Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:13][C@@H:14]([C@@H:16]2[CH2:20][C:19](=[O:21])[N:18]([C@@H:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH3:23])[CH2:17]2)[CH3:15])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]#[N:12])[CH:7]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:45]2[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>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.O>[C:11]([C:10]1[CH:9]=[N:8][N:6]2[CH:7]=[C:2]([C:48]3[CH:47]=[CH:46][C:45]([N:42]4[CH2:41][CH2:40][N:39]([C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH2:44][CH2:43]4)=[CH:50][CH:49]=3)[CH:3]=[C:4]([O:13][C@@H:14]([C@@H:16]3[CH2:20][C:19](=[O:21])[N:18]([C@@H:22]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[CH3:23])[CH2:17]3)[CH3:15])[C:5]=12)#[N:12]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Br)cn4ncc(C#N)c34)CC2=O)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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cn4ncc(C#N)c34)CC2=O)cc1
Temperature: 100 °C

Procedure:
To an appropriate sized microwave vial, 6-bromo-4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (91.0 mg, 0.188 mmol), (4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)boronic acid (86.5 mg, 0.282 mmol), cesium carbonate (184 mg, 0.565 mmol), dioxane (2.0 mL) and water (0.5 mL) were added. The mixture was degassed with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) catalyst (21.8 mg, 0.0188 mmol) was added and the solution was heated at 100° C. for 45 minutes. After cooling to room temperature, the reaction was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (100% EtOAc) to afford tert-butyl 4-(4-(3-cyano-4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)phenyl)piperazine-1-carboxylate.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.Cl[C:20]1[CH:25]=[N:24][CH:23]=[C:22]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)[N:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(Cl)(Cl)Cl.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>[CH3:32][N:29]1[CH2:28][CH2:27][N:26]([C:22]2[N:21]=[C:20]([C:9]3[CH:10]=[C:11]4[CH:17]=[CH:16][NH:15][C:12]4=[N:13][CH:14]=3)[CH:25]=[N:24][CH:23]=2)[CH2:31][CH2:30]1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: CN1CCN(c2cncc(Cl)n2)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: [Cs+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CN1CCN(c2cncc(-c3cnc4[nH]ccc4c3)n2)CC1
Temperature: 100 °C

Procedure:
The starting material 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (124) (50 mg, 0.2 mmol, 1 eq) and 2-chloro-6-(4-methylpiperazin-1-yl)pyrazine (63) (44 mg, 0.2 mmol, 1 eq) in DMF (5 mL) was degassed and purged under argon atmosphere for 10 min. To this reaction mixture was charged Cs2CO3 (133 mg, 0.4 mmol, 2 eq) followed by addition of Pd(PPh3)4 (0.01 mg, 0.04 mmol) and degassing and purging under argon for an additional 10 min. The reaction mixture was heated at 100° C. for 12 h in a sealed tube. After completion of the reaction, the reaction mixture was diluted with CHCl3 and filtered through Celite. The solvents were distilled off and the crude material was submitted for flash column purification in neutral alumina using 2% MeOH/CHCl3 to obtain pale yellow solid compound 5-(6-(4-methylpiperazin-1-yl)pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridine 125 in 20 mg quantity. The compound 125 was confirmed by 1HNMR and LCMS. 1H NMR (400 MHz, CDCl3) δ: 8.96 (d, J=1.5 Hz 1H), 8.55 (d, J=1.70 Hz, 1H), 8.30 (s, 1H), 8.08 (s, 1H), 7.35 (m, J=3.04, 1H), 6.60 (m, J=1.95 1H), 3.75 (m, J=5.00, 4H), 2.58 (m, J=5.12, 4H), 2.38 (s, 3H); MS m/z 294.9 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.CC1(C)O[C:17](=[O:18])[CH2:16][C:14](=[O:15])[O:13]1>O>[OH:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:3]2[C:2]=1[O:1][C:17](=[O:18])[C:16]([C:14]([OH:15])=[O:13])=[CH:4]2
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1cccc(O)c1O
Solvent: O
Product: O=C(O)c1cc2cccc(O)c2oc1=O
Temperature: 75 °C
Reaction time: 2 h

Procedure:
2,3-dihydroxybenzaldehyde (95.8 mg, 0.69 mmol) and Meldrum's acid (100 mg, 0.69 mmol) were combined in H2O (1 mL). The solution was stirred at 75° C. for 2 h. After cooling to room temperature, the precipitate was filtered and dried at suction to give 8-hydroxy-3-carboxy-coumarin.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[CH3:11])[C:5](O)=[O:6].S(Cl)([Cl:15])=O.CN(C)C=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[CH3:11])[C:5]([Cl:15])=[O:6]
Reactant: Cc1c(Cl)cc(C(=O)O)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1c(Cl)cc(C(=O)Cl)cc1Cl
Reaction time: 2 h
Yield: 110.3 %

Procedure:
A mixture of 3,5-dichloro-4-methylbenzoic acid (230 g, 1.12 moles), thionyl chloride (204 g, 1.71 moles), and dimethylformamide (30 milliliters(ml), in toluene (1 liter) was slowly warmed to 70° C. and stirred at that temperature for 2 hours. The toluene was eliminated in the rotavap to yield 276 g of 3,5-dichloro-4-methylbenzoyl chloride, used in the next step as such.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:17][CH:18]=[C:19]([C:21](O)=[O:22])[N:20]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:46][N:47]1[CH2:52][CH2:51][CH:50]([CH2:53][N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH2:49][CH2:48]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[O:17][CH:18]=[C:19]([C:21]([N:57]3[CH2:56][CH2:55][N:54]([CH2:53][CH:50]4[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]4)[CH2:59][CH2:58]3)=[O:22])[N:20]=2)(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)O)co2)c(C)c1
Reactant: CN1CCC(CN2CCNCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)N3CCN(CC4CCN(C)CC4)CC3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 2-{[(4-methoxy-2,6-dimethyl-benzenesulfonyl)-methyl-amino]-methyl}-oxazole-4-carboxylic acid (100 mg, 0.28 mmol), EDCI (75 mg, 0.39 mmol), HOBt (57 mg, 0.42 mmol) DIPEA (0.06 mL, 0.33 mmol), 1-(1-methyl-piperidin-4-ylmethyl)-piperazine (66 mg, 0.33 mmol) and DCM (10 mL).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12](/[CH:16]=[CH:17]/[C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=3)[CH2:21]O)=[N:13]2)=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+].CO>ClCCCl>[Cl:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12](/[CH:16]=[CH:17]/[C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=3)[CH2:21][Cl:3])=[N:13]2)=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: ClCc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (3.6 ml., 49.3 mmol) was added rapidly to a stirred solution of 3-[2(E)-(7-chloroquinolin-2-yl)ethenyl]benzyl alcohol (Example 6a part (ii)) (11.7 g, 39.5 mmol) in 1,2-dichloroethane (300 ml) at 50° C. giving an immediate yellow precipitate. The mixture was stirred for 1 hour and cooled to room temperature then the mixture was shaken with saturated sodium bicarbonate solution (400 ml) and methanol (50 ml) to give two clear phases. The aqueous phase was extracted with dichloromethane and the combined solvent phase was dried and evaporated.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[N+:11]([O-])([OH:13])=[O:12].O>C(Cl)Cl>[OH:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: Cc1ccc(O)cc1C#N
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(O)cc1C#N
Yield: 29.2 %

Procedure:
5-Hydroxy-2-methylbenzonitrile (D36, 475 mg, 3.57 mmol) was dissolved in DCM (5 mL) and 70% nitric acid (1 mL, 22 mmol) was added dropwise to the reaction. The mixture was stirred for 45 min before the addition of H2O (15 mL). The two phases were separated and the aqueous phase was extracted with DCM (2×). The combined organics were dried (Na2SO4) and concentrated by rotary evaporation to give a yellow solid. The crude residues were purified by flash column chromatography (silica, 10% EtOAc/90% iso-hexane to 50% EtOAc/50% iso-hexane) to give 5-hydroxy-2-methyl-4-nitrobenzonitrile (D37, 186 mg, 26%) as a yellow solid.
Reaction SMILES: ClC(Cl)(Cl)C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:28]([O:35][C:36]1[CH:41]=[C:40]([NH:42][C:43](=[O:55])[C:44]2[CH:49]=[CH:48][C:47]([O:50][CH2:51][CH:52]3[CH2:54][CH2:53]3)=[CH:46][CH:45]=2)[C:39](O)=[CH:38][N:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>C(#N)C.C(N(CC)CC)C>[CH2:28]([O:35][C:36]1[N:37]=[CH:38][C:39]2[O:55][C:43]([C:44]3[CH:45]=[CH:46][C:47]([O:50][CH2:51][CH:52]4[CH2:53][CH2:54]4)=[CH:48][CH:49]=3)=[N:42][C:40]=2[CH:41]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(Nc1cc(OCc2ccccc2)ncc1O)c1ccc(OCC2CC2)cc1
Agent: Cl
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: c1ccc(COc2cc3nc(-c4ccc(OCC5CC5)cc4)oc3cn2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 11.6 %

Procedure:
To a solution of hexachloroethane (4.09 g), triphenylphosphine (4.53 g) and triethylamine (2.41 mL) in acetonitrile (50 mL) was added N-(2-(benzyloxy)-5-hydroxypyridin-4-yl)-4-(cyclopropylmethoxy)benzamide (2.25 g), and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.25 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[C:10]1[S:14][C:13]([C:15](=[O:17])[CH3:16])=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:10]2[S:14][C:13]([C:15](=[O:17])[CH3:16])=[CH:12][C:11]=2[N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: Sc1ccc(Br)cc1
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2ccc(Br)cc2)s1

Procedure:
Prepared according to the procedure described as in Step B for example 1 from 4-Bromobenzenethiol (1.03 g, 5.5 mmol) and 1-(5-chloro-4-nitro-2-thienyl)ethanone (1.14 g, 5.5 mmol). The title compound was obtained as an orange solid (1.15 g, 58% yield). 1H NMR (300 MHz, CDCl3) δ: 8.07 (1H, s) 7.68 (2H, d, J=8.69 Hz), 7.53 (2H, d, J=8.69 Hz), 2.49 (3H, s).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26]1.[CH3:31][C:32]1[C:36]([C:37]2[CH:38]=[C:39]([S:47]([NH:50][CH:51]3[CH2:55][CH2:54][CH2:53][CH:52]3[C:56](O)=[O:57])(=[O:49])=[O:48])[C:40]3[CH:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=2)=[C:35]([CH3:59])[O:34][N:33]=1.CCN(C(C)C)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH:25]1([NH:30][C:56]([C@H:52]2[CH2:53][CH2:54][CH2:55][C@H:51]2[NH:50][S:47]([C:39]2[C:40]3[CH:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[C:37]([C:36]3[C:32]([CH3:31])=[N:33][O:34][C:35]=3[CH3:59])[CH:38]=2)(=[O:49])=[O:48])=[O:57])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NC1CCCC1
Reactant: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2C(=O)O)c2cccnc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(C)c1-c1cc(S(=O)(=O)N[C@@H]2CCC[C@@H]2C(=O)NC2CCCC2)c2cccnc2c1

Procedure:
To a mixture of HATU (38 mg, 0.10 mmol), cyclopentanamine (9 mg, 0.10 mmol), and 1S,2R)-2-(7-(3,5-dimethylisoxazol-4-yl)quinoline-5-sulfonamido)cyclopentanecarboxylic acid (21 mg, 0.05 mmol) in anhydrous DMF (1 mL), was added slowly Hunig's base (30 uL, 0.16 mmol) with stirring until the starting material acid disappeared (about 1 hr). The reaction mixture was acidified with aqueous citric acid to pH 2-3, then subjected to preparative HPLC to give (1S,2R)—N-cyclopentyl-2-(7-(3,5-dimethylisoxazol-4-yl)quinoline-5-sulfonamido)cyclopentanecarboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]([C:16]1[C:26]2[NH:25][C:24]3[N:27]=[CH:28][CH:29]=[CH:30][C:23]=3[CH2:22][NH:21][C:20]=2[CH:19]=[CH:18][CH:17]=1)=[O:15].[CH3:31]CCCCC.[H-].[Na+].CI>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]([C:16]1[C:26]2[NH:25][C:24]3[N:27]=[CH:28][CH:29]=[CH:30][C:23]=3[CH:22]([CH3:31])[NH:21][C:20]=2[CH:19]=[CH:18][CH:17]=1)=[O:15]
Reactant: CCCCCC
Reactant: Cn1ccc(-c2ccc(C(=O)c3cccc4c3Nc3ncccc3CN4)c(Cl)c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1Nc2cccc(C(=O)c3ccc(-c4ccn(C)n4)cc3Cl)c2Nc2ncccc21
Reaction time: 2 h
Yield: 47 %

Procedure:
Under anhydrous conditions, a solution of [2-chloro-4-(1-methyl-1H-pyrazol-3-yl)-phenyl]-(5,11-dihydro-pyrido[2,3-b][1,5]benzodiazepin-10-yl)-methanone of Example 19 (0.382 g, 0.92 mmol) in 10 mL of tetrahydrofuran was added dropwise to a stirred slurry of hexane washed sodium hydride (0.025 g, 1.02 mmol) in 2 mL of tetrahydrofuran. After the gas evolution ceased, methyl iodide (1 mL) was added and stirring was continued for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over sodium sulfate. The solvent was removed and the crude product purified by flash chromatography (on silica Merck-60, dichloromethane-ethyl acetate 2:1) to give the title compound (0.18 g, 47%). Crystallization from diethylether provided a light yellow solid (0.16 g), m.p. 249-250° C.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=O)=[CH:5][CH:4]=1.P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C.[CH3:31][N:32]([CH3:43])[CH2:33][CH2:34][NH:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([CH3:42])[CH2:38][CH2:37]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:31][N:32]([CH3:43])[CH2:33][CH2:34][N:35]([C@H:36]1[CH2:37][CH2:38][C@H:39]([CH3:42])[CH2:40][CH2:41]1)[C:9](=[O:11])[CH:8]=[CH:7][C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:14])=[CH:13][CH:12]=1
Reactant: CN(C)c1ccc(C=CC(=O)O)cc1
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCN(C(=O)C=Cc1ccc(N(C)C)cc1)[C@H]1CC[C@H](C)CC1

Procedure:
Using 2.0 g of 4-dimethylaminocinnamic acid, 1.9 ml of diethyl chlorophosphate, 3.5 ml of triethylamine, 60 ml of methylene chloride, 2.3 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexylamine (Example 78), and 0.04 g of 4-dimethylaminopyridine, a reaction similar to that conducted in Example 81 was carried out. As a result, 2.1 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-4-dimethylaminocinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:26][C:27](=[O:28])[C:4]=2[CH:3]=1)[CH2:13][CH2:12][N:11]([C:14]([C:16]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:15])[CH2:10][CH2:9]3.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([F:38])[CH:37]=1)[CH2:33]Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:26][C:27](=[O:28])[C:4]=2[CH:3]=1)[CH2:9][CH2:10][N:11]([C:14]([C:16]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[N:18]([CH2:33][C:32]2[CH:31]=[C:30]([F:29])[CH:37]=[C:36]([F:38])[CH:35]=2)[CH:17]=1)=[O:15])[CH2:12][CH2:13]3
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(Br)cc21
Reactant: Fc1cc(F)cc(CCl)c1
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4cc(F)cc(F)c4)c4cc(Cl)ccc34)CC2)c2ccc(Br)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 5-bromo-1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one with commercially available 3,5-difluorobenzyl chloride gave the title compound.
Reaction SMILES: N#N.C[Si](C)(C)[S:5][Si](C)(C)C.C[O-].[Na+].[CH3:15][C:16]1([C:21]2[O:25][C:24]([CH2:26][C:27]#[N:28])=[CH:23][CH:22]=2)[O:20][CH2:19][CH2:18][O:17]1>CN(C=O)C.O>[CH3:15][C:16]1([C:21]2[O:25][C:24]([CH2:26][C:27]([NH2:28])=[S:5])=[CH:23][CH:22]=2)[O:17][CH2:18][CH2:19][O:20]1
Reactant: C[Si](C)(C)S[Si](C)(C)C
Reactant: CC1(c2ccc(CC#N)o2)OCCO1
Agent: C[O-]
Agent: N#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(c2ccc(CC(N)=S)o2)OCCO1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), hexamethyldisilthiane (9.45 mL, 45.07 mmol) was added dropwise to a solution of NaOMe (2.51 g, 45.07 mmol) in dry DMF (40 mL) and the reaction mixture was stirred at rt for 15 min. This dark blue solution was then added to a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-yl]-acetonitrile (3.48 g, 18.03 mmol) in DMF (30 mL) and the reaction mixture was stirred for 16 h at rt. Water (300 mL) was then added and the mixture was extracted twice with EA (300 mL). The combined org. phases were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (6:4 hept-EA) gave the title compound as a yellow oil. TLC: rf (6:4 hept-EA)=0.18. LC-MS-conditions 02: tR=0.74 min, [M+H]+=228.44.
Reaction SMILES: NCCC[OH:5].C1C(=O)N(OC(CC[S:18][S:19][C:20]2[N:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=O)C(=O)C1.OP(O)(O)=O>C(Cl)Cl.CC(O)C>[N:25]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:19][S:18][OH:5]
Reactant: NCCCO
Reactant: O=C(CCSSc1ccccn1)ON1C(=O)CCC1=O
Agent: O=P(O)(O)O
Solvent: ClCCl
Solvent: CC(C)O
Product: OSSc1ccccn1
Reaction time: 1.25 h

Procedure:
3-Aminopropanol (0.76 ml, 10 mmol) was dissolved in a mixture of CH2Cl2 (5 ml) and 2-propanol (3 ml) and cooled in an ice bath. A solution of SPDP (1.23 g, 3.9 mmol) in CH2Cl2 (2 ml) was added dropwise in ca. 1 min. The mixture was stirred in the cooling bath for 1.25 h, and a 13% aqueous solution of NaH2PO4 (15 ml) and 85% H3PO4 (0.5 ml) were added. The products were extracted with ethyl acetate (2×30 ml), the organic layers were washed with 13% NaH2PO4, 15% KHCO3 and dried in vacuo. The crude compound 3 (1.14 g) was purified by flash-chromatography on silica-gel, elution with mixtures of CHCl3 and 2-propanol (100:0 to 100:7 by volume). Yield of pure compound 3 was 1.01 g (94%). TLC of compound 3 (CHCl3-2-propanol, 9:1): one spot, Rf ca. 0.3. 1H NMR of compound 3 (CDCl3), δ, ppm: 1.68 (quint., 6 Hz, 2H), 2.60 (t, 7 Hz, 2H), 3.05 (t, 7 Hz, 2H), 3.4 (br., 1H), 3.42 (q, 6 Hz, 2H), 3.62 (br., 2H), 6.99 (br., 1H), 7.10 (m, 1H), 7.58-7.65 (m, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.[C:30]1([S:36]C2C=CC=CC=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Na]>CN(C)C=O>[CH3:29][C:26]1[CH:25]=[CH:24][C:23]([C:20]2[CH:21]=[CH:22][C:16]3[O:15][CH2:14][CH2:13][C:12]([C:10]([NH:9][C:6]4[CH:7]=[CH:8][C:3]([CH2:2][S:36][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:4][CH:5]=4)=[O:11])=[CH:18][C:17]=3[CH:19]=2)=[CH:28][CH:27]=1
Reactant: c1ccc(Sc2ccccc2)cc1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCO3)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSc4ccccc4)cc2)CCO3)cc1
Yield: 113.9 %

Procedure:
A solution of N-(4-chloromethylphenyl)-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.15 g) and sodium phenyl sulfide (0.05 g.) in dimethylformamide (10 ml) was stirred at room temperature over night. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 7—(4-methylphenyl)-N-(4—(phenyl-thiomethyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 82) (0.13 g) as colorless crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:11]2)(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(CCc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CCc3ccccc3)CC2)cc1

Procedure:
4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperdine-4-carboxylic acid ethyl ester (3.0 g, 6.9 mmol) dissolved in THF:methanol 3:1 and 10N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.0 g (72%); off white powder, mp 208° C.; MS: 404.5 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[C:8]([O:13][OH:14])([CH2:11][CH3:12])([CH3:10])[CH3:9]>CCCCCC>[CH3:6][C:5]([O:14][O:13][C:8]([CH2:11][CH3:12])([CH3:10])[CH3:9])([CH2:4][C:2](=[O:1])[CH3:3])[CH3:7]
Reactant: CC(=O)C=C(C)C
Reactant: CCC(C)(C)OO
Solvent: CCCCCC
Product: CCC(C)(C)OOC(C)(C)CC(C)=O
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A reaction mixture of 11.8 g (0.12 mole) of mesityl oxide, 30 g of Amberlyst 15® sulfonic acid type ion-exchange resin, and 15.6 g (0.15 mole) of 89% t-amyl hydroperoxide was stirred at 25°-30° C. for 20 hours and at 40° C. for 1 hour. Hexane was added and the ion-exchange resin separated by filtration. The filtrate was washed with sodium bisulfite solution and with water and the organic layer dried over anhydrous magnesium sulfate. The hexane solvent was removed under reduced pressure and the 11.7 g of recovered product identified by its infrared spectrum.