Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.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>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: OB(O)c1ccc(Cl)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: C1CCOC1
Product: O=[N+]([O-])c1ccccc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.5 %

Procedure:
To a solution of 2-bromonitrobenzene (646 mg) in THF (17 ml) under nitrogen was added tetrakis(triphenylphosphine)palladium (0) (900 mg). The resulting mixture was stirred at room temperature for 20 min, then a solution of 4-chlorophenylboronic acid (1.0 g) in ethanol (17 ml) was added and the resulting mixture stirred at room temperature for 1 hr. 2M sodium carbonate (17 ml) was then added and the reaction heated to reflux for 2 hrs. The mixture was then allowed to cool and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 ml) and the aqueous layer removed. The organic phase was washed with brine (20 ml), dried (magnesium sulfate), filtered and concentrated. The reside was purified by flash chromatography (0–10% ethyl acetate/hexane) to afford the sub-title compound as a yellow solid (646 mg): 1H NMR (400 MHz, CDCl3) δ 7.24–7.31 (2H, m), 7.41–7.47 (3H, m), 7.52 (1H, m), 7.65 (1H, m), 7.90 (1H, d).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:23]([CH2:27][CH:28]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][NH2:35])[CH2:29]1)[CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22]>C(#N)C>[CH2:20]([N:23]([CH2:27][CH:28]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][NH:35][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:29]1)[CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22]
Reactant: CCCN(CCC)CC1CCN(CCN)C1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Solvent: CC#N
Product: CCCN(CCC)CC1CCN(CCNC(=O)N2c3ccccc3C(=O)Nc3cccnc32)C1
Yield: 22 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[3-[(dipropylamino)methyl]-pyrrolidin-1-yl]ethanamine in a yield of 22% of theory. Colourless crystals, m.p. 134°-138° C. (acetonitile).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[CH3:16][C:17]1[CH:21]=[C:20]([NH2:22])[N:19]([C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[N:28]3)[N:18]=1.ClCCl>N1C=CC=CC=1>[CH3:16][C:17]1[CH:21]=[C:20]([NH:22][S:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:15])([F:14])[F:1])=[CH:5][CH:6]=2)(=[O:12])=[O:11])[N:19]([C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[N:28]3)[N:18]=1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1cc(N)n(-c2cccc3ncccc23)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccc(OC(F)(F)F)cc2)n(-c2cccc3ncccc23)n1
Temperature: 80 °C
Yield: 10 %

Procedure:
To a stirring mixture of 4-(trifluoromethoxy)benzene-1-sulfonyl chloride (0.060 g, 0.23 mmol) and 3-methyl-1-(quinolin-5-yl)-1H-pyrazol-5-amine (prepared from Example 4 step b, 0.050 g, 0.22 mmol) in pyridine (1.0 mL) was heated at 80° C. for 1 h. After cooling to room temperature, dichloromethane was added to the reaction mixture and washed with 1 M aqueous sodium hydrogen sulfate (1 mL). The aqueous layer was further extracted with dichloromethane (2×5 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 2-10% methanol in dichloromethane) and purification by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.010 g, 0.022 mmol, 10%). 1H NMR (400 MHz, CDCl3) δ 8.75 (d, J=4.0 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.71 (s, 1H), 7.69 (s, 1H), 7.56 (t, J=8.4 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.21-7.17 (m, 4H), 6.12 (s, 1H), 2.34 (s, 3H); MS: (ES) m/z calculated for C20H16F3N4O3S [M+H]+ 449.1. found 449.7.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[CH3:16][N:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][C:23]#[N:24].Cl>ClCCCl>[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8]([C:21]1[N:17]([CH3:16])[C:18]([CH2:22][C:23]#[N:24])=[CH:19][CH:20]=1)=[O:9]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Cn1cccc1CC#N
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cn1c(CC#N)ccc1C(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 16.6 g. (0.125 mole) of aluminum chloride in 60 ml. 1,2-dichloroethane is added 26.2 g. (0.125 mole) of 2,4-dichlorobenzoyl chloride. The resulting solution is added slowly to a solution of 15 g. (0.125 mole) of 1-methylpyrrole-2-acetonitrile in 60 ml. 1,2-dichloroethane while cooling externally with an ice bath. After the addition is complete, the mixture is stirred for 40 minutes at room temperature followed by heating at reflux for 3 minutes. It is then poured into ice acidified with dilute hydrochloric acid. The organic phase is separated and washed successively with N,N-dimethyl-1,3-propanediamine, 3N hydrochloric acid, and saturated sodium chloride solution. It is then dried over magnesium sulfate and the solvent evaporated. The resulting red oily residue is chromatographed on a column packed with neutral alumina and eluted with benzene and ether. The first compound-bearing fractions upon evaporation yield a white solid, 5-(2',4'-dichlorobenzoyl)-1-methylpyrrole-2-acetonitrile, which is purified by recrystallization from methanol, m.p. 129-130° C. Analysis: Calcd. for C14H10Cl2N2O: N, 9.56%. Found: N, 9.51%.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([CH2:19][NH:20][C:21](=[O:24])[CH2:22]Cl)([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+]>C1COCC1>[CH:1]([N:14]1[CH2:17][C:16]2([CH2:19][NH:20][C:21](=[O:24])[CH2:22][O:18]2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)NCC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1COC2(CN1)CN(C(c1ccccc1)c1ccccc1)C2
Temperature: 75 °C
Reaction time: 0.17 h

Procedure:
N-((1-Benzhydryl-3-hydroxyazetidine-3-yl)methyl)-2-chloroacetamide (example 33, step d) (2.6 g) in THF (50 mL) was added dropwise over 90 minutes to a vigorously stirred solution at 75° C. of potassium tert-butoxide (1M in tert-butanol, 15.08 mL) and THF (150 mL) under nitrogen. After the addition was complete the mixture was stirred at 75° C. for 10 minutes and then cooled to room temperature. The solvents were removed under reduced pressure and the residue was partitioned between ethyl acetate and brine. The organic layer was dried over sodium sulphate, filtered and the solvent removed under reduced pressure to afford the subtitled compound. Yield 2.05 g.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1.[OH-].[K+].Br[CH2:14][CH:15]=[C:16]([CH3:25])[CH2:17][CH2:18][CH:19]=[C:20]([CH2:23][CH3:24])[CH2:21][CH3:22].[OH-].[Na+]>O1CCCC1.CN(C)C=O>[CH2:23]([C:20]([CH2:21][CH3:22])=[CH:19][CH2:18][CH2:17][C:16]([CH3:25])=[CH:15][CH2:14][O:1][C:2]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1)[CH3:24]
Reactant: CCC(=CCCC(C)=CCBr)CC
Reactant: Oc1ccc2c(c1)OCC2
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCC(=CCCC(C)=CCOc1ccc2c(c1)OCC2)CC
Temperature: 0 °C

Procedure:
10.9 g. of 6-hydroxy-2,3-dihydrobenzofuran are dissolved in 80 ml. of anhydrous dimethylformamide and treated, while stirring and with ice cooling at 0° C. with 5.3 g. of freshly powdered potassium hydroxide. The mixture is stirred for 1 hour at 0° C. under a nitrogen atmosphere and then added dropwise within 1 hour to a solution of 19.6 g. of 1-bromo-7-ethyl-3-methyl-2,6-nonadiene in 10 ml. of absolute tetrahydrofuran. The mixture is allowed to stir for 2 hours at 0° C. and for 2 hours at room temperature and then poured onto a mixture of 100 ml. of 10% by weight aqueous sodium hydroxide and 100 ml. of ice-water. The mixture is extracted three times with pentane, the extracts are washed successively with 10% by weight aqueous sodium hydroxide, water and saturated sodium chloride solution, dried over sodium sulfate and evaporated. By chromatography on silica gel with hexane/diethyl ether (19:1 parts by volume) there is obtained pure 6-[(7-ethyl-3-methyl-2,6-nonadienyl)-oxy]-2,3-dihydrobenzofuran which is distilled in a bulb-tube at 132° C./0.02 mmHg; nD20 = 1.5350.
Reaction SMILES: Cl.[I:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.C[O:21][C:22](=[O:31])[C:23]([CH3:30])([CH3:29])[CH2:24][C:25](=O)[CH2:26][CH3:27]>C(O)(C)(C)C>[I:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:10]3[C:15](=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:26]([CH3:27])=[C:25]2[CH2:24][C:23]([CH3:30])([CH3:29])[C:22]([OH:31])=[O:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(N(N)Cc2ccc(I)cc2)cc1
Reactant: CCC(=O)CC(C)(C)C(=O)OC
Agent: Cl
Solvent: CC(C)(C)O
Product: COc1ccc2c(c1)c(C)c(CC(C)(C)C(=O)O)n2Cc1ccc(I)cc1

Procedure:
Following the method of Example 2, but using 1-[4-iodobenzyl]-1-(4-methoxyphenyl)hydrazine hydrochloride and methyl-2,2-dimethyl-4-oxo-hexanoate as starting materials, using t-butanol as solvent, the title compound was prepared.
Reaction SMILES: [C:1]([C:3]1[C:12](=[O:13])[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:4]=1SC)#[N:2].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(#N)C>[C:1]([C:3]1[C:12](=[O:13])[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:4]=1[N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)#[N:2]
Reactant: CCOC(=O)c1c(SC)c(C#N)c(=O)n2ccccc12
Reactant: C1CCNCC1
Solvent: CC#N
Product: CCOC(=O)c1c(N2CCCCC2)c(C#N)c(=O)n2ccccc12

Procedure:
A mixture of 1.44 g of 3-cyano-1-ethoxycarbonyl- 2-methylthio-4H-quinolizin-4-one and 5.0 ml of piperidine in 10 ml of acetonitrile was heated under reflux for 10 hours. The reaction mixture was concentrated under reduced pressure and the residue was chromatographed on a silica gel column using a mixed solvent of ethyl acetate and n-hexane (2:1) as an eluent to obtain 0.95 g of 3-cyano-1-ethoxycarbonyl-2-piperidino-4H-quinolizin-4-one.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:4]=1[C:5](NC)=[O:6])=[O:2].C(=O)([O-])[OH:15].[Na+]>Cl>[CH:1]([C:3]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:4]=1[C:5]([OH:15])=[O:6])=[O:2]
Reactant: CNC(=O)c1ccc(Cl)cc1C=O
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: O=Cc1cc(Cl)ccc1C(=O)O

Procedure:
A mixture of 2-formyl-4-chloro-N-methylbenzamide (3.19 g) and 10M hydrochloric acid (30 ml) was heated at reflux for 18 hours. The mixture was cooled and basified with saturated sodium hydrogen carbonate solution. The solution was then washed with ethyl acetate, then acidified with 2M hydrochloric acid. The product was extracted with ethyl acetate and the combined extracts dried with magnesium sulfate. The solution was then filtered and concentrated. This furnished 2-formyl-4-chlorobenzoic acid as a yellow solid (2.22 g, 75%); 1H NMR (400 MHz, CDCl3) δ 6.65 (0.5H, brs), 7.50 (2H, m), 7.65 (1H, m), 7.85 (0.5H, brm), 8.05 (1H, m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:37]=[CH:36][C:28]([O:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[C:27]([F:38])[CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[CH:37]=[CH:36][C:28]([O:29][CH:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)=[C:27]([F:38])[CH:26]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: Fc1cc(Br)ccc1OC1CCOCC1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OC2CCOCC2)c(F)c1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 4-(4-bromo-2-fluoro-phenoxy)-tetrahydro-pyran (Intermediate 16) in analogy to Example 1a): MS (ISN): 496.1 and 498.2 (M−H)−.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH:11]1([N:14]([C@H:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C@@H:20]([CH3:28])[CH2:19]2)[C:15](=[O:17])[CH3:16])[CH2:13][CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1>[CH:11]1([N:14]([C@H:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([C:2]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=3)=[O:9])[C@@H:20]([CH3:28])[CH2:19]2)[C:15](=[O:17])[CH3:16])[CH2:12][CH2:13]1
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(=O)N(C1CC1)[C@@H]1C[C@H](C)Nc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)N(C1CC1)[C@@H]1C[C@H](C)N(C(=O)c2cccnc2)c2ccccc21
Temperature: 50 °C
Yield: 52.4 %

Procedure:
Nicotinoyl chloride hydrochloride (1.46 g) was added to a solution of Cis-N-cyclopropyl-N-(2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-acetamide (0.4 g) in pyridine (20 ml). The mixture was heated at 50° C. for 3 hours. After cooling, an aqueous solution of sodium carbonate was added and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and then the solvent was removed under reduce pressure. The crude compound was crystallized in diethyl ether to give Cis-N-cyclopropyl-N-[2-methyl-1-(pyridine-3-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-acetamide (0.3 g, 52.6% yield).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:27]=[CH:26][C:17]3[C:18]4[CH2:25][CH2:24][CH2:23][C:19]=4[C:20](=[O:22])[O:21][C:16]=3[CH:15]=2)[CH2:6][CH2:5]1.C(=O)(O)[O-].[Na+].[N+:33]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)([O-:35])=[O:34]>ClCCl>[N+:33]([C:36]1[CH:37]=[CH:38][C:39]([C:40]([NH:3][CH:4]2[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]3[CH:27]=[CH:26][C:17]4[C:18]5[CH2:25][CH2:24][CH2:23][C:19]=5[C:20](=[O:22])[O:21][C:16]=4[CH:15]=3)[CH2:6][CH2:5]2)=[O:41])=[CH:43][CH:44]=1)([O-:35])=[O:34]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: NC1CCN(CCCOc2ccc3c4c(c(=O)oc3c2)CCC4)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(NC1CCN(CCCOc2ccc3c4c(c(=O)oc3c2)CCC4)CC1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 4.15 g. (0.01 mole) 7-[3-(4-aminopiperidino)-propoxy]-2,3-dihydrocyclopenta[c][1]benzopyran-4(1H)-one dihydrochloride, 2.5 g. sodium bicarbonate and 60 ml. dichloromethane is mixed, while cooling with ice, with a solution of 1.86 g. (0.01 mole) 4-nitrobenzoyl chloride in 20 ml. dichloromethane. The reaction mixture is stirred for 14 hours at ambient temperature, filtered and the precipitate washed with water and dichloromethane and purified by chromatography on silica gel (elution agent dichloromethane:methanol, 9:1 v/v). There are obtained 2.5 g. (51% of theory) of the desired compound; m.p. 212°-213° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH:10]([O:23][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:35][CH2:36][CH2:37][C:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:39]>>[CH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:33]=[CH:34][C:25]=1[CH2:24][O:23][CH:10]1[CH:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](=[O:19])[NH:35][CH2:36][CH2:37][C:38](=[O:39])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:16][CH:15]=2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: NCCC(=O)c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)NCCC(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 36(b), by condensing (3RS,4RS)-4-(1-tert-butoxycarbonyl-3-naphthalen-2-ylmethoxy-piperidin-4-yl)-benzoic acid with 3-amino-1-phenyl-propan-1-one there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(3-oxo-3-phenyl-propylcarbamoyl)-phenyl]-piperidine-1-carboxylate as a colourless foam; MS: 593 (M+H)+.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH:11]=[CH:10]1>>[CH:1]([C:10]1=[CH:11][C:12]([O:14][C:9]1=[O:15])=[O:13])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1C=CC(=O)O1
Reactant: C=Cc1ccccc1
Product: O=C1C=C(C=Cc2ccccc2)C(=O)O1

Procedure:
U.S. Pat. No. 4,145,375 teaches a process for copolymerizing styrene and maleic anhydride by the steps of gradually mixing maleic anhydride with styrene in a mass stage under polymerizing conditions to form styrene-maleic anhydride polymer and then suspending the styrene-rich mixture in water, the styrene polymerization is completed as in a conventional mass/suspension polymerization system. Following polymerization, polymeric beads are separated from the water and dried. The disclosure indicates that after drying, the beads are likely to contain internal moisture and in addition approximately 15% of the bound maleic anhydride may be present in the acid rather than anhydride form, and, consequently, during extrusion, the acid portion reverts to the anhydride with the elimination of water. The disclosure indicates that a well-vented extruder is needed to produce a bubble-free extrudate.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([C:16]2[S:20][C:19]([C:21]([NH2:23])=O)=[N:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25]>O1CCOCC1>[CH3:1][C:2]([C:5]1[CH:6]=[C:7]([C:16]2[S:20][C:19]([C:21](=[S:25])[NH2:23])=[N:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1cc(-c2nnc(C(N)=O)s2)cc(C(C)(C)C)c1O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(-c2nnc(C(N)=S)s2)cc(C(C)(C)C)c1O
Yield: 58.5 %

Procedure:
A mixture of 1.5 g (4.5 mmol) of 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2-carboxamide and 1.0 g (2.2 mmol) of P2S5 in 20 ml of dioxane is warmed at reflux for one hour under a nitrogen atmosphere. The reaction is poured through a plug of SiO2, washing with t-butylmethylether. Recrystallization from toluene gives 0.45 g (1.6 g theor., 28%) of the thioamide as a yellow solid, mp 215°-216° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@@H:7]([C:12]([OH:14])=O)[CH2:6][CH2:5]2.C([O-])(=O)C.[NH4+:19].O>CN(C)C=O>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@@H:7]([C:12]([NH2:19])=[O:14])[CH2:6][CH2:5]2
Reactant: O=C(O)[C@H]1CCc2cc(I)ccc2O1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)[C@H]1CCc2cc(I)ccc2O1
Reaction time: 3 h

Procedure:
The crude carboxylic acid of Example 7 (30.4 g, 100 mmol) and CDl (19.5 g, 120 mmol) were stirred in N,N-dimethylformamide (300 mL) at room temperature for 2 hours to obtain a yellow solution. To this solution was then added ammonium acetate (23.1 g, 300 mmol). The resulting mixture was stirred for 3 hours. It was then cooled in an ice-water bath and water (400 mL) was then added dropwise to the reaction mixture to obtain a fine white precipitation which was stirred for 12 hours. The solid was collected by vacuum filtration, washed with water and dried by suction (25.8 g, 85%): 1H NMR (DMSO-d6) δ1.75-1.90 (m, 1H), 2.00-2.15 (m, 1H), 2.55-2.80 (m, 2H), 4.43-4.47 (dd, J=8.7, 3.3 Hz, 1H), 6.65 (d, J=8.1 Hz, 1H), 7.35 (m, 2H). CI-MS m/z 304 (M +H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:11][CH2:12][CH3:13])=[CH:2]1.[CH2:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(Cl)(Cl)Cl>[CH2:23]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:15]=2)[CH2:11][CH2:12][CH3:13])=[CH:2]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ClCc1ccccc1
Reactant: CCCC(c1c[nH]c2ccccc12)c1c[nH]c2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCC(c1cn(Cc2ccccc2)c2ccccc12)c1cn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
ST 1385 1,1-di-indol-3-yl-butane, 290 mg (1 mmol), was thoroughly mixed and blended with potassium tertbutylate (280 mg) and tetrabutylammonium bromide (20 mg). The mixture thus obtained was held under ultrasonic stirring at ambient temperature. 640 mg (5 mmol) of benzylchloride at 0° C. were then added and the ultrasonic stirring was continued for 2 hours at room temperature. At the end of this period, the reaction mixture was treated with H2O/CHCl3; the chloroform phase was separated, washed with a small amount of water, dried on Na2SO4, filtered and concentrated to dryness. The end product was isolated and purified chromatographically on silica gel, eluting with hexane:ethyl ether 95:5.351 mg of product were obtained with a 78% yield.
Reaction SMILES: Cl[C:2]([F:27])([F:26])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([N:18]2[CH2:20][CH:19]2[CH3:21])[C:4]=1[C:22]([O:24][CH3:25])=[O:23].C(N(CC)CC)C>C(O)C.[Pd]>[F:27][CH:2]([F:26])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([N:18]2[CH2:20][CH:19]2[CH3:21])[C:4]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1N1CC1C
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1N1CC1C
Reaction time: 18 h
Yield: 88.7 %

Procedure:
A mixture of 2.5 g (0.0059 mol) of product of Example 81, 0.6 g (0.0059 mol) of triethylamine and 0.25 g of 5% Pd/C (50% water coated) in 100 ml of ethanol was hydrogenated (446 kPa, for 18 hours at 50° C. The mixture was then filtered through celite and concentrated in vacuo to remove the ethyl alcohol. The residue was poured into water, and extracted with diethyl ether. The ether extract was washed with water, then dried over MgSO4. The dry ether phase was then concentrated in vacuo to yield 2.00 g of a yellow solid. This solid was then recrystallized in hexane to yield 1.28 g (56%) of product as a tan solid; mp 61° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:13][CH2:12]2)=[C:7]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[N:6]=1)=[O:4].O.[OH-].[Li+]>C1COCC1.O>[CH:11]1([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH2:12][CH2:13]1
Reactant: COC(=O)c1ccc(C2CC2)c(Nc2ccc(Cl)cc2Cl)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C2CC2)c(Nc2ccc(Cl)cc2Cl)n1
Yield: 10.1 %

Procedure:
A solution of 5-cyclopropyl-6-(2,4-dichloro-phenylamino)-pyridine-2-carboxylic acid methyl ester (62 mg, 184 μmol) and lithium hydroxide hydrate (9.3 mg, 221 μmol) in THF (100 μl) and water (50 μl) was stirred at ambient temperature for 20 h. The reaction mixture was poured onto 1 M HCl/ice water (1×20 mL) and extracted with i-PrOAc (2×25 mL). The combined organic layers were dried over sodium sulfate. The solvent was removed under reduced pressure to obtain the title compound (6 mg, 10%) as colorless liquid, which was sufficiently pure to be used in the next reaction step, MS (EI): m/e=323.3 [M+H]+.