@H:21]([C:25]([N:1]1[C:5]2([CH2:6][CH2:7][O:8][CH2:9][CH2:10]2)[CH2:4][CH2:3][CH:2]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:26])[CH:22]([CH3:23])[CH3:24])=[O:19]
Reactant: COC(=O)N[C@H](C(=O)Cl)C(C)C
Reactant: CCOC(=O)C1CCC2(CCOCC2)N1
Agent: N#C[Ag]
Solvent: ClCCl
Product: CCOC(=O)C1CCC2(CCOCC2)N1C(=O)[C@@H](NC(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 19.7 %

Procedure:
To a solution of ethyl 8-oxa-1-azaspiro[4.5]decane-2-carboxylate (166) (125 mg, 0.59 mmol) in anhydrous dichloromethane (2 mL) was added silver cyanide (98 mg, 0.73 mmol) followed by N-[(methyloxy)carbonyl]-L-valyl chloride (142 mg, 0.73 mmol) as a solution in anhydrous dichloromethane (3.5 mL) and the solution stirred at room temperature for 18 h under nitrogen. The reaction is filtered and treated with methanol and stirred for 5 minutes. The reaction is concentrated in vacuo and the residue purified by silica gel chromatography eluting with 30-100% hexanes/EtOAc to afford the title compound as a white solid (43 mg, 20% yield).
Reaction SMILES: C([O:5][C:6](=[O:25])[CH2:7][NH:8][CH2:9][C:10]1[CH:19]=[C:18]([Br:20])[CH:17]=[C:16]2[C:11]=1[N:12]=[C:13]([O:23]C)[C:14]([O:21]C)=[N:15]2)(C)(C)C>Br.C(O)(=O)C.C(OCC)C>[BrH:20].[Br:20][C:18]1[CH:17]=[C:16]2[C:11]([NH:12][C:13](=[O:23])[C:14](=[O:21])[NH:15]2)=[C:10]([CH2:9][NH:8][CH2:7][C:6]([OH:25])=[O:5])[CH:19]=1
Reactant: COc1nc2cc(Br)cc(CNCC(=O)OC(C)(C)C)c2nc1OC
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C(O)CNCc1cc(Br)cc2[nH]c(=O)c(=O)[nH]c12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
380 mg (0.921 mmol) of N-(7-bromo-2,3-dimethoxy-quinoxalin-5-ylmethyl)-glycine tert-butyl ester are dissolved in 6 ml of an approximately 25% solution of hydrogen bromide in acetic acid and the solution is stirred for two hours at 70° C. The mixture is cooled to 20° C. and diluted with diethyl ether. The solid is filtered off and washed with diethyl ether. After drying under a high vacuum, the title compound is obtained in the form of a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:35])([C:31]([F:34])([F:33])[F:32])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[N:28][NH:27][C:26]2=[O:30])=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:27]1[C:26](=[O:30])[N:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:15])([F:35])[C:31]([F:34])([F:33])[F:32])=[CH:24][CH:23]=2)[CH:29]=[N:28]1)[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]ncn1-c1ccc(OCC(F)(F)C(F)(F)F)cc1
Product: C[C@@H](n1ncn(-c2ccc(OCC(F)(F)C(F)(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 36.9 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.94 g of (1S)-1-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.16 g of 4-[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone, 0.68 g of 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone was obtained as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14](Cl)[N:13]=[C:12]([NH2:17])[N:11]=2)[C:7]([CH3:18])=[CH:6][C:5]=1[O:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[C:33]([O:37][C:38](=[O:43])[NH:39][CH2:40][CH2:41][SH:42])([CH3:36])([CH3:35])[CH3:34]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([S:42][CH2:41][CH2:40][NH:39][C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:43])[N:13]=[C:12]([NH2:17])[N:11]=2)[C:7]([CH3:18])=[CH:6][C:5]=1[O:19][CH3:20]
Reactant: CC(C)(C)OC(=O)NCCS
Reactant: COC(=O)c1cc(-c2cc(Cl)nc(N)n2)c(C)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2cc(SCCNC(=O)OC(C)(C)C)nc(N)n2)c(C)cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.9 %

Procedure:
5-(2-Amino-6-chloropyrimidin-4-yl)-2-methoxy-4-methylbenzoic acid methyl ester (118 mg, 0.38 mmol) obtained in Example 1-2 and potassium carbonate (212 mg, 1.5 mmol) were placed in a reaction vessel, and then N,N-dimethylformamide (1.0 ml) and (2-mercaptoethyl)carbamic acid tert-butyl ester (0.25 ml, 1.5 mmol) were added thereto. The mixture was stirred at room temperature for 15 hours. The reaction solution was diluted with ethyl acetate (100 ml), and sequentially washed twice with a saturated aqueous sodium bicarbonate solution (50 ml), twice with water (50 ml), and with a saturated aqueous sodium chloride solution (50 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:2) to yield 5-[2-amino-6-(2-tert-butoxycarbonylaminoethylsulfanyl)pyrimidin-4-yl]-2-methoxy-4-methylbenzoic acid methyl ester (143 mg) as a yellow oily material.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:20]O>O.C(OCC)(=O)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:20])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)c2ccccc12
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(O)c2ccccc12
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a solution of 4-hydroxy-1-naphthoic acid (2.18 g) in methanol (15 ml) was added sulfuric acid (1.0 ml), and the mixture was stirred at 70° C. for 3 hours. The solution was diluted with water and ethyl acetate. The organic layer was separated and washed with brine. The extract was dried over magnesium sulfate, filtrated and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with ethyl acetate and hexane to give methyl 4-hydroxy-1-naphthoate (1.64 g) as a white solid.
Reaction SMILES: [I:1][CH2:2][CH2:3][CH:4]=[C:5]([CH3:8])[CH:6]=[CH2:7].[C:9]1([P:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[I-].[PH4+]>C1C=CC=CC=1>[I-:1].[CH3:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH2:3][CH2:2][P+:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C=CC(C)=CCCI
Agent: [I-]
Agent: [PH4+]
Solvent: c1ccccc1
Product: C=CC(C)=CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 24 h

Procedure:
A mixture of 89.0 g. (0.40 mole) of iodo-4-methyl-3,5-hexadiene, 105 g. (0.40 mole) of triphenylphosphine and 350 ml. of benzene was stirred and refluxed for 8 hours. The solvent was removed in vacuo. After addition of about 1 1. of ether the oily mixture was left for one day at 0°. The crystallized salt was suction filtered, finely grinded and washed with ether, then dried for 4 hours at 80°/0.01 Torr. Obtained: 140 g. of phosphonium iodide, m.p. 124°-128°.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[C:24]1[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH:25]=1)C1C=CC=CC=1.[H][H]>[Pd]>[CH3:23][C:15]([C:13]1[CH:12]=[CH:11][C:10]([C:24]2[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH:25]=2)=[C:9]([OH:8])[CH:14]=1)([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: [H][H]
Reactant: CCCCCCC(C)(C)c1ccc(C2=CC(=O)CCC2)c(OCc2ccccc2)c1
Agent: [Pd]
Product: CCCCCCC(C)(C)c1ccc(C2=CC(=O)CCC2)c(O)c1
Yield: 35 %

Procedure:
A mixture of 400 mg. (0.988 mmole) of 3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]cyclohex-2-enone and 20 mg. of 5% palladium-on-carbon was stirred under one atmosphere of hydrogen pressure for 30 minutes. The reaction mixture was then filtered through diatomaceous earth with ether and the filtrate evaporated to a solid. The crude solid was recrystallized from petroleum ether to yield 110 mg. (35%) of the title compound, M.P. 122°-123° C.
Reaction SMILES: [F:1][CH:2]([F:27])[C:3]1[CH:4]=[CH:5][C:6]([F:26])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=2[C:19]2[C:23]([CH3:25])([CH3:24])[CH2:22][CH2:21][CH:20]=2)[CH:8]=1>CO.CCOC(C)=O.[Pd]>[F:27][CH:2]([F:1])[C:3]1[CH:4]=[CH:5][C:6]([F:26])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=2[CH:19]2[CH2:20][CH2:21][CH2:22][C:23]2([CH3:24])[CH3:25])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2cc(C(F)F)ccc2F)c(C2=CCCC2(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(-c2cc(C(F)F)ccc2F)c(C2CCCC2(C)C)c1
Temperature: 25 °C
Reaction time: 22.5 h

Procedure:
To a dry flask containing 83.3B (0.86 g, 2.30 mmol) in MeOH (10 mL) and EtOAc (2 mL) was added palladium, 10% wt on activated carbon (0.25 g, 0.23 mmol). After purging, the mixture was stirred under an atmosphere of hydrogen at room temperature. The reaction was monitored with TLC and LC-MS. After 22.5 hours, the reaction was filtered through Celite. After concentration, the residue was identified 83.3C and used without purification (0.86 g, 99%). MS ESI (pos.) m/e: 376.9 (M+H)+.
Reaction SMILES: O1CCOCCOCCOCCOCCOCC1.CC(C)([O-])C.[K+].[N+:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:31]2)([O-:27])=[O:26].[F:42][C:43]1[CH:50]=[C:49]([F:51])[CH:48]=[CH:47][C:44]=1[CH2:45]Br>C1COCC1>[F:42][C:43]1[CH:50]=[C:49]([F:51])[CH:48]=[CH:47][C:44]=1[CH2:45][N:33]1[C:34]2[C:30](=[CH:29][C:28]([N+:25]([O-:27])=[O:26])=[CH:36][CH:35]=2)[CH:31]=[C:32]1[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2n1Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under argon, 214 mg (0.81 mmol) of 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6) are initially charged in 43 ml of THF, and 9.73 ml (9.73 mmol) of 1-molar potassium tert-butoxide solution in THF and 2000 mg (8.11 mmol) of ethyl 5-nitro-1H-indole-2-carboxylate are added. The mixture is stirred at RT for 15 minutes and then cooled to 0° C. A solution of 1713 mg (8.11 mmol) of 2,4-difluorobenzyl bromide in 13 ml of TKF is slowly added dropwise. The ice-bath is removed and the mixture is stirred at RT for 1 hour. For work-up, the mixture is diluted with water and the THF is removed under reduced pressure using a rotary evaporator. The aqueous residue is extracted with ethyl acetate and the organic phase is washed with sat. sodium chloride solution, dried with sodium sulphate, filtered and dried under reduced pressure. The residue is purified by column chromatography (mobile phase: cyclohexane:ethyl acetate 5:1).
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16](Br)[CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Si:23]([O:30][CH2:31][CH2:32][N:33]([CH2:41][C:42]#[CH:43])[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].C(N(CC)CC)C>[Cu]I.C(#N)C>[C:1]12([CH2:11][NH:12][C:13]([C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([C:43]#[C:42][CH2:41][N:33]([CH2:32][CH2:31][O:30][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:25])[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:37])[CH3:38])[CH:15]=3)=[O:22])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C#CCN(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Br)ncc1Cl
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(CC#Cc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1)CCO[Si](C)(C)C(C)(C)C
Yield: 47.1 %

Procedure:
The sub-titled compound was prepared from N-(1 adamantylmethyl)-2-bromo-5-chloroisonicotinamide (Example 2(i)) (0.37 g), tert-butyl (2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)prop-2-yn-1-ylcarbamate (Example 11(i)) (0.54 g), copper (I) iodide (0.004 g), bis-triphenyphosphine palladium dichloride (0.014 g), triethylamine (6 ml) and anhydrous acetonitrile (6 ml) by the method of Example 2(iii). The crude product was purified by chromatography on silica gel eluting with, iso-hexane:ethyl acetate (8:1 to 4:1) to afford the sub-titled compound (0.28 g) as a yellow gum.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[F:12][C:13]([F:20])([F:19])[C:14]1([CH2:17][OH:18])[CH2:16][CH2:15]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:12][C:13]([F:20])([F:19])[C:14]1([CH2:17][O:18][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:16][CH2:15]1
Reactant: OCC1(C(F)(F)F)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2(C(F)(F)F)CC2)cc1
Reaction time: 8 h
Yield: 49.4 %

Procedure:
p-Toluenesulfonyl chloride (9.6 g, 50.35 mmol) was added at 0° C. to a mixture of (1-trifluoromethyl-cyclopropyl)-methanol (7 g, 49.96 mmol), triethylamine (7.7 mL, 55.24 mmol) and DMAP (0.61 g, 4.996 mmol) in 100 mL of DCM. The resulting mixture was stirred at 0° C. to RT overnight before being washed with aqueous 1M HCl. The aqueous layer was back extracted twice with DCM. The combined organic layers were dried (Na2SO4), filtered, and evaporated. The residue was purified by SiO2 flash chromatography (120 g SiO2, hexanes/[hexanes/Et2O 8/2] 100 to 0% hexanes) to give 7.26 g of toluene-4-sulfonic acid 1-trifluoromethyl-cyclopropylmethyl ester (49% yield).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.[F-].[K+]>C1(C)C=CC=CC=1.O.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>[Cl:8][C:7]1[C:2]([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Clc1nccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1ccc(-c2nccnc2Cl)cc1
Reaction time: 17.5 h
Yield: 43.6 %

Procedure:
Couple 2,3-dichloropyrazine (0.302 g, 2.03 mmol) and 4-chlorophenylboronic acid (0.320 g, 2.05 mmol), using tetrakis(triphenylphosphine)palladium(0) (0.124 g, 0.107 mmol), and potassium fluoride (0.355 g, 6.11 mmol) in toluene (19 mL) and water (5 mL), at 100° C. for 17.5 hr. Cool the reaction, partition the layers and extract the aqueous layer with ethyl acetate. Wash the combined organic layers with saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 0:100 to 35:65 ethyl acetate:hexanes), to give 2-chloro-3-(4-chlorophenyl)-pyrazine (0.199 g, 44%).
Reaction SMILES: [OH-].[NH4+:2].N.[CH2:4]([O:8][CH2:9][CH:10]=[CH2:11])[CH:5]1[O:7][CH2:6]1>>[CH2:9]([O:8][CH2:4][CH:5]([OH:7])[CH2:6][NH2:2])[CH:10]=[CH2:11]
Reactant: C=CCOCC1CO1
Reactant: [NH4+]
Agent: N
Agent: [OH-]
Product: C=CCOCC(O)CN
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Ammonium hydroxide (28%-30% (about 14.82 mol) of ammonia in water, 202 mL, 3 mol) was charged to a one liter, one-neck, round-bottom flask that was cooled in an ice bath. To the above solution allyl glycidyl ether (57.07 g, 0.5 mol) was added dropwise at 0° C. The mixture was allowed to warm up to room temperature and stirred for two days after completion of the allyl glycidyl ether addition. 3-Allyloxy-2-hydroxy-propylamine was separated by distillation at 76° C.-82° C. under 0-1 mbar as a clear liquid (˜33 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[NH:1]([C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)sc1N
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(-c2ccccc2)sc1Nc1ccccc1
Reaction time: 19 h

Procedure:
A vial was charged with copper acetate (77 mg, 0.425 mmol), ethyl 2-amino-5-phenylthiophene-3-carboxylate (100 mg, 0.404 mmol), phenylboronic acid (99 mg, 0.809 mmol), dichloromethane (2 ml), and triethylamine (0.113 ml, 0.809 mmol). The blue-green reaction mixture was magnetically stirred for 19 hours and then concentrated to a volume of 0.5 mL. The crude reaction mixture was purified by silica gel chromatography (7-60% dichloromethane/hexanes) to afford ethyl 2-anilino-5-phenylthiophene-3-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9](O)=[O:10])=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([Cl:16])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C(=O)Cl)c1ccc(Cl)cc1
Temperature: 80 °C
Yield: 97.4 %

Procedure:
2-(4-Chlorophenyl)-2-methylpropanoic acid (3.85 g, 19.4 mmol) in toluene (5 mL) was treated with thionyl chloride (5.00 g, 3.1 mL) and heated at 80° C. for 2 hours. The cooled solution was concentrated under reduced pressure to provide a yellow oil containing a crystalline residue. The mixture was dissolved in hexane, filtered and the filtrate concentrated to provide the compound as a pale yellow oil (4.10 g, 98%).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH3:13][O:14][C:15]1[C:16]2[C:21]([C:22]([O:33][CH3:34])=[C:23]3[C:28]=1[CH:27]=[C:26]([S:29](Cl)(=[O:31])=[O:30])[CH:25]=[CH:24]3)=[CH:20][CH:19]=[CH:18][CH:17]=2.O1CCCC1>C(N(CC)CC)C>[CH3:13][O:14][C:15]1[C:16]2[C:21]([C:22]([O:33][CH3:34])=[C:23]3[C:28]=1[CH:27]=[C:26]([S:29]([O:1][N:2]1[C:3](=[O:12])[C:4]4=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]4[C:6]1=[O:7])(=[O:31])=[O:30])[CH:25]=[CH:24]3)=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: COc1c2ccccc2c(OC)c2cc(S(=O)(=O)Cl)ccc12
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1c2ccccc2c(OC)c2cc(S(=O)(=O)ON3C(=O)c4ccccc4C3=O)ccc12

Procedure:
A mixture of 0.98 g of N-hydroxyphthalimide, 2.02 g of 9,10-dimethoxyanthracene-2-sulfonyl chloride and 40 ml of tetrahydrofuran was stirred on an ice bath, and 0.34 g of triethylamine was added.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][N:27]2[CH2:32][CH2:33][NH2:34])[CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[N:20]1([CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][N:27]2[CH2:32][CH2:33][NH:34][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: NCCN1CCCCC1CN1CCCC1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Solvent: CC#N
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCCCC2CN2CCCC2)c2ccccc21
Yield: 44 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-[(pyrrolidin-1-yl)methyl]-piperidin-1-yl]ethanamine in a yield of 44% of theory. Colourless crystals, m.p. 198° C. (from acetonitrile using fuller's earth).
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][S:8]([C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=2)(=[O:10])=[O:9])[CH:2]=1.Br[CH2:20][C:21]([O:23]C)=[O:22]>>[CH3:17][C:16]1[C:11]([S:8]([N:7]([CH2:20][C:21]([OH:23])=[O:22])[C:3]2[CH:2]=[C:1]([CH3:18])[CH:6]=[CH:5][CH:4]=2)(=[O:10])=[O:9])=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)CBr
Reactant: Cc1cccc(NS(=O)(=O)c2ncccc2C)c1
Product: Cc1cccc(N(CC(=O)O)S(=O)(=O)c2ncccc2C)c1

Procedure:
prepared by reaction of 3-methyl-pyridine-2-sulfonic acid m-tolylamide with methyl bromoacetate
Reaction SMILES: ClC1C=CC=C(C(OO)=O)C=1.[N:12]1([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]2)=[O:19])[CH2:17][CH2:16]S[CH2:14][CH2:13]1.[S:34]([O-:38])([O-])(=[O:36])=S.[Na+].[Na+]>C(Cl)Cl>[O:36]=[S:34]1(=[O:38])[CH2:14][CH2:13][N:12]([C:18]([N:20]2[CH2:21][CH2:22][CH:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:24][CH2:25]2)=[O:19])[CH2:17][CH2:16]1
Reactant: O=S([O-])([O-])=S
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)N2CCSCC2)CC1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)N2CCS(=O)(=O)CC2)CC1
Reaction time: 18 h

Procedure:
2.0 g of m-chloroperbenzoic acid was added to 1.0 g of tert-butyl [1-(thiomorpholine-4-carbonyl)piperidin-4-yl]carbamate in 10 ml of methylene chloride under cooling with ice-water bath. The reaction mixture was allowed to room temperature, and stirred for 18 hours. Aqueous saturated sodium thiosulfate solution was added to the reaction mixture, and this was extracted with EtOAc. The organic layer was washed with aqueous saturated sodium hydrogencarbonate and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting solid was washed with diisopropyl ether to obtain 607 mg of tert-butyl [1-(1,1-dioxothiomorpholine-4-carbonyl)piperidin-4-yl]carbamate.