Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:14]2[C:18](=[O:19])[CH:17]=[CH:16][C:15]2=[O:20])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2C(=O)C=CC2=O)[CH:2]=1.[C:21]1(=[O:27])[O:26][C:24](=[O:25])[CH:23]=[CH:22]1.C1(N)C=CC=C(N)C=1.CN(C)C=[O:39]>>[C:3]1([NH:7][C:21](=[O:27])/[CH:22]=[CH:23]\[C:24]([OH:26])=[O:25])[CH:4]=[CH:5][CH:6]=[C:1]([NH:14][C:18](=[O:19])/[CH:17]=[CH:16]\[C:15]([OH:20])=[O:39])[CH:2]=1
Reactant: CN(C)C=O
Reactant: O=C1C=CC(=O)O1
Reactant: O=C1C=CC(=O)N1c1cccc(N2C(=O)C=CC2=O)c1
Agent: Nc1cccc(N)c1
Product: O=C(O)/C=C\C(=O)Nc1cccc(NC(=O)/C=C\C(=O)O)c1

Procedure:
A typical example of this process is the formation of N,N'-m-phenylenedimaleimide. This involves the addition of maleic anhydride to a solution of m-phenylenediamine in dimethylformamide (DMF) and reacting these at a temperature of 35°-40° C. to form N,N'-m-phenylenedimaleamic acid, which is not isolated. The addition of sodium acetate and acetic anhydride follows, with a maximum reaction temperature for ring closure of 55°-60° C. On the completion of this reaction, a large excess of water is added, precipitating the N,N'-m-phenylenedimaleimide which is subsequently filtered, washed with water, and dried at a moderately elevated temperature. This process is outlined below: ##STR1## N,N'-m-phenylenedimaleimide
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C@H:13]([CH3:16])[CH2:14]O)[C:6]=2[CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:42]I>CCCCCCC.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C@H:13]([CH3:16])[CH2:14][I:42])[C:6]=2[CH:17]=1
Reactant: C[C@H](CO)CN1C(=O)COc2ccc(F)cc21
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: C[C@H](CI)CN1C(=O)COc2ccc(F)cc21
Yield: 100.5 %

Procedure:
The compound (S)-6-Fluoro-4-(3-hydroxy-2-methyl-propyl)-4H-benzo[1,4]oxazin-3-one (111MF03) (2.63 g, 11.0 mmol), triphenylphosphine (6.35 g, 24.2 mmol), imidazole (1.8 g, 26.4 mmol) and I2 (7.81 g, 30.8 mmol) were mixed according to GP9. CC (SiO2; Heptane/EtOAc 9:1-4) gave the title compound (111MF04) (3.86 g, 100%). 1H NMR (CDCl3) δ 6.97-6.93 (m, 1H), 6.82-6.78 (m, 1H), 6.73-6.68 (m, 1H), 4.63-4.53(m, 2H), 3.90 (d, J=6.8 Hz, 2H), 3.20-3.16 (m, 2H), 2.15-2.04 (m, 1H), 1.06 (d, J=6.4 Hz, 3H); 13C NMR (CDCl3) δ 165.0, 158.5 (d, J=240.2 Hz), 141.7 (d, J=2.3 Hz), 129.6 (d, J=10.4 Hz), 118.1 (d, J=9.2 Hz), 110.1 (d, J=23.4 Hz), 103.1 (d, J=28.7 Hz), 67.8, 46.3, 33.5, 18.9, 11.6.
Reaction SMILES: [O:1]=O.O=[O+][O-].[N+:6]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=C)([O-:8])=[O:7].CSC>C(Cl)Cl>[N+:6]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:1])([O-:8])=[O:7]
Reactant: O=O
Reactant: C=Cc1ccccc1[N+](=O)[O-]
Agent: O=[O+][O-]
Solvent: CSC
Solvent: ClCCl
Product: O=Cc1ccccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 91.5 %

Procedure:
Oxygen enriched with 10 m-moles of ozone are introduced at -20° C. in the course of 15 minutes into a solution of 1.50 g of o-nitrostyrene in 160 ml of methylene chloride. The faintly blue solution is scavenged with nitrogen until the colour has disappeared, treated with 10 ml of dimethyl sulphide and left to stand overnight at room temperature. The clear solution is concentrated in vacuo and the residue is taken up in ethyl acetate. The ethyl acetate solution is washed with water and sodium chloride solution, dried over sodium sulphate and concentrated. The crude product (1.75 g) is taken up in benzene and the solution is chromatographed through a column of silica gel (15 g). The first 100 ml of eluate are concentrated in vacuo, affording 1.39 g of pure o-nitrobenzaldehyde. Yield: 91.5% of theory.
Reaction SMILES: [C:1]([CH:3]([C:8]1[CH:13]=[C:12]([S:14][CH3:15])[N:11]=[CH:10][N:9]=1)C(OC)=O)#[N:2].[Cl-].[Na+].O.CS(C)=O>C(OCC)(=O)C>[CH3:15][S:14][C:12]1[N:11]=[CH:10][N:9]=[C:8]([CH2:3][C:1]#[N:2])[CH:13]=1
Reactant: COC(=O)C(C#N)c1cc(SC)ncn1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CSc1cc(CC#N)ncn1
Temperature: 160 °C
Yield: 56.3 %

Procedure:
A microwave vial was charged with methyl cyano[6-(methylthio)-4-pyrimidinyl]acetate (Intermediate 14, 700 mg, 3.14 mmol), sodium chloride (1.0 g, 17.11 mmol), water (1 mL) and DMSO (19 mL). The mixture was stirred and heated at 160° C. for 50 minutes in the microwave. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with brine. The organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was dissolved in DCM (10 mL) and purified by column chromatography (Biotage SP4) eluting with a gradient of 0-100% ethyl acetate and iso-hexane. Fractions containing the suspected product were combined and concentrated under reduced pressure to give the title compound (292 mg) as a yellow oil;
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[F:9][C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1.CCOC(C)=O>C1CCCCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[CH:11]=2)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: Oc1cccc(F)c1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: Fc1cccc(Oc2cncc(Cl)n2)c1
Yield: 92 %

Procedure:
Using Method DD with 2,6-dichloropyrazine (250 mg, 1.69 mmol) and 3-fluorophenol (166 μL, 1.86 mmol, d=1.25 g/mL), and purification by column chromatography (AcOEt:cyclohexane, 1:1), the title compound was obtained (347 mg). Yield: 92%. 1H NMR (250 MHz, DMSO-d6) δ 7.13-7.17 (m, 2H, Harom 4+6), 7.25 (d, 1H, Harom 2, JF=10.0 Hz), 7.52 (q, 1H, Harom 5, J=8.1 Hz), 8.54 (s, 1H, HPz 5), 8.56 (s, 1H, HPz 3). m/z: 224.0 [(M)+, calcd for C10H6ClFN2O 224.0].
Reaction SMILES: [Cl-].[NH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[CH2:6][NH3+:7].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>CC(N(C)C)=O>[NH2:2][C:3]1[CH:4]=[C:5]([CH2:6][NH:7][S:23]([CH3:22])(=[O:25])=[O:24])[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(C[NH3+])cc1N
Agent: [Cl-]
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CNS(C)(=O)=O)cc1N
Reaction time: 1 h

Procedure:
3 g of 3-amino-4-methoxycarbonylbenzylammonium chloride (18.8 mmol) are dissolved in 50 ml of dimethylacetamide, triethylamine (2.8 g, 27.7 mmol) is added, and the mixture is subsequently reacted at 0–10° C. with a solution of methanesulfonyl chloride (1.6 g, 13.8 mmol) in 20 ml of dimethylacetamide. After 1 h, the solvent is removed in vacuo and the residue is worked up by extraction with water/dichloromethane. The combined organic extracts are washed with water and dried (Na2SO4) and then evaporated on a rotary evaporator. The residue obtained is crystallized from water, whereupon 3 g (84%) of methyl 2-amino-4-methanesulfonylaminomethylbenzoate of melting point 120–121° C. are obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[C-]#N.[Na+].[N:25]12CCN(CC1)C[CH2:26]2.O>CS(C)=O>[CH3:19][C:18]([CH3:21])([CH3:20])[CH2:17][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=1)[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:26]#[N:25])[N:7]=1
Reactant: C1CN2CCN1CC2
Reactant: CC(C)(C)CN(Cc1ccc(I)cc1)c1ccnc(Cl)n1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)CN(Cc1ccc(I)cc1)c1ccnc(C#N)n1
Temperature: 75 °C
Reaction time: 21 h
Yield: 861.5 %

Procedure:
(2-Chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-(4-iodo-benzyl)-amine (10.0 g, 24.0 mmoles) and sodium cyanide (5.6 g, 0.12 moles) are dissolved in 40 ml of DMSO and 1,4-diaza bicyclo[2,2,2]octane (0.27 g, 2.4 mmoles) is added at rt. The mixture is stirred at 75° C. for 21 h. Water is added and the organic layer is extracted with AcOEt, washed with brine, dried over magnesium sulfate and concentrated. The crude product is purified by silica gel column chromatography to give 8.4 g of desired 4-[(2,2-dimethyl-propyl)-(4-iodo-benzyl)-amino]-pyrimidine-2-carbonitrile in 86% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:30]1[CH2:31][CH2:32][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:20])[CH2:28][CH2:29]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Reactant: Cc1ccccc1N1CCNCC1
Product: COc1nc2cc(Cl)ccc2nc1NC(=O)N1CCN(c2ccccc2C)CC1
Yield: 89 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(2-methylphenyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 89%). H NMR (300 MHz, CDCl3): δ 2.35 (s, 3H), 3.01 (s, 4H), 3.76 (s, 4H), 4.14 (s, 3H), 7.03-7.52 (m, 6H), 7.68-7.77 (m, 2H).
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][CH2:14][NH:15][CH2:16][CH:17]([OH:28])[CH2:18][O:19][C:20]2[N:21]=[N:22][C:23]([NH:26][NH2:27])=[CH:24][CH:25]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].[CH:29](=O)[CH:30]([CH3:32])[CH3:31]>>[ClH:1].[ClH:1].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][CH2:14][NH:15][CH2:16][CH:17]([OH:28])[CH2:18][O:19][C:20]2[N:21]=[N:22][C:23]([NH:26][N:27]=[CH:29][CH:30]([CH3:32])[CH3:31])=[CH:24][CH:25]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: CC(C)C=O
Reactant: COc1ccc(CCNCC(O)COc2ccc(NN)nn2)cc1OC
Agent: Cl
Product: COc1ccc(CCNCC(O)COc2ccc(NN=CC(C)C)nn2)cc1OC
Yield: 71 %

Procedure:
In a similar manner to Example 8 reaction of 2 g of (RS)-3-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-2-hydroxypropoxy]-6-hydrazinopyridazine dihydrochloride with (1.1 ml) of isobutyraldehyde afforded the title compound in 71% yield, m.p. 150°-152° C. (with decomp).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:16]2[C:20]3[CH:21]=[CH:22][C:23]([C:25]4[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=4)=[CH:24][C:19]=3[N:18]=[CH:17]2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[F:15])[CH:7]=1.[S:31]1[CH:35]=[CH:34][N:33]=[C:32]1[NH2:36]>>[F:15][C:9]1[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=1[C:6]1[CH:5]=[C:4]([N:16]2[C:20]3[CH:21]=[CH:22][C:23]([C:25]4[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=4)=[CH:24][C:19]=3[N:18]=[CH:17]2)[CH:3]=[C:2]([NH:36][C:32]2[S:31][CH:35]=[CH:34][N:33]=2)[CH:7]=1
Reactant: Cn1cc(-c2ccc3c(c2)ncn3-c2cc(Br)cc(-c3ccc(F)cc3F)c2)cn1
Reactant: Nc1nccs1
Product: Cn1cc(-c2ccc3c(c2)ncn3-c2cc(Nc3nccs3)cc(-c3ccc(F)cc3F)c2)cn1
Yield: 11.7 %

Procedure:
The compound was prepared from 1-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazole (0.05 g, 0.107 mmol) using the procedure of Example 280 and thiazol-2-amine (0.01 g, 0.10 mmol, 1.0 eq.) to yield the title product in 11.7% yield (0.06 g). 1H NMR (400 MHz CD3OD): δ 9.45 (s, 1H), 8.39 (s, 1H), 8.11 (s, 1H), 8.01 (s, 1H), 7.94 (s, 1H), 7.86-7.83 (m, 2H), 7.74 (s, 1H), 7.67-7.65 (m, 1H), 7.45 (s, 1H), 7.28-7.27 (d, 1H), 7.16-7.11 (m, 2H), 6.89 (d, 1H), 3.95 (s, 3H) LC-MS (ESI): Calculated mass: 484.52; Observed mass: 485.2 [M+H]+ (rt: 1.01 min).
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:14])[C:11]([Cl:13])=[CH:12][C:6]=2[N:5]=1.[N+]([C:18]1[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=1)([O-])=O>O1CCCC1>[Cl:13][C:11]1[C:10]([CH3:14])=[CH:9][C:7]2[NH:8][C:4]([S:3][C:18]3[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=3)=[N:5][C:6]=2[CH:12]=1
Reactant: Cc1cc2[nH]c(S)nc2cc1Cl
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc2[nH]c(Sc3ccc(C=O)o3)nc2cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.1 %

Procedure:
Aldehyde intermediate preparation: A mixture of sodium hydride (60% dispersion in mineral oil, 0.338 g, 8.46 mmol) and 2-mercapto-5-chloro-6-methyl-1H-benzimidazole (1.05 g, 5.29 mmol) in 35 ml of tetrahydrofuran is stirred at room temperature for 2 hours. 5-nitro-2-furaldehyde (0.746 g, 5.29 mmol) in 7 ml of tetrahydrofuran is then added dropwise over a 15 minute period and the mixture is stirred for 16 hours at room temperature. The reaction mixture is then concentrated under reduced pressure and dissolved in 100 ml ethyl acetate and washed with water (2×30 ml). The organic phase is dried over MgSO4 and concentrated under reduced pressure. The residue is triturated in diisopropylether and pentane and dried under vacuum to yield 854 mg of 5-(5-chloro-6-methyl-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde. Yield=55%. Analytical LC/MS (method B): retention time=3.64 min, m/z=272.97 (1Cl, positive ion mode).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[C:32]1([CH:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:39][NH2:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:40][CH2:39][CH:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:23])=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: NCC(c1ccccc1)c1ccccc1
Product: O=C(NCC(c1ccccc1)c1ccccc1)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2,2-diphenylethylamine as in General Procedure 10 to give the title compound. LCMS: m/z=626.96 (M+H+); retention time=1.06 minutes.
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[C:7]([Cl:13])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[C:14]([Cu])#[N:15].CN(C=O)C>C(Cl)Cl>[Cl:13][C:7]1[N:8]=[CH:9][C:10]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([C:14]#[N:15])[C:11]=2[CH3:12]
Reactant: Cc1c(Br)ccc2cc(Cl)ncc12
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(C#N)ccc2cc(Cl)ncc12
Temperature: 150 °C

Procedure:
To a flask containing a stir bar was added 7-Bromo-3-chloro-8-methylisoquinoline (0.63 g, 2.4 mmol), CuCN (0.33 g, 3.7 mmol), and DMF (10 mL). The mixture was then refluxed at 150° C. overnight. When the reaction was complete, as evidenced by LC analysis, the reaction flask was taken out of the oil bath and cooled to room temperature. To the mixture was then poured DCM (20 mL) and a precipitate formed immediately, which was filtered, re-dissolved in DCM, adsorbed into silica gel and purified by silica gel column chromatography (Hexanes:DCM→1:1) to provide the title product. LC/MS (IE, m/z): [M+1]+=203.
Reaction SMILES: [C:1]12[CH2:7][C:4](=[CH:5][CH:6]=1)[C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]2=1.[OH-:12].[Na+].[BH4-].[Na+]>O.O1CCCC1>[C:4]12[C:5](=[O:12])[CH:6]=[C:1]([CH:7]=1)[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]2=1
Reactant: [OH-]
Reactant: C1=C2CC(=C1)c1ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1C=C2C=C1c1ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of mercuric acetate (4 g) in water (10 ml) was treated with a solution of benzobicyclo[2.2.1]heptadiene (2 g) in tetrahydrofuran (25 ml) and the resulting mixture was stirred at room temperature for 24 hours. The solution was treated with a solution of 10% sodium hydroxide in water (5 ml), followed by sodium borohydride (0.5 g). The resulting mixture was stirred for 30 minutes and the resulting layers were separated. The aqueous layer was extracted with ether (2×30 ml) and the combined organic layers were dried over magnesium sulfate and concentrated on a rotary evaporator. The residue was combined with methylene chloride (25 ml) and pyridinium chlorochromate (3 g) and the solution was stirred at room temperature for 12 hours. The solution was washed with water (30 ml) and the organic layer was dried over magnesium sulfate. The solvent was removed on a rotary evaporator and the product was purified by preparative centrifugally accelerated radial thin layer chromatography using 25% ethyl acetate in hexane as the eluant. After removal of the eluant on a rotary evaporator, the product was obtained as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2OS(C(F)(F)F)(=O)=O.[CH3:21]CN(CC)CC.[Cl:28][C:29]1[CH:38]=[C:37]2[C:32]([C:33]([NH:39][CH:40]3[CH2:45][CH2:44][CH:43]([NH2:46])[CH2:42][CH2:41]3)=[CH:34][CH:35]=[N:36]2)=[CH:31][CH:30]=1.C(#N)C.ClCCl.CN(C=O)C>C(#N)C>[Cl:28][C:29]1[CH:38]=[C:37]2[C:32]([C:33]([NH:39][CH:40]3[CH2:41][CH2:42][CH:43]([NH:46][C:5]4[C:4]5[C:9](=[CH:10][CH:11]=[C:2]([CH3:21])[CH:3]=5)[O:8][C:7](=[O:12])[CH:6]=4)[CH2:44][CH2:45]3)=[CH:34][CH:35]=[N:36]2)=[CH:31][CH:30]=1
Reactant: NC1CCC(Nc2ccnc3cc(Cl)ccc23)CC1
Reactant: CCN(CC)CC
Reactant: O=c1cc(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2o1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ccc2oc(=O)cc(NC3CCC(Nc4ccnc5cc(Cl)ccc45)CC3)c2c1

Procedure:
To a conical microwave vessel (7.5 mL) equipped with a septum cap and a magnetic stirring bar was added a solution of a trifluoro-methanesulfonic acid 6-chloro-2-oxo-2H-chromen-4-yl ester (0.014 g; 0.043 mmol)) in dry acetonitrile (1 mL) containing Et3N (0.025 mL). Then, a solution of N-(7-chloro-quinolin-4-yl)-cyclohexane-1,4-diamine (0.0178 g; 1.5 eq.) in 1:1:1 mixture of acetonitrile/dichloromethane/DMF (1 mL) was added to the vessel and the resulting suspension was irradiated in Personal Chemistry Smith Synthesizer (150° C. for 180 s; 300 W). The resulting solution was evaporated to dryness. The residue was dissolved in 1.5 mL of a 1:1 mixture of DMSO/MeOH and purified by preparative reverse-phase HPLC. MS (DCI/NH3) m/z 433 [M+H]+.
Reaction SMILES: CC(=C)C[O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9]>CN1CCCC1=O.O>[OH:4][C:5]1[C:6]([CH2:8][C:7]([CH3:12])=[CH2:6])=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: C=C(C)COc1cccc(C(=O)OC)c1
Solvent: CN1CCCC1=O
Solvent: O
Product: C=C(C)Cc1c(O)cccc1C(=O)OC
Temperature: 200 °C
Reaction time: 30 h
Yield: 92.8 %

Procedure:
Methyl 3-(2-methylallyloxy)benzoate (Intermediate 167, 1.100 g, 5.3 mmol) was dissolved in 1-Methyl-2-pyrrolidinone (12 ml) and heated to 200° C. The solution was stirred for 30 h at the same temperature. After cooling, the mixture was diluted with water and extracted with ethyl acetate. Organic phase was dried over Na2SO4 and evaporated in vacuo to afford a crude product that was purified via Biotage SP1 with Cyclohexane/EtOAc as eluents (from 10/0 to 7/3 for 12 CV, 50 g SNAP Silica column). Fractions were collected and evaporated to afford the title compound (507 mg).
Reaction SMILES: [CH2:1]([C@@:8]1([O:22][C@H:21]([CH2:23][NH:24][C:25]([C@@H:27]([C@H:32]([C@@H:37]([C@@H:42]([CH2:47][O:48][C:49](=[O:51])[CH3:50])[O:43][C:44](=[O:46])[CH3:45])[O:38][C:39](=[O:41])[CH3:40])[O:33][C:34](=[O:36])[CH3:35])[O:28][C:29](=[O:31])[CH3:30])=[O:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]1[NH:52]C(OCC1C=CC=CC=1)=O)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1.O.[Pd]>[CH2:1]([C@@:8]1([O:22][C@H:21]([CH2:23][NH:24][C:25]([C@@H:27]([C@H:32]([C@@H:37]([C@@H:42]([CH2:47][O:48][C:49](=[O:51])[CH3:50])[O:43][C:44](=[O:46])[CH3:45])[O:38][C:39](=[O:41])[CH3:40])[O:33][C:34](=[O:36])[CH3:35])[O:28][C:29](=[O:31])[CH3:30])=[O:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]1[NH2:52])[OH:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)C(=O)NC[C@H]1O[C@@](O)(Cc2ccccc2)[C@H](NC(=O)OCc2ccccc2)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)C(=O)NC[C@H]1O[C@@](O)(Cc2ccccc2)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 2 h

Procedure:
A solution of 250 mg of 2,3,4,5,6-penta-O-acetyl-D-gluconic acid (benzyl 3,4-di-O-acetyl-2-benzyloxycarbonylamino-2,6-didesoxy-a-D-glucopyranosid-6-yl)-amide in 20 ml of dioxan and 2 ml water was hydrogenated at room temperature in the presence of palladium on charcoal (10%). After 2 hours, the catalyst was filtered off over a filter aid and the filtrate was concentrated. The residue was crystallized from ethyl acetate/ether and gave 2,3,4,5,6-penta-O-acetyl-D-gluconic acid (benzyl 3,4-di-O-acetyl-2-amino-2,6-didesoxy-a-D-glucopyranosid-6-yl)-amide, [a]+96.0° (c 0.2; dioxan), MS: m/z 741.1 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1C=C(Cl)[N:5]=[C:4](N2CCOCC2)[N:3]=1.[NH:15]1[CH2:20][CH2:19]S(=O)(=O)[CH2:17][CH2:16]1.[CH3:23][CH2:24][OH:25].C1COCC1>>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:16]([N:15]2[CH2:23][CH2:24][O:25][CH2:19][CH2:20]2)[CH:17]=1
Reactant: O=S1(=O)CCNCC1
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Reactant: CCO
Solvent: C1CCOC1
Product: Clc1cc(N2CCOCC2)ncn1
Temperature: 100 °C
Yield: 97 %

Procedure:
To a solution of 4-(4,6-dichloropyrimidin-2-yl)morpholine (1.0 equiv.) in EtOH:THF (1:1, 0.25 M) was added thiomorpholine 1,1-dioxide (1.0 equiv.) in one portion. The resulting mixture was heated to 100° C. for 42 h. The resulting mixture was then cooled to RT and concentrated in vacuo to yield an off white solid in The reaction mixture was then concentrated in vacuo and dried under high vacuum over 20 h to yield 4-(6-chloropyrimidin-4-yl)morpholine as a white solid in 97% yield. LCMS (m/z) (M+H)=333.0/334.9, Rt=0.68 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([CH:12]1CC2O[CH:13]1C=C2)(OC)=[O:9].Cl>O>[C:2]1([NH:1][C:8](=[O:9])[CH:12]=[CH2:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1CC2C=CC1O2
Reactant: Nc1ccccc1
Agent: Cl
Solvent: O
Product: C=CC(=O)Nc1ccccc1
Temperature: 140 °C
Reaction time: 15 h

Procedure:
7.2 parts 30% methanolic Na-methylate solution are added to 46.5 parts aniline. 77 parts 2-carbomethoxy-7-oxabicyclo(2,2,1)hept-5-ene are added drop-wise at 40° C. The reaction medium is then stirred for 15 hours at this temperature and neutralised with 4 parts concentrated hydrochloric acid. 50 parts water are added, and the organic phase separated off. The organic phase is reduced in a rotary evaporator at a bath temperature of 90° C. and under a vacuum of 20 Torr. The residue is heated in a vacuum of 20 Torr to 110° to 120° C. (bath temperature 140° C.). On conclusion of the furane separation, the sedimentation temperature increases and the product distills over. 27.5 parts N-phenylacrylamide with a boiling point of 135° C. at 0.4 Torr are obtained. The product recrystallised from the acetonitrile at -20° C. has a melting point of 114° to 115° C.
Reaction SMILES: [C:1]1([C:7]2([C:11]([Cl:13])=[O:12])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([N:16]([CH2:21][CH3:22])[CH2:17][CH2:18][CH2:19][OH:20])[CH3:15]>>[ClH:13].[C:1]1([C:7]2([C:11]([O:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:21][CH3:22])[CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C1(c2ccccc2)CCC1
Reactant: CCN(CC)CCCO
Product: CCN(CC)CCCOC(=O)C1(c2ccccc2)CCC1
Product: Cl

Procedure:
The title compound was prepared in an analogous manner to that in Example 36 by reacting 1-phenylcyclobutane-carbonyl chloride with 3-diethylaminopropanol at 80° C. for 5 h. The reaction mixture was filtered and chromatographed on silica gel using toluene-Et3N 95:5 as eluent. The yield was 0.8 g (45%); mp 108-111° C.; 1H NMR (D2O) δ 1.25 (t, 6H), 1.91-2.14 (m, 4H), 2.62 (m, 2H), 2.89 (m, 4H), 3.13 (q, 4H), 4.27 (t, 2H), 7.43 (m, 1H), 7.48 (m, 2H), 7.53 (m, 2H). Anal. (C18H27NO2.HCl) C, H, N.