Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(Cl)Cl>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:40])=[O:39])=[CH:34][CH:33]=1
Reactant: CCOC(=O)CC(CCCCCN)CCCCc1cccnc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC(CCCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCCc1cccnc1

Procedure:
To a solution of 1.0 g of ethyl 8-amino-3-[4-(3-pyridyl)-butyl]-octanoate in 100 ml of methylene chloride is added 3 g of triethylamine followed by the dropwise addition of a solution of 1.5 g of p-chlorophenylsulfonyl chloride in 15 ml of methylene chloride. The reaction mixture is concentrated then directly purified by chromatography on silica gel using 25% ethyl acetate in methylene chloride as eluent to yield ethyl 8-(p-chlorophenylsulfonamido)-3-[4-(3-pyridyl)-butyl]-octanoate.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1.C(N(CC)CC)C.[C:19]1([C:25](Br)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:11])[CH2:5][C:6]1[N:7]=[CH:8][N:9]([C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:10]=1
Reactant: COC(=O)Cc1c[nH]cn1
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 72 h

Procedure:
To a suspension of 1H-imidazole-4-acetic acid methyl ester hydrochloride (1, 7.48, 42.4 mmol) in methylene chloride (200 ml) was added triethylamine (17.7 ml, 127 mmol) and triphenylmethyl bromide (16.4 g, 50.8 mmol) and stirred for 72 h. After this time, reaction mixture was washed with sat. aq. sodium bicarbonate (100 ml) and water (100 ml). The organic layer was evaporated in vacuo and purified by flash chromatography (30-100% ethyl acetate/hexanes gradient elution) to provide 23 as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([CH:24]=[O:25])=[C:5]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH3:32][Mg]Br.O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[C:6]([CH:24]([OH:25])[CH3:32])=[C:5]2[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C[Mg]Br
Reactant: CS(=O)(=O)c1ccc(Cn2c(C=O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 6-bromo-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbaldehyde (500 mg) in THF (10 ml) was added dropwise a solution of methyl magnesium bromide in THF (3M, 0.4 ml) at room temperature, and the mixture was stirred for 10 min. The reaction mixture was added to water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from diisopropyl ether to give the title compound (490 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7][CH2:6]2.[Br-:13].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[Br:13][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[C:10]=1[NH:9][CH2:8][CH2:7][CH2:6]2
Reactant: [Br-]
Reactant: COc1ccc2c(c1)CCCN2
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1cc(Br)c2c(c1)CCCN2
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.9 %

Procedure:
Part A: A solution of 6-methoxy-1,2,3,4-tetrahydroquinoline (6.19 g, 37.9 mmol) in CH2Cl2 (76 mL) was treated with pyridinium tribromide (25.42 g, 79.7 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with sat NaHSO3 (50 mL) and water (50 mL). The dichloromethane was separated, dried (Na2SO4) and concentrated. The residue was chromatographed on silica gel using 20% ethyl acetate/hexanes as eluent to give 8-bromo-6-methoxy-1,2,3,4-tetrahydroquinoline (2.93 g, 32% yield): 1H NMR (300 MHz, CDCl3): δ 6.88 (s 1 H), 6.55 (s, 1 H), 3.71 (s, 3H), 3.37-3.33 (t, J=6.6, 2 H), 2.78-2.74 (t, 2 H), 1.97-1.89 (m, 2 H); LRMS (AP+) for (M+H)+: for C10H12NOBr Calculated: 241.1 found: 241.0.
Reaction SMILES: [CH:1]1([NH:5][C:6]2[C:7]([NH2:30])=[N:8][C:9]([C:13]3[C:21]4[C:16](=[N:17][CH:18]=[CH:19][CH:20]=4)[N:15]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[N:14]=3)=[N:10][C:11]=2[NH2:12])[CH2:4][CH2:3][CH2:2]1.C1N=CN([C:36](N2C=NC=C2)=[O:37])C=1.C(N(CC)CC)C>CN(C)C=O>[NH2:12][C:11]1[N:10]=[C:9]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[N:14]=2)[N:8]=[C:7]2[C:6]=1[N:5]([CH:1]1[CH2:4][CH2:3][CH2:2]1)[C:36](=[O:37])[NH:30]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1NC1CCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=O)n(C3CCC3)c12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
133 mg (0.26 mmol) of the compound from example 65A were initially charged in dimethylformamide (1.4 ml), then 213 mg (1.32 mmol) of N,N-carbonyldiimidazole and 0.44 ml (3.16 mmol) of triethylamine were added and the mixture was stirred at 100° C. overnight. Thereafter, another 200 mg (1.23 mmol) of N,N-carbonyldiimidazole were added and the mixture was again stirred at 100° C. overnight. The reaction mixture was purified directly by means of preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid gradient). This gave 79 mg (68% of theory) of the title compound in solid form.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH2:8]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:46])[C@@H:20]([NH:30][C:31]([C:33]2[CH:38]=[C:37](Cl)[N:36]=[C:35]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:34]=2)=[O:32])[CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:15][CH2:14]1)=[O:12])[CH3:9].O>C1COCC1>[CH2:8]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:46])[C@@H:20]([NH:30][C:31]([C:33]2[CH:38]=[C:37]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[N:36]=[C:35]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:34]=2)=[O:32])[CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:15][CH2:14]1)=[O:12])[CH3:9]
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(Cl)nc(-c3ccccc3)n2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(-n3ccnc3)nc(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Imidazole (3 mg) was added to a suspension of NaH (1.7 mg) in anhydrous THF (0.2 ml) at RT. After 30 min stirring at RT, 4-{(S)-4-tert-butoxycarbonyl-2-[(6-chloro-2-phenyl-pyrimidine-4-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester (25 mg) dissolved in THF (0.2 ml) was added. The mixture was allowed to stir at RT overnight. Water was added and the resulting mixture was extracted with DCM. The org. phases were dried (Na2SO4) and evaporated off.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Product: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl

Procedure:
As described for Reference Example 21, 25 g of 2-chloro-4-nitrobenzoic acid is reacted with thionyl chloride (124 ml) to give the product (27.0 g) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH2:22][C:21]([NH:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[CH:20][C:19]2=[O:29])=[CH:4][CH:3]=1.Cl[C:31]1C=CC(C2N=C3C=CC=CN3C=2CN2CC(OC)=CC2=O)=CC=1.CN1CCNCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH2:22][C:21]([N:23]3[CH2:31][CH2:28][N:26]([CH3:27])[CH2:25][CH2:24]3)=[CH:20][C:19]2=[O:29])=[CH:4][CH:3]=1
Reactant: CN(C)CCNC1=CC(=O)N(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)C1
Reactant: COC1=CC(=O)N(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)C1
Agent: CN1CCNCC1
Product: CN1CCN(C2=CC(=O)N(Cc3c(-c4ccc(Cl)cc4)nc4ccccn34)C2)CC1

Procedure:
The title compound was prepared according to the experimental for compound 237 from 1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4-methoxy-1H-pyrrol-2(5H)-one and 1-methylpiperazine. (56 mg, 47%) m/e+=422 (M+H+). 1H-NMR (400 MHz, CDCl3, δ): 8.47 (d, 1H, D, J=7.0 Hz), 7.73 (d, 2H, D, J=8.4 Hz), 7.62 (d, 1H, D, J=9.1 Hz), 7.47 (d, 2H, D, J=8.4 Hz), 7.25 (t, 1H, D, J=7.3 Hz), 6.85 (t, 1H, D, J=6.4 Hz), 5.09 (s, 2H), 4.74 (s, 1H), 3.57 (s, 2H), 3.03 (m, 4H), 2.36 (m, 4H), 2.27 (s, 3H).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:5]1[O:6][C:7](=[O:21])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:4].Cl[C:23]1[C:24]2[CH:31]=[CH:30][S:29][C:25]=2[N:26]=[CH:27][N:28]=1.C(N(CC)CC)C>CC(O)(C)C>[C:15]1([C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:21])[O:6][C:5]=2[CH:3]([NH:2][C:23]2[C:24]3[CH:31]=[CH:30][S:29][C:25]=3[N:26]=[CH:27][N:28]=2)[CH3:4])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1ncnc2sccc12
Reactant: CC(N)c1oc(=O)c2ccccc2c1-c1ccccc1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: CC(Nc1ncnc2sccc12)c1oc(=O)c2ccccc2c1-c1ccccc1
Yield: 46.7 %

Procedure:
3-(1-aminoethyl)-4-phenyl-1H-isochromen-1-one hydrochloride (intermediate E2 50 mg, 0.166 mmol), 4-chlorothieno[2,3-d]pyrimidine (36.8 mg, 0.215 mmol), triethylamine (0.046 ml, 0.331 mmol) were reacted in 2-methylpropan-2-ol (1 ml) at 80° C. for 6 hrs and at 50° C. for 60 hrs. 4-Chlorothieno[2,3-d]pyrimidine (5.7 mg, 0.033 mmol), triethylamine (0.09 ml, 0.066 mmol) were added and the mixture reacted at 90° C. for 4 hrs. The crude was purified via reverse phase chromatography with a Biotage C18 30 g SNAP column (Phase A, water 95%, ACN 5%, formic acid 0.1%); Phase B ACN 95%, water 5%, formic acid 0.1%) to give the title compound (31 mg, 47%).
Reaction SMILES: C([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[N:12][N:13]=[C:14]2[CH2:21][C:22]1[C:27]([Cl:28])=[CH:26][N:25]=[CH:24][C:23]=1[Cl:29])C1C=CC=CC=1.[ClH:30]>C(O)(=O)C.C1(C)C=CC=CC=1>[ClH:28].[ClH:30].[Cl:29][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([Cl:28])[C:22]=1[CH2:21][C:14]1[C:15]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:9]([OH:8])[C:10]=2[CH:11]=[N:12][N:13]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1OCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
5-Benzyloxy-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (4.3 g, 10.08 mmoles), prepared as described in example 71, in glacial acetic acid and 37% HCl was put in a flask under stirring at room temperature for ½ hour, then at 60° C. for 1 hour. The mixture was brought to dryness, taken up more times in toluene to give a solid which was triturated in acetone and dried to give 4.04 g of the title compound (yield: 98%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[CH:11]=[C:10]([C:25]([OH:27])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH2:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30][NH:29]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:25]([N:29]3[CH2:30][CH2:31][C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:28]3)=[O:27])[CH:11]=[C:12]([C:14]([NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[O:24])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3ccc(C)nc3)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(=O)N3CCc4ccccc4C3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-((6-methylpyridin-3-yl)methylcarbamoyl)-biphenyl-3-carboxylic acid (50 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL) were added 1,2,3,4-tetrahydroisoquinoline (50 mg, 0.38 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol) and N,N-diisopropylethylamine (120 μL, 0.69 mmol). The reaction mixture was stirred for 16 hours at 25° C. The reaction solution was purified by preparative HPLC to afford the final product as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][S:7][CH2:8][C:9]([NH:11][OH:12])=[O:10])=[CH:4][CH:3]=1.[OH:15]O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][S:7]([CH2:8][C:9]([NH:11][OH:12])=[O:10])=[O:15])=[CH:13][CH:14]=1
Reactant: OO
Reactant: O=C(CSCc1ccc(Cl)cc1)NO
Solvent: CC(=O)O
Product: O=C(CS(=O)Cc1ccc(Cl)cc1)NO
Temperature: 50 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
31.7 g (0.091 mol) of p-chlorobenzylmercaptoacetohydroxamic acid are mixed with 100 ml of anhydrous acetic acid and 9.1 ml of hydrogen peroxide of 110 volumes strength are added. The temperature, which is 20° C. at the start, rises and solution of the precipitate formed is also observed. The temperature is maintained at 50° C. and after several minutes it is found that the sulphinyl derivative sets solid. 50 ml of acetic acid are now added and the temperature is kept at 50° C. for 1 hour whilst stirring vigorously. The mixture is cooled and the p-chlorobenzylsulphinyl-acetohydroxamic acid is filtered off. This acid is recrystallised from acetic acid and filtered off, the precipitate is washed with water and with ethanol, and dried, and 31.9 g of CRL 40,411 are collected. Yield 85%; instantaneous melting point 210° C. (with decomposition).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[CH:15]=[CH:16]/[CH:17]=O)=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:25]([CH2:27]P(=O)(OCC)OCC)#[N:26]>>[CH3:1][C:2]1[O:6][C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[CH:15]=[CH:16]/[CH:17]=[CH:27]/[C:25]#[N:26])=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1oc(COc2ccccc2/C=C/C=O)nc1-c1ccccc1
Reactant: CCOP(=O)(CC#N)OCC
Product: Cc1oc(COc2ccccc2/C=C/C=C/C#N)nc1-c1ccccc1

Procedure:
According to the method described for Reference Example 35, (E)-3-[2-(5-methyl-4-phenyl-2-oxazolylmethoxy)phenyl]-2-propen-1-al was allowed to react with diethyl cyanomethylphosphonate to give (E,E)-5-[2-(5-methyl-4-phenyl-2-oxazolylmethoxy)phenyl]-2,4-pentadienenitrile. Recrystallization from ethanol-chloroform gave colorless prisms, m.p.128°-129° C.
Reaction SMILES: O[CH:2]=[C:3]1[C:8](=[O:9])[CH:7]=[CH:6][C:5]([CH3:16])([C:10]#[C:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4]1.Cl.[NH2:18]O>C(O)C.O>[CH3:16][C:5]1([C:10]#[C:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4][C:3]2[CH:2]=[N:18][O:9][C:8]=2[CH:7]=[CH:6]1
Reactant: NO
Reactant: CC1(C#C[Si](C)(C)C)C=CC(=O)C(=CO)C1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC1(C#C[Si](C)(C)C)C=Cc2oncc2C1
Yield: 99.5 %

Procedure:
To a solution of 6-(hydroxymethylene)-4-methyl-4-((trimethylsilyl)ethynyl)-cyclohex-2-enone (147 mg, 0.63 mmol) in ethanol (15 mL) was added a solution of hydroxylamine hydrochloride (452 mg) in water (0.65 mL). The mixture was heated under reflux for 1 h. To the mixture was added water (50 mL). The aqueous mixture was extracted with methylene chloride/ether (1:2, 50 mL ×3). The extract was washed with saturated aqueous sodium bicarbonate solution (50 mL ×1) and brine (50 mL ×1), dried over MgSO4, and filtered. The filtrate was evaporated in vacuo to give 9 as a crystalline solid (145 mg, quantitative yield): 1H NMR (CDCl3) δ 8.06 (1H, s), 6.47 (1H, d, J=9.9 Hz), 6.03 (1H, d, J=9.9 Hz), 3.07 (1H, d, J=16.1 Hz), 2.77 (1H, d, J=16.1 Hz), 1.37 (3H, s), 0.14 (9H, s). This material was used without further purification for the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([NH2:13])[CH:7]=1)[CH3:2].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[OH:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])=[CH:7][C:8]=1[NH:13][S:23]([C:20]1[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=1)(=[O:25])=[O:24]
Reactant: CCOC(=O)Cc1ccc(O)c(N)c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(O)c(NS(=O)(=O)c2ccc(OC)cc2)c1

Procedure:
Ethyl(3-amino-4-hydroxyphenyl)acetate is reacted with 4-methoxybenzene sulfonyl chloride in chloroform in the presence of triethylamine, to give ethyl 2-[4-hydroxy-3-[[(4-methoxyphenyl)sulfonyl]amino]phenyl]acetate.
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1.BrC1C=CC(C(O)=O)=CC=1.ONC(=O)CCC(N)=O.[NH:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[CH2:42][N:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1>O1CCCC1>[Br:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]([N:37]2[CH2:41][CH2:40][CH2:39][C@H:38]2[CH2:42][N:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)=[O:17])=[CH:15][CH:14]=1
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(Br)cc1
Reactant: C1CN[C@H](CN2CCCC2)C1
Agent: NC(=O)CCC(=O)NO
Agent: O=C(O)c1ccc(Br)cc1
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cc1)N1CCC[C@H]1CN1CCCC1
Yield: 93 %

Procedure:
Procedure X′: To a stirring solution of 4-bromobenzoic acid-2,5-dioxo-pyrrolidin-1-yl ester (3.5 g, 11.7 mmol), [which can be prepared from 4-bromobenzoic acid and N-hydroxy succinamide by the method of C Mitsos, Chem Pharm Bull 48(2),211-214 (2000), or purchased from Ambinter, CAS# 80586-82-9], in tetrahydrofuran (0.15M), add (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine and heat to reflux for four hours. After this time, remove the heat and wash the reaction with water while extracting with 10% isopropanol/dichloromethane. Dry the organics with sodium sulfate, filter and concentrate in vacuo. Purify on a silica column eluting with 2M ammonia in methanol and dichloromethane to give (4-bromo-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-yl)methanone (93% yield with 80% purity). MS (m/e): 337.1 (M+1)
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH2:8].[C:9](OCC)(=[O:15])[C:10](OCC)=[O:11]>COC=COC>[NH:1]1[C@@H:2]2[C@@H:3]([CH2:4][CH2:5][CH2:6][CH2:7]2)[NH:8][C:10](=[O:11])[C:9]1=[O:15]
Reactant: CCOC(=O)C(=O)OCC
Reactant: N[C@@H]1CCCC[C@@H]1N
Agent: COC=COC
Product: O=C1N[C@H]2CCCC[C@H]2NC1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
To a solution of cis-1,2-diaminocyclohexane (4.8 g, 42 mmol) in dimethoxy ethylene (100 mL) was added slowly diethyl oxalate (28.5 mL, 210 mmol). The reaction mixture was stirred at room temperature for 0.5 h and at 100° C. for 2 h. After the suspension was cooled down to room temperature, the resulting white solid precipitate was collected by filtration. The precipitate was washed with diethyl ether and dried to yield (4aR,8aS)-octahydro-2,3-quinoxalinedione (4.6 g, 66%). LCMS: (M+H)+: 169.1.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]Cl)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1.[CH3:25][NH:26][CH3:27]>CC(CC(C)C)=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:26]([CH3:27])[CH3:25])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: CNC
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl
Solvent: CC(=O)CC(C)C
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCN(C)C

Procedure:
Using 5 g of N-(trans-4-methylcyclohexyl)-4-(2-chloroethoxy)-3-methoxycinnamamide (Example 138), 100 ml of methylisobutylketone, and 150 ml of a 50% aqueous dimethylamine solution, a reaction similar to that conducted in Example 107 was carried out. As a result, 3.59 g of N-(trans-4-methylcyclohexyl)-4-(2-dimethylaminoethoxy)-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: C(O[C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=O)(C)(C)C.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([CH2:27][NH2:28])[CH2:25][NH2:26])=[CH:20][C:19]=1[CH3:29].C(=O)([O-])[O-].[K+].[K+].II>CN(C)C=O.C(O)(C)(C)C>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:27][N:28]3[C:6](=[O:16])[NH:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=4[C:14]3=[N:26][CH2:25]2)=[CH:20][C:19]=1[CH3:29]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1C=O
Reactant: Cc1cc(C(CN)CN)ccc1N
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)(C)O
Product: Cc1cc(C2CN=C3c4ccccc4NC(=O)N3C2)ccc1N
Temperature: 75 °C
Reaction time: 3 h
Yield: 23.7 %

Procedure:
A flask was charged with (2-formyl-phenyl)-carbamic acid tert-butyl ester (8.8 g, 0.040 mol), 2-(4-amino-3-methyl-phenyl)-propane-1,3-diamine (10.0 g, 0.056 mol), t-butanol (177 mL), and N,N-dimethylformamide (53 mL). The mixture was stirred at 70-80° C. for 3 h. To the stirred, cooled (40-50° C.) mixture were added anhydrous potassium carbonate (16.6 g) and iodine (20.3 g). The batch was then stirred at 80° C. for at least 5 h or until HPLC analysis showed that the reaction had proceeded to greater the 98% completion. The cooled reaction mixture was filtered through a celite pad (8.8 g) and the filter cake was rinsed with MeOH (110 mL). The filtrate and rinse were diluted with toluene (90 mL) and concentrated to dryness under reduced pressure. The residue was stirred with aqueous 20 wt % sodium thiosulfate pentahydrate (180 mL) for 1 h at ambient temperature. This mixture was extracted with CH2Cl2 (2×180 mL) and the separated organic layers were concentrated to dryness in vacuo. The concentrate (20 g) was dissolved with methanol (10 mL) and loaded onto a Biotage KP-Sil SNAP cartridge (100 g) that had been pre-equilibrated with 300 mL 5% v/v triethylamine in hexane. A Biotage unit was used to elute the cartridge with an ethyl acetate-hexane gradient (0% to 80%). Clean fractions were collected, combined, and concentrated to dryness under reduced pressure as quickly as possible to provide the title compound as a yellow solid (2.9 g 23% yield).