Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([CH:14]3[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:31])C(=O)C1>C(Cl)Cl>[Br:31][C:10]1[N:11]=[C:12]([CH:14]2[CH2:15][CH2:16][CH:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:19]2)[O:13][C:9]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: COC(=O)C1CCC(c2ncc(Sc3ccc(Cl)cc3)o2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)C1CCC(c2nc(Br)c(Sc3ccc(Cl)cc3)o2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
To a solution of methyl 4-{5-[(4-chlorophenyl)sulfanyl]-1,3-oxazol-2-yl}cyclohexanecarboxylate (3.762 g, 10.69 mmol) in DCM (107 ml) was added NBS (2.093 g, 11.76 mmol) and the reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica 330 g, 0 to 25% EtOAc in hexane), to give methyl 4-{4-bromo-5-[(4-chlorophenyl)sulfanyl]-1,3-oxazol-2-yl}cyclohexanecarboxylate (3.5 g), as a ca. 2:1 mixture of trans/cis isomers. LCMS: M+H 430.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[O:10][CH2:11][CH2:12][CH2:13][NH2:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:19]1[S:23][C:22]([NH2:24])=[N:21][N:20]=1>>[N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[O:10][CH2:11][CH2:12][CH2:13][NH:14][C:19]2[S:23][C:22]([NH2:24])=[N:21][N:20]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nnc(Br)s1
Reactant: NCCCOc1cccc(CN2CCCC2)c1
Product: Nc1nnc(NCCCOc2cccc(CN3CCCC3)c2)s1

Procedure:
The compound is prepared by a method analogous to that of Example 51 from 3-[3-(1-pyrrolidinylmethyl)-phenoxy]1-propanamine and 5-bromo-1,3,4-thiadiazole-2-amine.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:4]=[C:5]([O:20][CH3:21])[CH:6]=[CH:7][C:8]=2[N:9]=[C:10]2[C:15]=1[CH:14]=[C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]1=[CH:11]2.[C-]#N.[K+].[Cu][C:26]#[N:27]>CO>[C:26]([C:2]1[C:3]2[CH:4]=[C:5]([O:20][CH3:21])[CH:6]=[CH:7][C:8]=2[N:9]=[C:10]2[C:15]=1[CH:14]=[C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]1=[CH:11]2)#[N:27]
Reactant: COc1ccc2nc3cc4ccccc4cc3c(Cl)c2c1
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: COc1ccc2nc3cc4ccccc4cc3c(C#N)c2c1
Temperature: 170 °C
Reaction time: 4.5 h
Yield: 176 %

Procedure:
A mixture of 12-chloro-2-methoxy-benz[b]acridine (562 mg, 1.905 mmol), potassium cyanide (136 mg, 2.096 mmol) and copper(I) cyanide (86 mg, 0.953 mmol) in methanol. (3.7 ml) was stirred at 170° C. in a sealed-tube for 4.5 hours. The resulting mixture was filtrated, and the solid was washed with chloroform/methanol (2:1, 10 ml). The combined filtrate was evaporated under reduced pressure to give a residue, which was flash-chromatographed on a silica column packed with chloroform and eluted with 1% methanol/chloroform to yield 12-cyano-2-methoxy-benz[b]acridine (477 mg, 88%). Rf 0.6 (silica gel, 1% methanol/chloroform). MS (CI, CH4): m/z 285 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH:14](=O)[CH2:15][CH2:16][CH3:17]>CS(C)=O.Cl>[OH:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[C:11]=1[CH:14]=[CH:15][CH2:16][CH3:17])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Reactant: CCCC=O
Agent: Cl
Solvent: CS(C)=O
Product: CCC=CC1=C(O)C(=O)c2ccccc2C1=O
Temperature: 75 °C
Reaction time: 4 h
Yield: 38.2 %

Procedure:
To a solution of 20 gram (0.11 moles) of 2-hydroxy-1,4-naphthoquinone in 150 ml of DMSO and 20 ml of concentrated hydrochloride (37%) solution at 75° C., 20 ml of n-butyraldehyde (0.23 mol) was added. The mixture was vigorously stirred at the temperature of 72-78° C. for 4 hours, and then cooled by addition of 300 ml of ice water, and the resulting mixture was extracted with 300 ml of dichloromethane twice. The combined organic phases was washed successively with 500 ml of water, and 500 ml of 5% sodium bisulfite, and 500 ml of 4% sodium bicarbonate, and finally extracted with 400 ml of 5% sodium carbonate twice. The combined sodium carbonate extract was neutralized by addition of concentrated hydrochloric acid to pH 7.2-7.6. After chilling to 0° C., the mixture was filtered, and the resulting brick red solid was washed with cold water and dried under vacuum. 9.6 gram of product was obtained: 38.6% yield. 1H NMR (in CDCl3) δ 1.12 (t, J=8, 3H), 2.31 (m, 2H), 6.60-6.65 (m, 1H), 7.07-7.15 (m, 1H), 7.66-7.77 (m, 3H), 8.06-8.15 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][N:11]1[O:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=O.C[O-].[Na+].[NH3:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][N:11]1[O:15][CH2:16][CH2:17][CH2:18][C:19]([NH2:27])=[O:21]
Reactant: CCOC(=O)CCCON1CCNC1=Nc1c(Cl)cccc1Cl
Reactant: N
Agent: C[O-]
Agent: [Na+]
Product: NC(=O)CCCON1CCNC1=Nc1c(Cl)cccc1Cl

Procedure:
5.51 g. of ethyl 4-{[2-[(2,6-dichlorophenyl)imino]-1-imidazolidinyl]oxy}butyrate, 200 mg. of sodium methylate and methanolic ammonia are warmed under pressure for 24 hours. The solution is then evaporated in vacuo. The residue is recrystallized from methylene chloride/diethyl ether and then from benzene/cyclohexane (1:1), whereupon 4-{[2-[(2,6-dichlorophenyl)imino]-1-imidazolidinyl]oxy}butyramide, m.p. 140°-141°, is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][CH:7]=1.C[Si]([C:13]#[N:14])(C)C.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[C:3]([C:13]#[N:14])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][n+]1cccc(Cl)c1
Reactant: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1ncccc1Cl
Yield: 66.4 %

Procedure:
3-Chloropyridine-1-oxide (2.59 g, 20 mmol), trimethylsilyl cyanide (5.95 g, 60 mmol), and triethylamine (4.05 g, 40 mmol) were combined in 40 mL of acetonitrile and reacted as described in example 763A. The solvent was removed in vacuo and the residue partitioned between CH2Cl2 and 3M potassium carbonate. The organic layer was separated, washed with brine, dried (MgSO4), and concentrated in vacuo. Purification of the crude product by silica gel chomatography using 5% ether/CH2Cl2 as the eluent gave compound 775B (1.84 g, 67%) as a white crystalline solid. HPLC: 100% at 1.64 min(YMC S5 ODS column) eluting with 10-90% aqueous methanol containing 0.2% phosphoric acid over a 4 min gradient monitoring at 220 nm. MS (ES): m/z 139.0 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([CH3:10])[CH2:3][P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6].[H-].[Na+].[CH2:13](Br)[CH:14]=[C:15]([CH2:17][CH2:18][CH:19]=[C:20]([CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH3:21])[CH3:16]>C1COCC1>[C:2]([CH:3]([P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6])[CH2:13][CH:14]=[C:15]([CH3:16])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:21])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])(=[O:1])[CH3:10]
Reactant: COP(=O)(CC(C)=O)OC
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COP(=O)(OC)C(CC=C(C)CCC=C(C)CCC=C(C)C)C(C)=O
Temperature: 20 °C
Reaction time: 2 h

Procedure:
Dimethyl 2-oxopropylphosphonate (560 μL, 4.0 mmol) was added dropwise to a stirred suspension of sodium hydride (50% oil suspension, prewashed with hexane) (210 mg, 4.8 mmol) in anhydrous THF (15 mL) at 20° C. under an Argon atmosphere. The resulting slurry was stirred at 20° C. for 2 hours to allow for complete formation of the sodio derivative and then treated dropwise with farnesyl bromide (1.14 mL, 4.2 mmol). The cloudy yellow mixture was stirred at 20° C. for 2 hours and then quenched with saturated NH4Cl solution. The resulting mixture was washed with water, dried, filtered and evaporated to give the crude product which was purified by flash chromatography on a silica gel column. Elution of the column with hexane:ethyl acetate:methanol (40:10:1, v:v:v) gave the title compound as gum.
Reaction SMILES: [CH2:1]([C:3]([OH:8])([CH2:6][CH3:7])[C:4]#[CH:5])[CH3:2].C[Li].[CH3:11][S:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1>C1COCC1.CCCCCC>[CH2:4]([C:3]([OH:8])([CH2:6][CH3:7])[C:1]#[C:2][CH:17]([C:16]1[CH:19]=[CH:20][C:13]([S:12][CH3:11])=[CH:14][CH:15]=1)[OH:18])[CH3:5]
Reactant: CSc1ccc(C=O)cc1
Reactant: C#CC(O)(CC)CC
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(O)(C#CC(O)c1ccc(SC)cc1)CC
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-ethyl-1-pentyn-3-ol (7.7 ml) in 300 ml anhydrous THF, was added dropwise 100 ml of 1.4 M methyllithium in hexane at −78° C. under argon. The mixture was further stirred for 30 minutes, followed by dropwise addition of 4-(methylthio)benzaldehyde (9.3 ml). The reaction mixture was stirred for another 12 hours, during which the cold bath was removed such that the reaction temperature reached room temperature slowly. Then the reaction was quenched by adding dilute aqueous HCl. The solvent was removed in vacuo and the resulting residue was extracted with brine and dichloromethane (150 ml×3). The organic layer was concentrated under reduced pressure and the resulting crude product was purified by recrystallization from hexane and ethylacetate (4:1) to give 11.8 g of 4-ethyl-1-{4-(methylthio)phenyl}-2-hexyn-1,4-diol as a low-melting solid. mp: 64-65° C. NMR: δ1.04 (t, J=7.5 Hz, 6H), 1.70 (q, J=7.5 Hz, 4H), 2.49 (s, 3H), 5.47 (s, 1H), 7.26 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H). IR (cm−1): 3368, 2970, 2207, 1637, 1589, 1262, 1093.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]1[CH:21]=[C:22]([N:27]=[C:28]=[O:29])[CH:23]=[CH:24][C:25]=1[F:26]>>[F:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]([NH:1][C:2]2[CH:18]=[CH:17][CH:16]=[C:4]([O:5][C:6]3[CH:11]=[CH:10][N:9]=[C:8]4[NH:12][C:13](=[O:15])[NH:14][C:7]=34)[CH:3]=2)=[O:29])[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: O=C=Nc1ccc(F)c(F)c1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)Nc1ccc(F)c(F)c1
Yield: 23 %

Procedure:
Method G was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 3,4-difluoro-phenylisocyanate to afford the title compound (16 mg, 23%). 1H-NMR (DMSO), δ (ppm), J (Hz): 6.45 (d, 1H, HPyr, J=5.9), 6.76 (s, 1H, Harom2′, J=2.2, J=11.05), 7.26-7.40 (m, 5H, Harom 6′, Harom 2, Harom 4, Harom 5, Harom 6), 7.56-7.68 (m, 1H, Harom 5′), 7.78 (d, 1H, HPyr), 8.55 (d, 1H, Harom 4′, J=7.2), 9.00 (s, 1H, NHurea), 9.01 (s, 1H, NHurea), 11.17 (s, 1H, NHim), 11.36 (s, 1H, NHim); MS-LC, Rf=7.07 min, (C19H13F2N5O3), m/z: 398.1 [M++1], 100.
Reaction SMILES: Br[C:2]1[C:6](=[O:7])[C:5]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[O:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C=CC=CC=1.C(O)C.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>[CH3:21][S:18]([C:15]1[CH:16]=[CH:17][C:12]([C:3]2[O:4][C:5]3([CH2:11][CH2:10][CH2:9][CH2:8]3)[C:6](=[O:7])[C:2]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: OB(O)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(C2=C(Br)C(=O)C3(CCCC3)O2)cc1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(C2=C(c3ccccc3)C(=O)C3(CCCC3)O2)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 74.6 %

Procedure:
To a stirred solution of 3-bromo-2-(4-(methylsulfonyl)phenyl)-1-oxa-spiro[4,4]non-2-en-4-one (77 mg) in 5 ml of toluene and 15 ml ethanol, were added 15 mg of tetrakis(triphenylphosphine)palladium(0), 5 ml of 2 M aqueous sodium carbonate solution, and 27 mg of benzeneboronic acid. Then the reaction solution was stirred at 90° C. for 12 hours. The reaction solvent was evaporated off under reduced pressure and the resulting residue was extracted with 20 ml water and dichloromethane (30 ml×1). The organic layer was concentrated in vacuo and the resulting crude product mixture was purified by column chromatography (hexane/ethylacetate) to obtain 57 mg of 2-{4-(methylsulfonyl)phenyl}-3-phenyl-1-oxa-spiro[4,4]non-2-en-4-one as a solid. mp: 184-185° C. NMR: δ2.09 (m, 6H), 2.17 (m, 2H), 3.06 (s, 3H), 7.26 (m, 2H), 7,35 (m, 3H), 7.81 (d, J=8.1 Hz, 2H), 7.92 (d, J=8.1 Hz, 2H). IR (cm−1): 2925, 1695, 1591, 1403, 1150, 771.
Reaction SMILES: C[Li].C([O:5][CH2:6][CH3:7])C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21]C(N(OC)C)=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.O>O1CCCC1>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:6](=[O:5])[CH3:7])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: CON(C)C(=O)Cc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CCOCC
Agent: [Li]C
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Cc1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
A solution of methyllithium in diethyl ether (40 mL, 44 mmol) was diluted with tetrahydrofuran (120 mL), and a solution of 2-(4′-bromobiphenyl-4-yl)-N-methoxy-N-methylacetamide (12 g, 37 mmol) in tetrahydrofuran (50 mL) was added at −78° C., followed by stirring at the same temperature for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate, and subsequently the solvent was distilled off under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.50 (hexane/ethyl acetate=4/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (7.6 g, 26 mmol) as a white solid (yield 71%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[F:16].[CH3:17][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([OH:9])[CH3:17])=[CH:4][C:3]=1[F:16]
Reactant: C[Mg]Br
Reactant: O=C(c1ccccc1)c1ccc(Br)c(F)c1
Solvent: C1CCOC1
Product: CC(O)(c1ccccc1)c1ccc(Br)c(F)c1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a stirred solution of (4-bromo-3-fluorophenyl)-phenylmethanone (200 mg, 0.717 mmol) in THF (6 mL) was added 1.4 M of methylmagnesium bromide in THF (1.8 mL, 2.5 mmol) slowly at −78° C. The reaction was stirred at −78° C. for 4 h. The reaction was quenched with sat. aq. NaHCO3 at −78° C. The crude material was extracted with DCM and concentrated in vacuo to afford the title compound as a colorless oil which was used for next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]([NH:18][CH3:19])=[O:17])[CH:13]=[CH:14][CH:15]=2)[C:5]([C:20]#[N:21])=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][OH:31])=[CH:24][CH:23]=2)[C:3]=1[C:32]#[N:33].[NH:34]1[CH2:38][CH2:37][C@@H:36]([OH:39])[CH2:35]1.O>O1CCCC1>[C:20]([C:5]1[C:6]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]([NH:18][CH3:19])=[O:17])[CH:13]=[CH:14][CH:15]=2)=[N:7][C:2]([N:34]2[CH2:38][CH2:37][C@@H:36]([OH:39])[CH2:35]2)=[C:3]([C:32]#[N:33])[C:4]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][OH:31])=[CH:24][CH:23]=1)#[N:21]
Reactant: CNC(=O)c1cccc(CSc2nc(Cl)c(C#N)c(-c3ccc(OCCO)cc3)c2C#N)c1
Reactant: O[C@@H]1CCNC1
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(CSc2nc(N3CC[C@@H](O)C3)c(C#N)c(-c3ccc(OCCO)cc3)c2C#N)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
73 mg (0.15 mmol) of 3-[({6-chloro-3,5-dicyano-4-[4-(2-hydroxyethoxy)phenyl]pyridin-2-yl}sulfanyl)methyl]-N-methylbenzenecarboxamide Example 84A were initially charged in 1.5 ml of tetrahydrofuran. After addition of 26.6 mg (0.31 mmol) of (R)-3-pyrrolidinol, the mixture was stirred at RT for 30 min. Water was added to the reaction mixture until a clear solution had formed. The solution was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]1[CH2:13][CH2:12][C:11](=S)[NH:10][CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[C:8]1=[O:24].C(O)CCC.[N:39]1([CH2:45][CH2:46][C:47]([NH:49][NH2:50])=O)[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[F:30][C:28]([F:31])([F:29])[C:26]1[CH:25]=[C:5]([CH:4]=[C:3]([C:2]([F:33])([F:32])[F:1])[CH:27]=1)[CH2:6][N:7]1[CH2:13][CH2:12][C:11]2[N:10]([C:47]([CH2:46][CH2:45][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[N:49][N:50]=2)[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[C:8]1=[O:24]
Reactant: NNC(=O)CCN1CCOCC1
Reactant: O=C1C(Cc2ccc(Cl)c(Cl)c2)NC(=S)CCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCCCO
Product: O=C1C(Cc2ccc(Cl)c(Cl)c2)n2c(CCN3CCOCC3)nnc2CCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
To a solution of 106 mg (0.2 mmol) (RS)-1-(3,5-bis-trifluoromethyl-benzyl)-3-(3,4-dichloro-benzyl)-5-thioxo-[1,4]diazepan-2-one in 1 ml of butan-1-ol 42 mg (0.24 mmol) of 3-morpholin-4-yl-propionic acid hydrazide was added. The reaction mixture was stirred at 130° C. overnight. After evaporation of the solvent in vacuum water (5 ml) was added and the mixture was extracted three times with ethyl acetate. The combined organic layers are dried (MgSO4) and concentrated. The residue was purified by column chromatography (SiO2, dichloromethane/methanol=95:5) to yield 77 mg (59.2%) of the title compound as a light yellow solid. MS m/e (%): 650.0 (M+H+, 100).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:34]1([NH2:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CN1C(=O)CCC1>[CH:34]1([NH:40][C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:16]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=3[N:12]=2)=[O:6])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(NC4CCCCC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and cyclohexylamine in NMP. ES-MS m/e (%): 468 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:6][C@@H:5]([CH2:7][C:8]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[O:9])[C:4](=[O:18])[O:3]1.[Br:20]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:20][C:5]1([CH2:7][C:8]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[O:9])[C:4](=[O:18])[O:3][C:2]([CH3:19])([CH3:1])[O:6]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)OC(=O)[C@H](CC(=O)O[Si](C)(C)C(C)(C)C)O1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)OC(=O)C(Br)(CC(=O)O[Si](C)(C)C(C)(C)C)O1
Reaction time: 0.08 h

Procedure:
A solution of (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid, t-butyldimethylsilyl ester (20.9 g, 72.4 mmol) in carbon tetrachloride (200 ml) was treated with N-bromosuccinimide (14.18 g, 79.6 mmol) and 2,2′-azobisisobutyronitrile (0.30 g) and the resulting mixture was heated under reflux while irradiating with a 500 W lamp. After ˜5 minutes, a mild exothermic reaction was observed and the mixture was heated for an additional 5 minutes. The reaction mixture was then cooled in an ice bath and the floating succinimide was filtered and washed with a small amount of carbon tetrachloride. The filtrate was used immediately as such for the next step. 1H NMR (400 MHz, CDCl3) δ: 0.27 (s, 3), 0.28 (s, 3), 0.94 (s, 9), 1.66 (s, 3), 1.84 (s, 3), 3.62 (m, 2).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[C:4]([NH:10][CH3:11])[CH:3]=1.[C:12]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13]>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:17]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:4]([NH:10][CH3:11])[CH:3]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CNc1cc(Cl)ncc1C=O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cnc(Cl)cc1NC

Procedure:
To a solution of 6-chloro-4-(methylamino)pyridine-3-carboxaldehyde (3.41 g, 20 mmol) in THF (120 mL) was added (carbethoxymethylene)triphenylphosphorane (8.35 g, 24 mmol). The mixture was heated at reflux for 16 h, and was then cooled and concentrated. The residue was chromatographed on silica gel (12% ethyl acetate in hexanes eluant) to provide the title compound. MS (m/z) 241.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[N:5][CH:4]=1.[CH2:15]([N:17]=[C:18]=[S:19])[CH3:16]>CCOCC>[CH2:15]([NH:17][C:18]([N:12]1[CH2:13][CH2:14][N:9]([C:7]2[CH:6]=[N:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=2)[CH2:10][CH2:11]1)=[S:19])[CH3:16]
Reactant: COc1cncc(N2CCNCC2)n1
Reactant: CCN=C=S
Solvent: CCOCC
Product: CCNC(=S)N1CCN(c2cncc(OC)n2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 1.94 g. of 1-(6-methoxypyrazinyl)piperazine in 25 ml. of anhydrous ether is added dropwise a solution of 0.87 g. of ethylisothiocyanate in 25 ml. of anhydrous ether. The mixture is stirred 30 minutes and the solid collected and recrystallized from 80% ethanol, giving 2.27 g. of the desired product as white crystals, m.p. 120°-122° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[NH:12][N:11]=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([C:34](=O)[CH2:35][CH2:36][CH3:37])[C:29](OCC)=[O:30])=[CH:23][CH:22]=1)#[N:14].N12CCCN=C1CCCCC2.C(N(CC)C1C=CC=CC=1)C>Cl>[O:30]=[C:29]1[C:28]([CH2:27][C:24]2[CH:25]=[CH:26][C:21]([C:16]3[C:15]([C:13]#[N:14])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:22][CH:23]=2)=[C:34]([CH2:35][CH2:36][CH3:37])[N:12]2[N:11]=[CH:10][CH:9]=[C:8]2[N:7]1[CH:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Reactant: c1cc(NC2CCOCC2)[nH]n1
Agent: Cl
Solvent: CCN(CC)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2ccnn12
Temperature: 180 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A mixture of N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine (1.00 g), ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (4.20 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.9 mL) and N,N-diethylaniline (10 mL) was stirred at 180° C. overnight, allowed to cool, and poured into 1 M hydrochloric acid (50 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (2.39 g, 88%).
Reaction SMILES: [NH:1]([C:3]([S:5][CH3:6])=[NH:4])[NH2:2].O.[C:8]1([C:14]([CH:16]=O)=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:6][S:5][C:3]1[N:1]=[N:2][CH:16]=[C:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=1
Reactant: CSC(=N)NN
Reactant: O=CC(=O)c1ccccc1
Solvent: O
Product: CSc1nncc(-c2ccccc2)n1
Yield: 73.2 %

Procedure:
3-(Methylsulfanyl)-5-phenyl-1,2,4-triazine (2.93 g, 73%) was prepared from methyl hydrazinecarbimidothioate (2.07 g, 19.7 mmol) and phenylglyoxal monohydrate (2.89 g, 19.7 mmol) according to the general procedure of Preparation 2.