Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[F:16][C:17]1[C:22](F)=[C:21]([F:24])[C:20]([F:25])=[C:19]([F:26])[C:18]=1[F:27].O>CN(C)C=O>[F:16][C:17]1[C:18]([F:27])=[C:19]([F:26])[C:20]([F:25])=[C:21]([F:24])[C:22]=1[O:3][C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1
Reactant: Fc1c(F)c(F)c(F)c(F)c1F
Reactant: OC1(c2ccccc2)CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1c(F)c(F)c(OC2(c3ccccc3)CCNCC2)c(F)c1F
Temperature: 50 °C
Yield: 44 %

Procedure:
To a suspension of sodium hydride (60% in oil, 6.4 g) in 50 ml of dry dimethylformamide was added, over a period of ten minutes, a solution of 25 g of 4-hydroxy-4-phenylpiperidine in 100 ml of dry dimethylformamide. After stirring at 50° C., for thirty minutes, the reaction mixture was cooled to ice bath temperature (5° C.). A solution of 18.6 ml of hexafluorobenzene in 100 ml of dry dimethylformamide was then added over a period of thirty minutes, and the resulting mixture stirred at ambient temperature for twenty hours. The mixture was poured into 500 ml water, stirred for five minutes, and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, evaporation of the solvents afforded a residue which was purified by means of high pressure liquid chromatography (silica gel; elution with 20% methanol/dichloromethane) to afford 21 g (44%) of 4-(2,3,4,5,6-pentafluorophenoxy)-4-phenylpiperidine as an oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(#N)C>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CNc1ccccc1
Reactant: CCOC(=O)C(Br)c1ccccc1
Solvent: CC#N
Product: CCOC(=O)C(c1ccccc1)N(C)c1ccccc1
Temperature: 100 °C
Yield: 64.2 %

Procedure:
N-methylaniline (2.88 ml, 26.6 mmol) was added to a solution of ethyl 2-bromo-2-phenylacetate (4.65 ml, 26.6 mmol) in acetonitrile (55 ml). The reaction was heated in sealed tube under microwave irradiation at 100° C. for 30 minutes. Acetonitrile was evaporated, residue was taken up with EtOAc and washed sequentially with 1N NaHCO3, 1N HCl and brine. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The residue was triturated with hexane and then purified by flash chromatography (Petroleum ether/EtOAc=97/3) to obtain ethyl 2-(methyl(phenyl)amino)-2-phenylacetate (4.6 g, 64.3% yield).
Reaction SMILES: F[B-](F)(F)F.C[O+:7]([CH3:9])[CH3:8].[F:10][C:11]([F:52])([F:51])[C:12]1[CH:13]=[C:14]([C@H:22]([N:24]([CH3:50])[C:25]([N:27]2[CH2:41][CH2:40][C@:30]3([NH:34]C(=O)[CH:32]([C:36]([O:38][CH3:39])=[O:37])[CH2:31]3)[CH2:29][C@@H:28]2[C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=2[CH3:49])=[O:26])[CH3:23])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1>ClCCl>[F:52][C:11]([F:10])([F:51])[C:12]1[CH:13]=[C:14]([C@H:22]([N:24]([CH3:50])[C:25]([N:27]2[CH2:41][CH2:40][C@:30]3([N:34]=[C:8]([O:7][CH3:9])[CH:32]([C:36]([O:38][CH3:39])=[O:37])[CH2:31]3)[CH2:29][C@@H:28]2[C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=2[CH3:49])=[O:26])[CH3:23])[CH:15]=[C:16]([C:18]([F:19])([F:21])[F:20])[CH:17]=1
Reactant: COC(=O)C1C[C@@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)NC1=O
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=O)C1C[C@@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N=C1OC

Procedure:
A solution of Trimethyloxonium tetrafluoroborate (10.35 mg, 0.070 mmol) and methyl (5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-2-oxo-1,8-diazaspiro[4.5]decane-3-carboxylate (Intermediate 35, 36 mg) in Dichloromethane (DCM) (2 ml) was stirred at rt for 2 hrs. The mixture was washed with NaHCO3 saturated solution and the aqueous layer was extracted with DCM. The organic layers were combined, filtered through a phase separator tube and concentrated obtaining the intermediate methyl(5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methy)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-2-(methyloxy)-1,8-diazaspiro[4.5]dec-1-ene-3-carboxylate:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])=[C:19]([O:37][CH3:38])[CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.C(O)C>Cl>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])=[C:19]([O:37][CH3:38])[CH:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)c(OC)c2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)c(OC)c2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (660 mg), 1 N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml), and ethanol (6 ml) was stirred at room temperature for 3 hours, diluted with 1 N hydrochloric acid (3 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[3-ethoxy-1-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (510 mg, yield: 82%) was obtained. This was recrystallized from ethanol-hexane. Melting point: 122–123° C.
Reaction SMILES: [CH:1]1([O:6][CH2:7][C:8]2[S:12][C:11]([NH:13][C:14]([C:16]3[CH:32]=[CH:31][C:19]([O:20][C@@H:21]4[CH2:26][CH2:25][C@H:24]([C:27]([O:29]C)=[O:28])[CH2:23][CH2:22]4)=[CH:18][CH:17]=3)=[O:15])=[N:10][N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+].Cl>C1COCC1.O>[CH:1]1([O:6][CH2:7][C:8]2[S:12][C:11]([NH:13][C:14]([C:16]3[CH:32]=[CH:31][C:19]([O:20][C@@H:21]4[CH2:26][CH2:25][C@H:24]([C:27]([OH:29])=[O:28])[CH2:23][CH2:22]4)=[CH:18][CH:17]=3)=[O:15])=[N:10][N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)Nc3nnc(COC4CCCC4)s3)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1nnc(COC2CCCC2)s1)c1ccc(O[C@H]2CC[C@@H](C(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74 %

Procedure:
0.446 g of methyl cis-4-[4-(5-cyclopentyloxymethyl[1.3.4]thiadiazol-2-ylcarbamoyl)-phenoxy]cyclohexanecarboxylate (0.97 mmol, 1 eq.) is placed in 10 mL of THF with stirring, at room temperature, 0.111 g of lithium hydroxide monohydrate (2.64 mmol, 2.7 eq.) dissolved in 10 mL of water is added and the mixture is stirred for 36 hours and left to stand for 48 hours. Aqueous 1N hydrochloric acid solution is then added to acidic pH. The precipitate formed is filtered off and washed with water and with ethanol. 0.320 g of cis-4-[4-(5-cyclopentyloxymethyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenoxy]-cyclohexanecarboxylic acid is obtained.
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].Cl[CH2:21][P:22](=[O:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[N:12]([CH2:21][P:22](=[O:25])([CH3:24])[CH3:23])[CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CP(C)(=O)CCl
Reactant: CCCCn1c(=O)c2[nH]cnc2n(CCCC)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1c(=O)c2c(ncn2CP(C)(C)=O)n(CCCC)c1=O
Temperature: 25 °C

Procedure:
5 g (0.01 9 mol) of 1,3-dibutylxanthine were stirred at 80° C. for 6 hours with 2.88 g (0.0228 mol) of chloromethyldimethylphosphine oxide and 3.2 g (0.0228 mol) of potassium carbonate in 80 ml of DMF. The solution was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. The residue which remained was crystallized in petroleum ether/ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([N:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1)=[N:16][N:15]=[CH:14]2.[OH:27]OS([O-])=O.[K+]>CO.O>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([N:21]1[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]1)=[N:16][N:15]=[CH:14]2
Reactant: O=S([O-])OO
Reactant: Cc1ccc(C(N)=O)cc1-c1ccc2c(N3CCSCC3)nncc2c1
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(N)=O)cc1-c1ccc2c(N3CCS(=O)CC3)nncc2c1
Temperature: 25 °C

Procedure:
A mixture of 4-methyl-3-[1-(thiomorpholin-4-yl)phthalazin-6-yl]benzamide (0.6 mmol) (Method A) in 10 mL methanol/H2O (8:2) was stirred at RT was treated with oxone® monopersulfate compound (1 mmol). The mixture was stirred at 0° C.-50° C. over 1h. The mixture was quenched with 20 mL sat. N2SO3, extracted with dichloromethane (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, concentrated in vacuo and purified by silica gel chromatography eluting with 1-5% 2 M ammonia methanol in dichloromethane to give the title compound. Found MS(ES+): 381(M+H)+.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[CH:6]=[C:7]([CH:10]=O)[CH:8]=[CH:9][C:2]=12.[NH2:12][CH:13]1[CH2:18][CH2:17][C:16]([CH2:20][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)([OH:19])[CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.ClC(Cl)C>[N:1]1[S:5][N:4]=[C:3]2[CH:6]=[C:7]([CH2:10][NH:12][CH:13]3[CH2:18][CH2:17][C:16]([CH2:20][CH2:21][C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=5)[N:25]=[CH:24][N:23]=4)([OH:19])[CH2:15][CH2:14]3)[CH:8]=[CH:9][C:2]=12
Reactant: O=Cc1ccc2nsnc2c1
Reactant: COc1ccc2ncnc(CCC3(O)CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CO
Product: COc1ccc2ncnc(CCC3(O)CCC(NCc4ccc5nsnc5c4)CC3)c2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Molecular sieve, type 3A, (1 g) and benzo[1,2,5]thiadiazol-5-carbaldehyde (0.066 g, 0.4 mmol) were added to a solution of 4-amino-1-[2-(6-methoxy-quinazolin-4-yl)-ethyl]-cyclohexanol (0.116 g, 0.38 mmol) in methanol (1 ml) and dichloroethane (3 ml). The reaction mixture was stirred at room temperature for 20 hours and sodium triacetoxyborohydride (0.22 g, 1.04 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and then filtered over Hydromatrix (wetted with an NaHCO3 solution, 2 ml) and subsequently washed with dichloromethane. The filtrate was concentrated to dryness by rotary evaporation. The residue was purified by column chromatography on silica gel (dichloromethane/MeOH 9/1 1% NH4OH).
Reaction SMILES: N1C=CN=CC=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[S:22])=[CH:16][CH:15]=1>CCOCC>[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH:8]2[C:9]2[CH:8]=[N:7][CH:12]=[CH:11][N:10]=2)=[S:22])=[CH:16][CH:15]=1
Reactant: Fc1ccc(N=C=S)cc1
Reactant: c1cnc(N2CCNCC2)cn1
Solvent: CCOCC
Product: Fc1ccc(NC(=S)N2CCNCC2c2cnccn2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 4.92 g. of 1-(2-pyrazinyl)piperazine in 50 ml. of anhydrous ether is added dropwise a solution of 4.59 g. of 4-fluorophenyl isothiocyanate in 50 ml. of anhydrous ether with stirring. Stirring is continued for 30 minutes and the resulting solid is collected. This solid is dissolved in a mixture of 200 ml. of ethanol, and 75 ml. of acetone with heat, then concentrated to 200 ml. and cooled giving 7.43 g. of the desired product as a white solid, m.p. 195°-197° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[C:9](Br)[CH:10]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>CN(C)C=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>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[C:9]([C:23]2[CH:24]=[CH:25][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:21][CH:22]=2)[CH:8]=[N:7][CH:6]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1cncc(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: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cncc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 80 °C
Yield: 76.8 %

Procedure:
81 mg (0.07 mmol)Pd(PPh3)4 was added under argon at room temperature to a solution of 1.0 g (4.63 mmol) methyl-5-bromo-pyridine-3-carboxylate in 23 ml N,N-dimethylformamide and the mixture was heated to 80° C. Then 2.26 g (6.94 mmol) cesium carbonate and 0.97 g (5.09 mmol) of 4-(trifluoromethyl)phenyl boronic acid were added and the mixture was stirred at 80° C. over night. The reaction mixture was cooled to room temperature, filtered, and the filtrate evaporated. The residue was taken up with ethyl acetate, washed twice with water, dried over sodium sulphate and evaporated. Chromatography on silica (eluent: ethyl acetate/n-heptane 1:3) gave 1.0 g (68%) of 5-(4-Trifluoromethyl-phenyl)-nicotinic acid methyl ester
Reaction SMILES: Cl.Cl.[N:3]1([C:9]2[C:10]3[CH2:17][CH2:16][CH:15]([OH:18])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:19]([O:23][C:24]([N:26]([CH:39]([CH3:41])[CH3:40])[CH2:27][CH:28]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:29](O)=[O:30])=[O:25])([CH3:22])([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH:28]([C:29]([N:6]2[CH2:5][CH2:4][N:3]([C:9]3[C:10]4[CH2:17][CH2:16][CH:15]([OH:18])[C:11]=4[N:12]=[CH:13][N:14]=3)[CH2:8][CH2:7]2)=[O:30])[CH2:27][N:26]([CH:39]([CH3:40])[CH3:41])[C:24](=[O:25])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[CH:33][CH:34]=1
Reactant: OC1CCc2c1ncnc2N1CCNCC1
Reactant: CC(C)N(CC(C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC(C)N(CC(C(=O)N1CCN(c2ncnc3c2CCC3O)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
To a solution of 4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (40 mg, 0.14 mmol) in DCM (20 mL) and TEA (2 mL) was added 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (47 mg, 0.14 mmol) and HBTU (52 mg, 0.14 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was removed and the residue was subject to chromatography on silica gel, eluted by ethyl acetate to afford the tert-butyl 2-(4-chlorophenyl)-3-(4-(7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (49 mg, 66%). MS (APCI+) [M+H] +544.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.S([O:19][CH3:20])(OC)(=O)=O>C(#N)C.C(=O)(O)[O-].[Na+].O>[CH2:11]([O:10][C:8]([C:7]1[C:2]([Cl:1])=[CH:3][C:20](=[O:19])[N:5]([CH3:4])[CH:6]=1)=[O:9])[CH3:12]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cn(C)c(=O)cc1Cl
Temperature: 120 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
Ethyl 4,6-dichloronicotinate [prepared according to the literature procedure of J. Chem. Soc. 5163 (1963)] (3.19 g, 14.5 mmol) and dimethyl sulfate (6.0 mL, 63 mmol) were combined in a thick-walled glass tube with a Teflon cap. The tube was sealed and heated in a 120° C. sand bath. After 5 h, the reaction was cooled to ambient temperature and diluted with acetonitrile (100 mL) and saturated aqueous sodium bicarbonate solution (100 mL). The reaction mixture was stirred vigorously overnight (ca. 18 h). This mixture was further diluted with water and extracted with dichloromethane (3×). The combined extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford 4-chloro-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester (2.65 g, 85% yield) as an oil that solidified upon standing.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][N:21]=2)[CH2:16][C:15]1=[O:23]>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=[C:16]1[C:17]2[C:22](=[N:21][CH:20]=[CH:19][CH:18]=2)[NH:14][C:15]1=[O:23])([CH3:3])[CH3:2]
Reactant: O=C1Cc2cccnc2N1
Reactant: COc1ccc(C=O)cc1C(C)C
Product: COc1ccc(C=C2C(=O)Nc3ncccc32)cc1C(C)C

Procedure:
3-Isopropyl-4-methoxybenzaldehyde was condensed with 7-aza-2-oxindole to give 0.25 g of 3-(3-isopropyl-4-methoxybenzylidene)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one as a yellow-orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH3:9])[C:3]=1[F:10].[Br:11]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH2:9][Br:11])[C:3]=1[F:10]
Reactant: Cc1c(F)ccc(Br)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(Br)c(F)c1CBr
Yield: 105.3 %

Procedure:
Bromo-2,4-difluoro-3-methyl-benzene (22 g, 0.106 M) and N-bromosuccinimide (22.7 g, 0.128 M) were dissolved in tetrachloromethane (800 mL). Dibenzoylperoxide (0.52 g, 2 mM) was added and the mixture was irradiated for 1 h. Succinimide was removed by filtration of the cooled mixture and the filtrate was washed with water. The water phase was extracted with dichloromethane. Organic phases were pooled, dried with MgSO4 and and evaporated to yield a yellowish oil (32 g). The residue was purified by column chromatography (silica gel; n-hexane) to yield 28.4 g (94%) of the title compound as a colorless oil. MS (EI): 286.0 (M)+.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH:9]2[CH2:21][OH:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(Cl)(=O)=O>ClCCl.C(N(CC)CC)C>[O:22]([CH2:21][CH:9]1[N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc(CN2CCN(Cc3ccccc3)C(COc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 6 g portion of 1,4-bis(phenylmethyl)-2-piperazinemethanol was dissolved in 90 ml of dichloromethane together with 4.26 ml of triethylamine and then cooled to 0°-5° C. A 2.04 ml portion of methanesulfonyl chloride was added and the mixture was allowed to warm to room temperature over 2 hours. The mixture was washed with ice cold sodium bicarbonate solution, followed twice with ice water, dried, filtered and evaporated. The residue was dissolved in dimethylformamide and added to a solution of 2.07 g of sodium phenol and 1.02 g of 50% sodium hydride in 30 ml of dimethylformamide under argon. This mixture was stirred for 48 hours, water was added and the mixture extracted twice with ether. The extracts were combined, washed with water, dried, filtered and evaporated, giving a gum which was crystallized from methanol with refrigeration, giving 4.1 g of 3-phenoxymethyl-1,4-bis(phenylmethyl)piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.S([O-])([O-])=O.[Na+].[Na+]>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][Br:17])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccc(Cl)c(Cl)c2)c(F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Fc1cc(CBr)ccc1-c1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h

Procedure:
3′,4′-dichloro-2-fluoro-4-methyl-biphenyl (29 g, 0.114 mol), N-bromosuccinimide (21.2 g, 0.119 mol), benzoyl peroxide (1.4 g, 0.004 mol) were dissolved in acetonitrile (190 ml). The mixture was refluxed for 3 hours, then cooled, mixed with a solution of sodium sulphite (2.2 g) in water (54 ml), stirred for 30 minutes and then allowed to rest to separate the phases. The lower aqueous phase was separated and extracted with dichloromethane (29 ml). The upper phase was concentrated under vacuum, mixed with water (10 ml), and dichloromethane (58 ml) and stirred. The organic phases were separated and put together, washed twice with water (29 ml), and concentrated under vacuum. The compound 3′,4′-dichloro-2-fluoro-4-bromomethyl-biphenyl was isolated as an orange oil (35.7 g, 94% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].C([O-])(=O)C.[NH4+:16]>CC(C)=O.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:16])=[O:7]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(C)=O
Solvent: ClCCl
Product: COc1cccc(C(N)=O)c1
Temperature: 25 °C
Yield: 49.8 %

Procedure:
17 g of 3-methoxybenzoyl chloride were dissolved in 200 ml acetone. 15.5 g of ammonium acetate were added to the solution and the reaction mixture was stirred for several hours at room temperature. Then it was dissolved in dichloromethane. The dichloromethane phase was dried by adding sodium carbonate and concentrated. 7.5 g of 3-methoxybenzamide were obtained as a colorless solid.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.Cl.[CH3:19][NH:20][O:21][CH3:22]>ClCCl>[CH:1]1([CH2:7][CH2:8][C:9]([N:20]([O:21][CH3:22])[CH3:19])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNOC
Reactant: O=C(Cl)CCC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)CCC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
3-Cyclohexylpropionic chloride (1.00 g, 5.71 mmol) was dissolved in dichloromethane (10 mL). Under ice-cooled condition, pyridine (0.910 mL, 11.3 mmol) and N,O-dimethylhydroxylamine hydrochloride (840 mg, 8.57 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate after adding a saturated sodium hydrogen carbonate aqueous solution. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→80/20) to give 3-cyclohexyl-N-methoxy-N-methylpropaneamide (1.13 g, yield 99%).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[C:23]([O:27][C:28]([N:30](C(OC(C)(C)C)=O)[C@@H:31]([C:45](O)=O)[CH2:32][CH2:33][C@@H:34]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:38]=1[F:44])[CH2:35][NH2:36])=[O:29])([CH3:26])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[F:44][C:38]1[C:39]([F:43])=[CH:40][CH:41]=[CH:42][C:37]=1[C@H:34]1[CH2:35][NH:36][C:45](=[S:10])[C@H:31]([NH:30][C:28](=[O:29])[O:27][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:32][CH2:33]1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC[C@H](CN)c1cccc(F)c1F)C(=O)O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=S
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Lawesson's reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] (2.90 g, 7.18 mmol) was added to a suspension of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate (4.79 g, 14.1 mmol, described in Intermediate 4) in toluene (250 mL) and the mixture was heated to 90° C. After 1 h, the reaction was allowed to cool to ambient temperature and concentrated under reduced pressure. The residue was partially purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc—100:0 to 85:15.