Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([N+:19]([O-:21])=[O:20])=[CH:4][C:5]([CH3:18])=[C:6]([NH:8][C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1.[SH:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[OH:29][C:26]1[CH:27]=[CH:28][C:23]([S:22][C:2]2[C:3]([N+:19]([O-:21])=[O:20])=[CH:4][C:5]([CH3:18])=[C:6]([NH:8][C:9](=[O:17])[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:7]=2)=[CH:24][CH:25]=1
Reactant: Oc1ccc(S)cc1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1NC(=O)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(Sc2ccc(O)cc2)cc1NC(=O)Cc1ccccc1
Temperature: 25 °C
Yield: 71.5 %

Procedure:
The product from Example 265A (0.305 g, 1.0 mmol), 4-mercaptophenol (0.151 g, 1.2 mmol, 1.2 eq) and cesium carbonate (0.782 g, 2.4 mmol, 2.4 eq) in dimethyl formamide (10 mL) was heated at 110° C. for 2 h, cooled to room temperature, and poured over ice water (100 mL). This mixture was extracted with ethyl acetate (3×150 mL) and the combined organic phases were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue was purified by chromatography on silica gel eluting with 1:1 hexane/ethyl acetate to provide the title compound as a yellow solid (0.282 g, 72%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[OH:23].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[O:23][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1
Reactant: COc1ccc2oc(=O)cc(Cl)c2c1
Reactant: Oc1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc2oc(=O)cc(Oc3c(Cl)cccc3Cl)c2c1
Temperature: 25 °C
Yield: 73 %

Procedure:
A stirred mixture of 4-chloro-6-methoxycoumarin (1.0 g, 4.75 mmole) , 2,6-dichlorophenol (0.85 g, 5.22 mmole) and K2CO3 (0.98 g, 7.12 mmole) in acetonitrile, under N2, is heated at reflux temperature for 16 hours, cooled to room temperature and poured into ice water. This mixture is extracted several times with ether. The extracts are combined and concentrated in vacuo to give a tan solid residue. The residue is crystallized from ethyl acetate/hexane to afford the title product as tan crystals, 1.17 g (73% yield), mp 170°-171° C., identified by IR, 1HNMR, 13CNMR, and mass spectral analyses.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([CH3:10])=[CH:8][N:7]=[C:6]([CH2:11]O)[CH:5]=1)[CH3:2].S(Cl)([Cl:15])=O.CCOCC>C(Cl)Cl>[ClH:15].[Cl:15][CH2:11][C:6]1[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:9]([CH3:10])=[CH:8][N:7]=1
Reactant: CCOc1cc(CO)ncc1C
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCOc1cc(CCl)ncc1C
Product: Cl
Reaction time: 2 h

Procedure:
4.7 g of 4-ethoxy-5-methyl-2-pyridylmethanol, dissolved in 30 ml of methylene chloride, were added dropwise at 0° to 2.4 ml of thionyl chloride in 60 ml of methylene chloride. After stirring at room temperature for 16 hours 400 ml of ether were added dropwise thereto while cooling and the mixture was stirred at room-temperature for a further 2 hours. The separated crystals were filtered off under suction and washed with ether. There was obtained 2-chloromethyl-4-ethoxy-5-methylpyridine hydrochloride of melting point 144-146° .
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[CH2:13][CH2:12]2)[CH:5]=1.[O:27]1[CH2:31][CH2:30][CH:29]([CH2:32]S([O-])(=O)=O)[CH2:28]1>>[O:27]1[CH2:31][CH2:30][CH:29]([CH2:32][N:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]([CH:14]3[CH2:13][CH2:12][N:11]([CH2:10][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([OH:2])=[O:26])[CH2:16][CH2:15]3)=[CH:18]2)[CH2:28]1
Reactant: COC(=O)c1cccc(CN2CCC(c3c[nH]c4ccccc34)CC2)c1
Reactant: O=S(=O)([O-])CC1CCOC1
Product: O=C(O)c1cccc(CN2CCC(c3cn(CC4CCOC4)c4ccccc34)CC2)c1

Procedure:
This compound was prepared following the procedure described in example 1 (part E) starting with 0.1 g (0.28 mmol) of 3-[4-(1H-indol-3-yl)-piperidin-1-ylmethyl]-benzoic acid methyl ester (example 28, part A) and 0.72 g (0.4 mmol) of (tetrahydro-furan-3-yl)-methansulfonate. After standard purification, 0.04 g (34% of yield) of the expected acid were obtained.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:27][CH3:28])=[C:10]([NH:12][C:13]2[O:14][C:15]([C:18]3[CH:19]=[C:20]([C:24](=[O:26])[CH3:25])[CH:21]=[CH:22][CH:23]=3)=[CH:16][N:17]=2)[CH:11]=1)(=[O:5])=[O:4])[CH3:2].C(O[CH:34](OC(C)(C)C)[N:35]([CH3:37])[CH3:36])(C)(C)C>CN(C=O)C>[CH3:34][N:35]([CH3:37])/[CH:36]=[CH:25]/[C:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:15]2[O:14][C:13]([NH:12][C:10]3[CH:11]=[C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:7]=[CH:8][C:9]=3[O:27][CH3:28])=[N:17][CH:16]=2)[CH:19]=1)=[O:26]
Reactant: CCS(=O)(=O)c1ccc(OC)c(Nc2ncc(-c3cccc(C(C)=O)c3)o2)c1
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(OC)c(Nc2ncc(-c3cccc(C(=O)/C=C/N(C)C)c3)o2)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
The title compound (3.0 g, 7.5 mmol) from Example 200 was combined with dimethylformamide ditertbutylacetal (10.0 g, 4.9 mmol) in DMF (ca. 4 mL). After the reaction was stirred at 130° C. for 2 h, the excess solvent was evaporated under reduced pressure. The crude product was coated onto silica gel and chromatographed on silica gel using dichloromethane (98%) and methanol (20%) as eluent affording the title compound (1.6 g, 3.9 mmol) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[CH:8]([CH3:12])[C:9]([OH:11])=[O:10].[CH2:18](C(C(OCC)=O)C(OCC)=O)[CH2:19]C>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[CH:8]([CH2:12][CH2:18][CH3:19])[C:9]([OH:11])=[O:10]
Reactant: CCCC(C(=O)OCC)C(=O)OCC
Reactant: CC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Product: CCCC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1

Procedure:
N-(3,5-difluoro-benzyl)-2-propyl-malonamic acid was prepared in analogy to N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid (example 1) from diethyl propyl-malonate.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][CH2:7]/[CH:8]=[C:9]1\[CH2:10][C@@H:11]2[C@H:15]([CH2:16]\1)[C@@H:14]([CH2:17][CH2:18][CH:19]([OH:26])[CH:20]([F:25])[CH2:21][CH2:22][CH2:23][CH3:24])[C@H:13]([O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1)[CH2:12]2)=[O:4].[OH-].[Na+]>CO>[C:3]([CH2:5][CH2:6][CH2:7]/[CH:8]=[C:9]1\[CH2:10][C@@H:11]2[C@H:15]([CH2:16]\1)[C@@H:14]([CH2:17][CH2:18][CH:19]([OH:26])[CH:20]([F:25])[CH2:21][CH2:22][CH2:23][CH3:24])[C@H:13]([O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1)[CH2:12]2)([OH:4])=[O:2]
Reactant: CCCCC(F)C(O)CC[C@@H]1[C@H]2C/C(=C/CCCC(=O)OC)C[C@H]2C[C@H]1OC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCC(F)C(O)CC[C@@H]1[C@H]2C/C(=C/CCCC(=O)O)C[C@H]2C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(1S,2R,3R,5S)-7(E)-(4-Methoxycarbonylbutylidene)-2-[4(RS)-fluoro-3(RS)-hydroxy-octyl ]-3-tetrahydropyranyloxybicyclo[3.3.0]octane (12) (0.185 g) was dissolved in methanol. To the solution, an aqueous solution of 1N sodium hydroxide (6.5 ml) was added. The mixture was stirred at room temperature for 4 hours. After a usual work-up a crude product (1S,2R,3R,5S)-7(E)-(4-carboxybutylidene)-2-[4(RS)fluoro-3(RS )-hydroxyoctyl]-3-tetrahydropyranyloxybicyclo[3.3.0]octane (13) was obtained. Yield: 0.184 g
Reaction SMILES: [C:1]([CH:4]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2].[H-].[Na+].[Br:26]Br>O1CCCC1.ClCCl>[C:1]([C:4]([Br:26])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)C(CCCCCCCOC1CCCCO1)C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C(Br)(CCCCCCCOC1CCCCO1)C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 2-acetyl-9-tetrahydropyranyloxy-nonanoate (20 g) in dry tetrahydrofuran (100 ml) was added dropwise to a stirred suspension of sodium hydride (2.01 g of 80% oil dispersion) in dry tetrahydrofuran (50 ml), under nitrogen. The mixture was warmed to reflux for 10 minutes. The clear solution was allowed to cool to room temperature then a solution of bromine (3.15 ml) in dry dichloromethane (50 mls) was added rapidly. After stirring for 30 minutes, during which time a yellow precipitate was formed, the mixture was partitioned between water and ether. The ether solution was washed with brine, dried and evaporated in vacuo at low temperature (<30° C.). The ethyl 2-acetyl-2-bromo-9-tetrahydropyranyloxy-nonanoate was obtained as a dark yellow oil (27.1 g.) which still contained a small amount of solvent.
Reaction SMILES: Br[C:2]1[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][C:3]=1[CH:10]=[O:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(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>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][C:3]=2[CH:10]=[O:11])=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC1(C)CCC(Br)=C(C=O)C1
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: [K+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1(C)CCC(c2ccc(Cl)cc2)=C(C=O)C1
Temperature: 25 °C
Yield: 76.9 %

Procedure:
A suspension of 2-bromo-5,5-dimethylcyclohex-1-enecarbaldehyde (250 mg, 1.15 mmol), 4-chlorophenyl boronic acid (270 mg, 1.727 mmol) and Pd(Ph3P)4 (66.5 mg, 0.058 mmol) in dioxane (2.5 mL) was stirred at room temperature in a 5 mL microwave vial under an atmosphere of nitrogen. A solution of potassium carbonate (318 mg, 2.3 mmol) in water (0.3 mL) was added and the solution became clear. The vial was capped and heated to 100° C. for 12 minutes in a microwave. The reaction was cooled to room temperature, diluted with CH2Cl2, filtered through a plug of Celite, and concentrated. The crude residue was purified by flash chromatography on silica gel (0-25% EtOAc/heptanes) to afford 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enecarbaldehyde as a clear colorless oil (220 mg, 77% yield).
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:15]=[C:14]([S:16][CH3:17])[C:8]([C:9]([O:11]CC)=[O:10])=[C:7]([S:18][CH3:19])[CH:6]=2)[CH2:3][CH2:2]1.[Li+].[OH-]>CO.O>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([S:18][CH3:19])[C:8]([C:9]([OH:11])=[O:10])=[C:14]([S:16][CH3:17])[CH:15]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1c(SC)cc(OC2CC2)cc1SC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSc1cc(OC2CC2)cc(SC)c1C(=O)O

Procedure:
To a microwave heating vial was add ethyl 4-(cyclopropyloxy)-2,6-difluorobenzoate (1 g, 4.13 mmol) and DBU (2.18 ml, 14.5 mmol). The reaction mixture was cooled with dry ice acetone bath. Methanethiol (˜1 ml) was condensed into the vial. The vial was sealed and the resulting reaction mixture was heated at 100° C. with microwave for 1 hour. The volatiles were removed by a stream of nitrogen. The residue was diluted with 60 ml ether, extracted with 2×30 ml 5% KOH. The aqueous portion was acidified with concentrated HCl to cause precipitation. The mixture was filtered and the precipitate was washed with 15 ml water. The resulting solid was air dried to give 0.37 g desired product as white solid. The organic portion was washed with 60 ml 1N HCl, dried over sodium sulfate, filtered and concentrated to give 0.78 g oil which contains mostly ethyl 4-(cyclopropyloxy)-2,6-bis(methylthio)benzoate. It was dissolved in 20 ml methanol and 3 ml water. LiOH (2 g) was added. The resulting reaction mixture was refluxed for 24 hours. The volatiles were removed, and the residue was dissolved in 40 ml water, washed with 30 ml ether, acidified with concentrated HCl to cause precipitation. It was filtered, washed with 20 ml water, air dried to give 0.52 g desired product as light yellow solid.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:32]([O:34]C)=[O:33])=[CH:12][C:13]=3[N:14]3[CH2:21][C:20](=[O:22])[N:19]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH2:18][C:17]4[CH:28]=[CH:29][CH:30]=[CH:31][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br>C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:32]([OH:34])=[O:33])=[CH:12][C:13]=3[N:14]3[CH2:21][C:20](=[O:22])[N:19]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH2:18][C:17]4[CH:28]=[CH:29][CH:30]=[CH:31][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)N(CCN(C)C)Cc1ccccc1-3
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN(C)CCN1Cc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2CC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
To a solution of methyl 14-cyclohexyl-6-[2-(dimethylamino)ethyl]-7-oxo-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate in DCM (0.02 M) was added dropwise a solution of BBr3 in DCM (1 M). The solution was stirred at RT for 30 min. Volatiles were removed in vacuo. The crude was then purified by automated RP-MS-HPLC (stationary phase: column Waters XTERRA prep. C18, 5 um, 19×100 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound as a white powder (20%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[C@@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:40]([O:42][C:43]([C@@H:45]1[CH2:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[N:46]1[C:54](=[O:63])[C@@H:55]([NH2:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:44])[CH3:41].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:40]([O:42][C:43]([C@@H:45]1[CH2:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[N:46]1[C:54](=[O:63])[C@@H:55]([NH:62][C:10](=[O:12])[C@@H:9]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:14])[CH3:13])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:44])[CH3:41]
Reactant: CCOC(=O)[C@@H]1Cc2ccccc2N1C(=O)[C@@H](N)c1ccccc1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H]1Cc2ccccc2N1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
In a 50 mL round-bottomed flask, (S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid (1.52 g, 7.48 mmol, Eq: 1.5) and HATU (1.9 g, 5 mmol, Eq: 1) were combined with DCM (20 mL) to give a light yellow suspension. (S)-1-((S)-2-amino-2-phenyl-acetyl)-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester hydrochloride (1.8 g, 5 mmol, Eq: 1) was added and followed by diisopropylethylamine (7 mL, 40 mmol, Eq: 8). The reaction was stirred at rt overnight. The crude reaction mixture was concentrated in vacuo, and then dissolved in EtOAc (75 mL). The solution was washed with water and brine, dried and concentrated in vacuo. The crude material was purified by flash chromatography (10% to 30% EtOAc in hexanes) to afford (S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-2-phenyl-acetyl}-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester (2.3 g) as a white foam, m/z=510 (M+H).
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC(OC)=O)C=CC=1OC.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:44]=[CH:45][C:46]=1[O:47][CH3:48])[C:32]([C:34]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[C:36]([O:42][CH3:43])[CH:35]=1)=O.C(OP([CH2:57][C:58]#[N:59])(=O)OCC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:32]([C:34]2[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[C:36]([O:42][CH3:43])[CH:35]=2)=[CH:57][C:58]#[N:59])[CH:44]=[CH:45][C:46]=1[O:47][CH3:48]
Reactant: COc1cc(OC)cc(C(=O)c2ccc(OC)c(OC)c2)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1cc(OC)cc(C(=CC#N)c2ccc(OC)c(OC)c2)c1

Procedure:
3-(3,4-Dimethoxyphenyl)-3-(3′,5′-dimethoxyphenyl)acrylonitrile was prepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3,4,3′,5′-tetramethoxybenzophenone (0.7 g, 2.3 mmol), diethylcyanomethylphosphonate (0.42 mL, 2.5 mmol) and lithium hexamethyldisilazide (1.9 mL, 2.5 mmol, 1.3 M) with a reaction time of 60 hours at room temperature. The crude product was purified by flash chromatography (silica gel, 1% ethyl acetate/methylene chloride) to afford 0.66 g (81%) of a mixture of the E and Z isomers as a white solid: mp 88-90° C.; 1H NMR (CDCl3) δ 7.10-6.80 (m, 6 H), 6.61-6.40 (m, 6 H), 5.66 (s, 1 H), 5.61 (s, 1 H), 3.94 (s, 3 H), 3.91 (s, 3 H), 3.87 (s, 3 H), 3.84 (s, 3 H), 3.80 (s, 3 H), 3.77 (s, 6 H); 13C NMR (CDCl3) δ 162.7, 162.5, 160.7, 160.6, 151.1, 150.6, 148.8, 148.5, 141.3, 138.9, 131.1, 129.2, 123.2, 122.1, 118.2, 118.0, 112.6, 110.9, 110.7, 110.7, 107.6, 107.0, 102.1, 102.0, 93.4, 93.1, 56.0, 55.9, 55.5, 55.4; Anal. Calcd for C19H19NO4. Theoretical: C, 70.14; H, 5.89; N, 4.30. Found: C, 70.33; H, 5.89; N, 4.03.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]([C:23]1[N:28]=[C:27]([O:29][CH2:30][C:31]([F:34])([F:33])[F:32])[CH:26]=[C:25]([O:35][CH2:36][C:37]([F:40])([F:39])[F:38])[N:24]=1)[C:11](=[O:22])[NH:12][C:13]1[S:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:43][O:44][CH2:45]Br>CN(C=O)C>[CH2:1]([O:8][CH2:9][N:10]([C:23]1[N:28]=[C:27]([O:29][CH2:30][C:31]([F:32])([F:33])[F:34])[CH:26]=[C:25]([O:35][CH2:36][C:37]([F:39])([F:40])[F:38])[N:24]=1)[C:11](=[O:22])[N:12]([CH2:43][O:44][CH3:45])[C:13]1[S:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)s1)N(COCc1ccccc1)c1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Reactant: COCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCN(C(=O)N(COCc1ccccc1)c1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1)c1ccc(C(F)(F)F)s1
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
To a solution of 3-(benzyloxymethyl)-3-(4,6-bis(2,2,2-trifluoroethoxy)pyrimidin-2-yl)-1-(5-(trifluoromethyl)thiophen-2-yl)urea (250 mg, 0.41 mmol) in anhydrous DMF (2.5 mL), with an internal temperature of ≦−10° C., was slowly added NaH (20 mg, 0.5 mmol, 60% dispersion in mineral oil). The mixture was stirred 30 minutes resulting in a clear yellow solution. To this solution was slowly added a solution of bromomethyl methyl ether (51.6 mg, 0.41 mmol) in anhydrous DMF (0.5 mL). After 2.5 h the reaction was quenched with ice and diluted with EtOAc (25 mL). The mixture was extracted with H2O (3×15 mL) and brine (15 mL). The EtOAc solution was dried (Na2SO4), filtered and evaporated to give crude product. The crude product was purified by silica gel chromatography (2 to 6% EtOAc in pet ether) to afford the product as a pale yellow gum (185 mg, 69%). 1H NMR (400 MHz, Acetone-d6) δ 7.29-7.08 (m, 6H), 6.82 (d, J=3.9 Hz, 1H), 5.90 (s, 1H), 5.40 (s, 2H), 5.10 (s, 2H), 4.79 (q, J=8.7 Hz, 4H), 4.69 (s, 2H), 3.27 (s, 3H); ESIMS m/z 649 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([N:11]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:3]=1.[H][H]>[Ni].C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N:11]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]2[CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[CH:3]=1
Reactant: Cc1cn(-c2cc(Cl)ccc2[N+](=O)[O-])c(C2CCCCC2)n1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Cc1cn(-c2cc(Cl)ccc2N)c(C2CCCCC2)n1

Procedure:
3.2 g 4-Chloro-2-(2-cyclohexyl-4-methyl-imidazol-1-yl)-nitrobenzene, 50 ml ethanol, and 0.5 g Raney-Nickel were heated in a closed vessel with 10 bar hydrogen at 40-45° C. The catalyst was filtered off and the solvent was removed by distillation.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[C:11]([Cl:17])[CH:10]=2)=[O:5])C.[NH2:19][C@@H:20]([C:31]([OH:33])=[O:32])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1>>[C:31]([C@H:20]([NH:19][C:7]1[C:6]([C:4]([OH:3])=[O:5])=[CH:15][C:14]2[C:9](=[CH:10][C:11]([Cl:17])=[C:12]([Cl:16])[CH:13]=2)[N:8]=1)[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)([OH:33])=[O:32]
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CCOC(=O)c1cc2cc(Cl)c(Cl)cc2nc1Cl
Product: O=C(O)c1cc2cc(Cl)c(Cl)cc2nc1N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Yield: 29 %

Procedure:
In close analogy to the procedure described in Example 32, 2,6,7-trichloroquinoline-3-carboxylic acid ethyl ester is reacted with D-tryptophan (heating for 39 h) to provide the title compound in 29% yield as pale yellow powder.
Reaction SMILES: CS[C:3]1[S:4][CH2:5][CH2:6][N:7]=1.Cl.[Cl:9][C:10]1[C:11]([NH:17][NH2:18])=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1>C(O)(C)C>[Cl:9][C:10]1[C:11]([NH:17][NH:18][C:3]2[S:4][CH2:5][CH2:6][N:7]=2)=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cccc(Cl)c1NN
Reactant: CSC1=NCCS1
Agent: Cl
Solvent: CC(C)O
Product: Cc1cccc(Cl)c1NNC1=NCCS1

Procedure:
A solution of 11.2 g (5% excess) of 2-methylthio-2-thiazoline in 20 ml of isopropanol was added slowly in the course of 30 minutes to a suspension, which was stirred under reflux, of 15.5 g (0.08 mol) of 3-chloro-2-tolyl-hydrazine hydrochloride in 100 ml of isopropanol.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8](O)([CH3:22])[C:9]3[C:14]([C:15]4([CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]4)[C:6]=2[CH:5]=[CH:4][CH:3]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3.C(=O)([O-])[O-].[Na+].[Na+]>Cl>[OH:1][C:2]1[C:7]2[C:8](=[CH2:22])[C:9]3[C:14]([C:15]4([CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]4)[C:6]=2[CH:5]=[CH:4][CH:3]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CN1CCC2(CC1)c1ccccc1C(C)(O)c1c(O)cccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C=C1c2ccccc2C2(CCN(C)CC2)c2cccc(O)c21

Procedure:
4,10-Dihydroxy-1',10-dimethyl-9,10-dihydroanthracene-9-spiro-4'-piperidine (5 mg.) in hydrochloric acid (1 ml., 3N) is warmed on the steam bath for 10 minutes. The reaction mixture is basified with sodium carbonate and extracted with ether. The ether extract is washed with brine and evaporated to give a gum which on crystallisation from ethanol gives 4-hydroxy-1'-methyl-10-methylene-9,10-dihydroanthracene-9-spiro-4'-piperidine, m.p. 117°-120°C.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][N:12]3[C:16]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])=[C:15]([CH:22]4[CH2:24][CH2:23]4)[N:14]=[C:13]3[CH2:25][CH3:26])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35].C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.[Pd]>[CH:22]1([C:15]2[N:14]=[C:13]([CH2:25][CH3:26])[N:12]([CH2:11][C:8]3[CH:9]=[CH:10][C:5]4[O:4][C:3]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[NH:33][S:34]([C:37]([F:40])([F:38])[F:39])(=[O:36])=[O:35])=[CH:2][C:6]=4[CH:7]=3)[C:16]=2[C:17]([NH:19][CH2:20][CH3:21])=[O:18])[CH2:24][CH2:23]1
Reactant: CCNC(=O)c1c(C2CC2)nc(CC)n1Cc1ccc2oc(-c3ccccc3NS(=O)(=O)C(F)(F)F)c(Br)c2c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCNC(=O)c1c(C2CC2)nc(CC)n1Cc1ccc2oc(-c3ccccc3NS(=O)(=O)C(F)(F)F)cc2c1
Reaction time: 4 h
Yield: 50.2 %

Procedure:
A solution of the product of Example 8 (0.25 g) in ethyl acetate (15 ml) was stirred under a hydrogen atmosphere over 10% palladium on carbon (0.3 g; 50% aqueous paste) at room temperature for 3 h. Solid sodium carbonate (70 mg) was added and the reaction continued for a further 4 h. The mixture was filtered and the filtrate evaporated. The residue was purified by column chromatography eluting with System F (20:1) increasing to (5:1) to give the title compound as a white powder (0.11 g), m.p. 165°-172°.