Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[CH:14]([CH2:15][CH3:16])[C:13](=[O:17])[C:12]([CH3:19])([CH3:18])[C:11]2=[O:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:21][Mg]Br.C1COCC1>>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C:11](=[O:20])[C:12]([CH3:19])([CH3:18])[C@:13]([OH:17])([CH3:21])[C@H:14]2[CH2:15][CH3:16])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[Mg]Br
Reactant: CCC1C(=O)C(C)(C)C(=O)N1c1ccc(C#N)c(Cl)c1
Solvent: C1CCOC1
Product: CC[C@H]1N(c2ccc(C#N)c(Cl)c2)C(=O)C(C)(C)[C@@]1(C)O

Procedure:
Using 2-chloro-4-(5-ethyl-3,3-dimethyl-2,4-dioxopyrrolidin-1-yl)benzonitrile (48 mg) and methylmagnesium bromide-THF solution (1.65 mL, 1.0 mol/L), and in the same manner as in Example 2, the title compound was obtained as a colorless solid (yield: 27 mg, 53%).
Reaction SMILES: [BrH:1].[CH2:2]([N:4]([CH2:32][CH3:33])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]2[N:16]([CH3:17])[C:15]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])[CH:20]=3)(O)[CH2:14][S:13]2)=[CH:7][CH:6]=1)[CH3:3]>C(O)(=O)C>[BrH:1].[CH2:32]([N:4]([CH2:2][CH3:3])[C:5]1[CH:6]=[CH:7][C:8]([N:11]=[C:12]2[N:16]([CH3:17])[C:15]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([S:26](=[O:30])(=[O:31])[N:27]([CH3:28])[CH3:29])[CH:20]=3)=[CH:14][S:13]2)=[CH:9][CH:10]=1)[CH3:33]
Reactant: CCN(CC)c1ccc(N=C2SCC(O)(c3ccc(Cl)c(S(=O)(=O)N(C)C)c3)N2C)cc1
Agent: Br
Solvent: CC(=O)O
Product: CCN(CC)c1ccc(N=c2scc(-c3ccc(Cl)c(S(=O)(=O)N(C)C)c3)n2C)cc1

Procedure:
Obtained by a procedure analogous to that indicated in Example 1 (b), from 2-(4-diethylaminophenyl-imino)-4-(4-chloro-3-dimethylsulfamoylphenyl)-3-methyl-thiazolidin-4-ol hydrobromide. After heating in glacial acetic acid, the solvent is distilled off until the volume is 30 ml, and the desired product is precipitated with 150 ml of diisopropyl ether. Colorless crystals; melting point 257° C. (with decomposition).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([O:18]CC)=[O:17])=[C:10]([O:21][CH3:22])[CH:9]=2)=[CH:6][C:5](=[N:23][C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=2[CH3:32])[N:4]([CH3:33])[C:3]1=[O:34].[OH-].[Na+]>CO>[C:16]([CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[N:2]([CH3:1])[C:3](=[O:34])[N:4]([CH3:33])[C:5](=[N:23][C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[CH3:32])[CH:6]=2)=[CH:9][C:10]=1[O:21][CH3:22])([OH:18])=[O:17]
Reactant: CCOC(=O)COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=O)n2C)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=O)n2C)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3,4-dihydro-1,3-dimethyl-6-(4-ethoxycarbonylmethoxy-3-methoxyphenyl)-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone as obtained in Example 16 (0.67 g) in methanol (4 ml) was added 1N aqueous sodium hydroxide (2.38 ml) and the mixture was stirred at ambient temperature for 2 hours. After removal of the solvent, the residue was dissolved in water (5 ml), neutralized with 1-Nhydrochloric acid and extracted with chloroform. The organic layer was dried over sodium sulfate, evaporated, and triturated in diisopropyl ether to give 3,4-dihydro-6-(4-carboxymethoxy-3-methoxyphenyl)-1,3-dimethyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (0.47 g).
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:10]([OH:12])=[CH:9][CH:8]=[CH:7][C:6]=2[O:5][CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Cl[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=1>CN(C)C=O>[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=2)[O:5][CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC1CCOc2cccc(O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CCOc2cccc(Oc3ccc([N+](=O)[O-])cn3)c21
Temperature: 110 °C
Yield: 37.7 %

Procedure:
In a 0.5-2 ml Microwave vial 4-methylchroman-5-ol (Intermediate 211, 38.7 mg, 0.212 mmol) K2CO3 (88 mg, 0.636 mmol) and 2-chloro-5-nitropyridine (33.6 mg, 0.212 mmol) were dissolved in N,N-dimethylformamide (DMF) (2 mL) to give a light brown solution. The reaction vessel was sealed and heated under microwave irradiation at 110° C. for 1 hour. After cooling the reaction was quenched with 5 mL of water and diluted with 10 mL of ethyl acetate. Phases were separated by a separating funnel. The aqueous phase was extracted with 3×10 mL of ethyl acetate. The collected organic layer was dried using a hydrophobic frit and evaporated in vacuo to give the title compound (22.9 mg) as a colorless oil.
Reaction SMILES: [OH-].[K+].[CH:3]1([S:8][CH2:9][C:10]([O:12]CC)=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4]1>CCO>[CH:3]1([S:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCOC(=O)CSC1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CSC1CCCC1
Temperature: 25 °C

Procedure:
A solution of 20% aqueous KOH (14.8 g, 52.8 mmol) was added to a solution of the product from Example 143A (8.89 g, 46.7 mmol) in EtOH (30 mL), and the resulting mixture was heated at reflux for 3 hours. The reaction solution was cooled to room temperature and concentrated under vacuum. The residue was diluted with water (20 mL) and CH2Cl2 (50 mL) and cooled in ice as 37% HCl (15 mL) was added gradually with good stirring (final pH˜2). The aqueous layer was separated and extracted with CH2Cl2 (50 mL) and the combined organic phase was washed with brine (30 mL), dried (Na2SO4), filtered, and concentrated under vacuum to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.44-1.66 (m, 4H), 1.67-1.86 (m, 2H), 1.93-2.12 (m, 2H), 3.14-3.31 (m, 1H), 3.30 (s, 2H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:18]([OH:20])=[O:19])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]2([CH3:17])[CH3:16])([CH3:3])[CH3:2].[CH2:21]([O:28][C:29](=[O:39])[CH:30]=[CH:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.CN(C)CCCN=C=NCC.C(OCC)(=O)C>ClCCl.CN(C)C1C=CN=CC=1.CCCCCC>[CH2:21]([O:28][C:29]([CH:30]=[CH:31][C:32]1[CH:37]=[CH:36][C:35]([O:19][C:18]([C:6]2[CH:7]=[C:8]3[C:13](=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=2)[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]3([CH3:17])[CH3:16])=[O:20])=[CH:34][CH:33]=1)=[O:39])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)c1cc(C(=O)O)cc2c1OC(C)(C)CC2(C)C
Reactant: O=C(C=Cc1ccc(O)cc1)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)c1cc(C(=O)Oc2ccc(C=CC(=O)OCc3ccccc3)cc2)cc2c1OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
(Intermediate 34, 0.05 g, 0.18 mmol) and 3-(4-hydroxy-phenyl)-acrylic acid benzyl ester (described in Journal of Natural Products, 1990, 53 (4), p 821-824, Bankova V., 0.046 g, 0.18 mmol) in anhydrous dichloromethane (5 mL) was treated with 4-(dimethylamino)pyridine (0.052 g, 0.27 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.044 g, 0.36 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then subjected to flash column chromatography using 20% ethyl acetate in hexane as the eluent to afford the title compound as a white solid (0.076 g, 83%).
Reaction SMILES: [CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH2:13][NH:14][CH3:15])([CH3:3])[CH3:2].[O:16]=[C:17]1[NH:26][C:25]2[N:24]=[CH:23][C:22](/[CH:27]=[CH:28]/[C:29]([OH:31])=O)=[CH:21][C:20]=2[CH2:19][CH2:18]1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH2:13][N:14]([CH3:15])[C:29](=[O:31])/[CH:28]=[CH:27]/[C:22]1[CH:23]=[N:24][C:25]2[NH:26][C:17](=[O:16])[CH2:18][CH2:19][C:20]=2[CH:21]=1)([CH3:3])[CH3:2]
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CNCc1oc2ccccc2c1C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)oc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
To a solution of (3-isopropylbenzofuran-2-yl)-N-methylmethanamine (115 mg, 0.57 mmol) in DMF (5 mL) were added in sequential order (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid (111 mg, 0.51 mmol), 1-hydroxybenzotriazole (77 mg, 0.57 mmol), diisopropylethylamine (289 uL, 1.54 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (109 mg, 0.57 mmol). The mixture was stirred at room temperature overnight, cooled in an ice bath and water added with rapid stirring. The product precipitated and was filtered, triturated with ether and dried to yield the title compound as a white solid (38 mg, 17%): 1H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.38 (s, 1H), 8.07 (s, 1H), 7.75-7.73 (d, J=7.6 Hz, 1H), 7.53-7.49 (m, 2H), 7.26-7.18 (m, 3H), 4.99-4.80 (rotamers, 2s, 2H), 3.40-3.35 (m, 1H), 3.32 (s, 3H), 2.91-2.89 (m, 2H), 2.55-2.53 (m, 2H), 1.37-1.36 (d, J=6.8 Hz, 6H); MS (ESI) m/e 404 (C24H25N3O3+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15](=O)/[CH:16]=[CH:17]/[N:18](C)C)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:22][C:23]1[CH:24]=[C:25]([NH:29]N)[CH:26]=[CH:27][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15]3[N:29]([C:25]4[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[CH:24]=4)[N:18]=[CH:17][CH:16]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(Cl)c2)ccc1=O
Reactant: NNc1cccc(Cl)c1
Product: O=c1ccn(-c2cccc(Cl)c2)nc1-c1ccnn1-c1cccc(Cl)c1

Procedure:
The product was obtained starting from 1-(3-Chloro-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-23) and 3-chloro-phenylhydrazine according to the method described for example 1. MS: M=383.0 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(N=Cc2ccccc2)cc1
Temperature: 25 °C
Yield: 100.7 %

Procedure:
A mixture of 4-amino-benzoic acid ethyl ester (3.3 g, 20.0 mmol), benzaldehyde (2.4 g, 22.0 mmol) and p-toluenesulfonic acid (76 mg, 0.4 mmol) in toluene (60.0 mL) was heated to reflux for 12 h. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-(benzylidene-amino)-benzoic acid ethyl ester (5.1 g, quant.) as a light yellow solid: LC/MS m/e calcd for C16H15NO2 (M+H)+: 254.3, observed: 254.1.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=1)([O-])=O.O.[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15][C:16]([CH3:18])=O.S([O-])([O-])(=O)=O.[Ca+2]>C(O)C.[Pd].CC(O)=O>[N:8]1[C:7]2[CH:11]=[CH:12][C:4]([NH:1]/[C:16](/[CH3:18])=[CH:15]\[C:14]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5][C:6]=2[NH:10][CH:9]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=[N+]([O-])c1ccc2nc[nH]c2c1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)/C=C(/C)Nc1ccc2nc[nH]c2c1

Procedure:
An 82 g. (0.5 mole) sample of 5-nitrobenzimidazole in 900 ml of ethanol was reduced over 4 g. of 5% Pd/C catalyst containing 50% H2O. After a pressure drop of 108 lb. (calcd. 106 lb.), the reduction stopped. After filtration of the catalyst, 65 g. (0.5 mole) of ethyl acetoacetate, 20 g. of anhydrous calcium sulfate, and 0.5 ml of HOAc was added. After filtration of the anhydrous calcium sulfate the solution was concentrated in vacuo till till a solid remained. The product was filtered and washed with fresh ethanol and air-dried. The yield was 84 g. (69%), m.p. 160°-162°C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:22])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:8].[CH2:23](OC(OCC)OCC)C>>[Cl:22][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH3:23])=[CH:21][C:6]=1[C:7]([NH:9][CH2:10][C:11]12[CH2:12][CH:13]3[CH2:19][CH:17]([CH2:16][CH:15]([CH2:14]3)[CH2:20]1)[CH2:18]2)=[O:8]
Reactant: Nc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: CCOC(OCC)OCC
Product: CNc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 120 °C

Procedure:
Amino amide from Example 55 (0.12 g) was dissolved in triethylorthoformate (1.07 ml) and heated at 120° C. for three hours. The triethylorthoformate was removed by vacuum distillation. The residue was dissolved in ethanol (5 ml). The solution was cooled to 0° C. under nitrogen, sodium borohydride (0.104 g) was added and the mixture refluxed for three hours at 90° C. The ethanol was removed under reduced pressure, water (20 ml) was added to the residue, the product was extracted into ethyl acetate (3×50 ml), dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with dichloromethane:ethyl acetate (1:1) to give the title compound as a white solid (0.04 g).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:14]=[CH:15][C:16]=1[CH2:17][NH:18][C:19]1[N:20]([C:30]2[N:31]=[CH:32][N:33]=[C:34]([NH2:37])[C:35]=2[N:36]=1)[C@@H:21]1[O:29][C@H:26]([CH2:27][OH:28])[C@@H:24]([OH:25])[C@H:22]1[OH:23])=[O:5])C.[OH-].[Na+]>CO>[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:14]=[CH:15][C:16]=1[CH2:17][NH:18][C:19]1[N:20]([C:30]2[N:31]=[CH:32][N:33]=[C:34]([NH2:37])[C:35]=2[N:36]=1)[C@@H:21]1[O:29][C@H:26]([CH2:27][OH:28])[C@@H:24]([OH:25])[C@H:22]1[OH:23])([OH:5])=[O:3]
Reactant: CCOC(=O)CCCCOc1cc(-c2ccccc2)ccc1CNc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ncnc2c1nc(NCc1ccc(-c3ccccc3)cc1OCCCCC(=O)O)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 21 h
Yield: 113.1 %

Procedure:
To a solution of 8-[3-(4-ethoxycarbonylbutoxy)-biphenyl-4-ylmethylamino]adenosine (0.077 g) in methanol (1.3 mL) was added 2 mol/L aqueous sodium hydroxide (0.098 mL), and the resulting mixture was stirred at room temperature for 21 hours and then at 50° C. for 2 hours. Two mol/L aqueous sodium hydroxide (0.098 mL) was added and stirring was continued for additional 64 hours. The reaction mixture was cooled to room temperature, quenched by addition of 2 mol/L hydrochloric acid (0.227 mL) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=4/1) to give the title compound (0.083 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3]1.[CH3:14][O:15][C:16]1[C:29]2[CH2:28][CH2:27][C@H:26]3[C@H:21]([CH2:22][CH2:23][CH2:24][NH:25]3)[C:20]=2[CH:19]=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[C:29]2[CH2:28][CH2:27][C@H:26]3[C@H:21]([CH2:22][CH2:23][CH2:24][N:25]3[C:11]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:2]([CH3:1])[CH:3]=3)=[O:13])[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc2c1CC[C@@H]1NCCC[C@H]21
Reactant: Cn1cc(C(=O)O)c2ccccc21
Product: COc1cccc2c1CC[C@H]1[C@@H]2CCCN1C(=O)c1cn(C)c2ccccc12
Yield: 82 %

Procedure:
The title compound is prepared from 1-methyl-1H-indole-3-carboxylic acid and cis-7-methoxy-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 82% of theory; LC (method 1): tR=4.39 min; Mass spectrum (ESI+): m/z=375 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([Cl:21])=[CH:4][C:5]([Cl:20])=[C:6]([CH:19]=1)[CH2:7][O:8][Si](C(C)C)(C(C)C)C(C)C.[CH2:22]([O:29][C@@H:30]1[C@@H:36]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@H:35]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C@@H:34]([CH2:53][O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[O:33][CH:31]1O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[Cl:20][C:5]1[CH:4]=[C:3]([Cl:21])[C:2]([CH:31]2[C@H:30]([O:29][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C@@H:36]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C@H:35]([O:45][CH2:46][C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C@@H:34]([CH2:53][O:54][CH2:55][C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)[O:33]2)=[CH:19][C:6]=1[CH2:7][OH:8]
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: CC(C)[Si](OCc1cc(Br)c(Cl)cc1Cl)(C(C)C)C(C)C
Product: OCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c(Cl)cc1Cl

Procedure:
With similar method described in Step 3 of Example 92, (5-bromo-2,4-dichlorobenzyloxy)triisopropylsilane (compound 82, 41.7 g, 101 mmol) and 2,3,4,6-tetra-O-benzyl-D-glucopyranose (compound 2, 45.4 g, 84.0 mmol) were converted to title compound (47.6 g, 81%, ca. 8:1 mixture of anomers (13:0) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.C1C(=O)N([Br:21])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2)nn1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2ccccc2)nn1

Procedure:
Synthesized using compound 65b (982 mg, 5.77 mmol), NBS (1.13 g, 6.35 mmol) and DBPO (70 mg, 0.29 mmol) in carbon tetrachloride according to Method A. Crude product was purified by flash chromatography on silica-gel using hexane/ethyl acetate (4:1) as eluent. Product was used directly in the next step without further characterization. Orange solid. Yield: 53 mg, 4%. (ESI): m/z=250.67 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][N:6]=1.Br[CH2:14][CH2:15][CH2:16][Cl:17]>>[CH3:1][O:2][C:3](=[O:12])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][N:6]=1)[CH2:14][CH2:15][CH2:16][Cl:17]
Reactant: COC(=O)Cc1ccc(Br)cn1
Reactant: ClCCCBr
Product: COC(=O)C(CCCCl)c1ccc(Br)cn1

Procedure:
Key building block 2-(5-bromo-pyridin-2-yl)-5-chloro-pentanoic acid (XII) can be prepared according to Scheme 8. Starting with commercially available 5-bromo-2-iodo-pyridine (XXXV), copper-catalyzed reaction with malonic acid diethyl ester furnishes 2-(5-bromo-pyridin-2-yl)-malonic acid diethyl ester (XXXVI). Hydrolysis and decarboxylation under basic conditions gives (5-bromo-pyridin-2-yl)-acetic acid (XXXVII), which subsequently can undergo nucleophilic acyl substitution with thionyl chloride in methanol to provide (5-bromo-pyridin-2-yl)-acetic acid methyl ester (XXXVIII). Deprotonation of XXXVIII with strong base followed by alkylation with 1-bromo-3-chloropropane gives 2-(5-bromo-pyridin-2-yl)-5-chloro-pentanoic acid methyl ester (XXXIX), which can then be hydrolyzed under aqueous basic conditions to furnish key building block 2-(5-bromo-pyridin-2-yl)-5-chloro-pentanoic acid (XII).
Reaction SMILES: [Br:1][CH2:2][C:3]([OH:5])=[O:4].[CH2:6](O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]CC>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[Br:1][CH2:2][C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:4]
Reactant: O=C(O)CBr
Reactant: CCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCOC(=O)CBr
Reaction time: 1.5 h
Yield: 117.4 %

Procedure:
20 g of bromoacetic acid, 22 g of n-decyl alcohol, and 2.5 g of p-toluenesulfonic acid were added to 150 ml of toluene, and the azeotropic dehydration was carried out for 1.5 hours. After cooling the mixture by allowing it to stand, the toluene was removed under reduced pressure and then vacuum distillation was performed, to obtain 41 g of n-octyl bromoacetate (121° C., 10 mmHg).
Reaction SMILES: C(OC1C=CC(N2CCNCC2)=CC=1F)C1C=CC=CC=1.C(Br)CCCCCCC.[F:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[C:35]([F:40])=[CH:34][C:33]=1[N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.CS(O[CH2:52][CH2:53][CH2:54][CH:55]1[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1)(=O)=O>>[CH:55]1([CH2:54][CH2:53][CH2:52][N:44]2[CH2:45][CH2:46][N:41]([C:33]3[CH:34]=[C:35]([F:40])[C:36]([O:38][CH3:39])=[CH:37][C:32]=3[F:31])[CH2:42][CH2:43]2)[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1
Reactant: CS(=O)(=O)OCCCC1CCCCC1
Reactant: COc1cc(F)c(N2CCNCC2)cc1F
Agent: Fc1cc(N2CCNCC2)ccc1OCc1ccccc1
Solvent: CCCCCCCCBr
Product: COc1cc(F)c(N2CCN(CCCC3CCCCC3)CC2)cc1F
Yield: 97.6 %

Procedure:
Production Example 38 was repeated except that 1-(4-benzyloxy-3-fluorophenyl)piperazine and n-octyl bromide were replaced with 1-(2,5-difluoro-4-methoxyphenyl)piperazine (5.72 g) and 3-cyclohexylpropyl methanesulfonate (5.52 g), to provide crude 1-(3-cyclohexylpropyl)-4-(2,5-difluoro-4-methoxyphenyl)piperazine (8.618 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.C(/[B:10]1[O:18][C:15]([CH3:17])([CH3:16])[C:12]([CH3:14])([CH3:13])[O:11]1)=C\C>ClCCl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[C:2]1(=[CH:1][B:10]2[O:18][C:15]([CH3:17])([CH3:16])[C:12]([CH3:14])([CH3:13])[O:11]2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: CC1CCCC1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: CC1(C)OB(C=C2CCCC2)OC1(C)C
Yield: 34.4 %

Procedure:
A solution of methylcyclopentane (100 mg, 1.22 mmol), and trans-1-propenylboronic acid pinacol ester (204 mg, 1.22 mmol) in dry dichloromethane (6 mL) was bubbled with nitrogen for 5 minutes. Grubbs Catalyst, 2nd generation (52 mg, 0.06 mmol) was added and the reaction mixture was refluxed overnight. The solution was concentrated in vacuo and the residue was purified by preparative TLC (cyclohexane/ethyl acetate 90/10) to provide 2-(cyclopentylidenemethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (21a) (88 mg, 0.42 mmol, 35%)
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[N:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH:26]([CH2:36][Cl:37])[C:12]2=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14]2[C:22]([O:24][CH3:25])=[O:23])C1C=CC=CC=1.C([O-])=O.[NH4+]>O1CCCC1.[Pd]>[CH3:25][O:24][C:22]([C:14]1[C:13]2[C:17](=[C:9]([OH:8])[CH:10]=[C:11]3[N:28]([C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[CH2:27][CH:26]([CH2:36][Cl:37])[C:12]3=2)[NH:16][C:15]=1[C:18]([F:21])([F:20])[F:19])=[O:23]
Reactant: COC(=O)c1c(C(F)(F)F)[nH]c2c(OCc3ccccc3)cc3c(c12)C(CCl)CN3C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)c1c(C(F)(F)F)[nH]c2c(O)cc3c(c12)C(CCl)CN3C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
In 2.63 ml of tetrahydrofuran, was dissolved 106.7 mg (198 μmol) of methyl 5-benzyloxy-3-t-butoxycarbonyl-1-chloromethyl-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo[3,2-e]indole-8-carboxylate. Thereto, 64 mg of 10% palladium on carbon was added, and then 656.4 μl of 25% ammonium formate was added dropwise under ice cooling. The mixture was stirred for one hour, and then the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain methyl-3-t-butoxycarbonyl-1-chloromethyl-5-hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo[3,2-e]indole-8-carboxylate in a yield of 87.9 mg (99%).