Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:12]=[CH:11][N:10]3[N:13]=[C:14]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[N:17]=4)=[C:9]3[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:35]N1C(=O)CCC1=O.[OH-].[Na+]>ClCCl>[Br:35][C:8]1[C:9]2[N:10]([N:13]=[C:14]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[N:17]=2)[CH:11]=[CH:12][C:7]=1[NH:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Fc1ccc(-c2nn3ccc(NC4CCCC4)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Fc1ccc(-c2nn3ccc(NC4CCCC4)c(Br)c3c2-c2ccnc(NC3CCCC3)n2)cc1
Reaction time: 0.17 h
Yield: 84.9 %

Procedure:
N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo-[1,5-α]pyridin-5-amine (100 mg, 0.22 mmol) was dissolved in dichloromethane (5 mL) and treated with N-bromosuccinimide (40 mg, 0.22 mmol). The reaction mixture was stirred for 10 minutes. Additional dichloromethane and 1N aqueous sodium hydroxide was added. The phases were separated, the organic phase washed with water, dried (magnesium sulfate), filtered and concentrated to dryness to give 100 mg of the title compound as a yellow foam. 1H NMR (CDCl3): δ 8.32 (d, 1H), 8.22 (d, 1H), 7.53 (q, 2H), 7.04 (t, 2H), 6.53 (m, 2H), 5.17 (d, 1H), 4.72 (d, 1H), 4.33 (m, 1H), 3.95 (m, 1H), 2.1–1.4 (m, 16H); 19F NMR (CDCl3): δ −113.97; MS m/z 536 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[Cl:19][C:20]1[CH:21]=[C:22]([N:27]=[C:28]=[S:29])[CH:23]=[C:24]([Cl:26])[CH:25]=1>C(OCC)(=O)C>[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:28](=[S:29])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:23]=[C:24]([Cl:26])[CH:25]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1cc(Cl)cc(Cl)c1
Reaction time: 72 h
Yield: 83.1 %

Procedure:
A mixture of 3-amino-4-methoxy-N-phenyl-benzamide (0.277 g, 1.14 mmol) and 3,5-dichlorophenyl isothiocyanate (0.238 g, 1.17 mmol) in ethyl acetate (30 mL) was warmed until a solution was obtained, then allowed to stand at room temperature for 3 days. The reaction was concentrated until a crystalline precipitate was obtained then allowed to stand overnight at room temperature. The solid was collected by filtration, rinsed with ethyl acetate/hexane, and dried to afford the product (0.423 g); m.p. 195-197° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([C:19](OC)=[O:20])=[C:13]([C:15](OC)=[O:16])[N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:6]=2[CH:30]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:19][OH:20])=[C:13]([CH2:15][OH:16])[N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:6]=2[CH:30]=1
Reactant: COC(=O)c1nc2n(c1C(=O)OC)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1nc2n(c1CO)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reaction time: 1 h
Yield: 64.7 %

Procedure:
A solution of 7.29 g of dimethyl 8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-1,2-dicarboxylate in 100 ml of tetrahydrofuran was cooled to −78° C. and20 ml of a 1M lithium aluminium hydride solution in tetrahydrofuran was added dropwise in a manner such that the temperature did not exceed −70° C. After completion of the addition the mixture was brought slowly to room temperature and stirred for 1 h. Then, it was treated dropwise with saturated sodium potassium tartrate solution and stirred well for 12 h. The insoluble material was filtered off, the filtrate was concentrated and the residue was recrystallized from isopropanol. The concentrated mother liquor was purified by chromatography on 300 g of silica gel with dichloromethane/methanol/glacial acetic acid 90:10:2 and the fractions containing the product, after removal of the solvent, were again recrystallized from isopropanol. There were thus isolated a total of 4.1 g (65%) of [8-chloro-6-(2-fluorophenyl)-2-hydroxymethyl-4H-imidazo[1,2-a]-[1,4]benzodiazepin-1-yl]-methanol of m.p. 222° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC)=O.Cl.[NH2:23][CH2:24][C:25](=[O:38])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1>O.C1COCC1.CCN(CC)CC>[CH3:37][O:36][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][C:31]=1[O:34][CH3:35])[O:27][CH2:26][C:25](=[O:38])[CH2:24][NH:23][C:13]([C@@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15]
Reactant: COc1ccc(OCC(=O)CN)cc1OC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(OCC(=O)CNC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1OC
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
To a THF (14 ml) solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.557 g) and Et3N (0.790 ml), ethyl chloroformate (0.295 g) was added over an ice bath, followed by stirring at the same temperature for 30 minutes. The reaction mixture was added at 0° C. to a THF (7 ml) solution of the compound (0.701 g) obtained in Example 19-(3) and the mixture was stirred at room temperature for 17 hours. After adding water and performing extraction with AcOEt, the organic layer was washed with saturated aqueous sodium chloride, dried (MgSO4), filtered and concentrated to give a crude product, which was further purified by silica gel chromatography (AcOEt/hexane) to give the titled compound (0.540 g, brown amorphous.)
Reaction SMILES: [CH2:1]([C:8]1[C:9]2[CH2:32][NH:31][CH2:30][CH2:29][C:10]=2[N:11]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]3)=[C:17]([O:27][CH3:28])[CH:16]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](O)(=[O:35])[CH3:34].C(O)C=O.C([BH3-])#N.[Na+]>CO>[CH2:1]([C:8]1[C:9]2[CH2:32][N:31]([CH2:34][CH2:33][OH:35])[CH2:30][CH2:29][C:10]=2[N:11]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]3)=[C:17]([O:27][CH3:28])[CH:16]=2)[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: COc1cc(Nc2nc3c(c(Cc4ccccc4)n2)CNCC3)ccc1-n1cnc(C)c1
Agent: O=CCO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1cc(Nc2nc3c(c(Cc4ccccc4)n2)CN(CCO)CC3)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 25.3 %

Procedure:
4-Benzyl-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (400 mg, 0.94 mmol, example 106) was dissolved in methanol (10 mL). Acetic acid (0.054 mL, 0.94 mmol) was added followed by glycoaldehyde (56.3 mg, 0.94 mmol). The reaction mixture was stirred at room temperature for 15 minutes and sodium cyanoborohydride (58.9 mg, 0.94 mmol) was added. After 1 h the solvent was evaporated, the crude purified by preparative HPLC yielding 2-(4-benzyl-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanol (112 mg, 25.2%). MS (ES+) m/z 471.3 (M+H)+
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C1C(=O)N([Br:17])C(=O)C1.[O-]S([O-])(=S)=O.[Na+].[Na+]>CC#N>[Br:17][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([CH3:9])[C:2]=1[F:1]
Reactant: Cc1c(N)cccc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: Cc1c(N)ccc(Br)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-fluoro-2-methylaniline (20 g, 0.16 mol) in CH3CN (500 mL) was added NBS (31.3 g, 0.176 mol) in portions at 10° C. The resulting mixture was stirred at room temperature for 30 minutes. Upon completion, saturated Na2S2O3 (500 mL) was added slowly into the reaction mixture at 10° C. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was washed with petroleum ether affording the title compound (20 g), which was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6): δ 7.08 (t, 1H), 6.40 (dd, 1H), 5.35 (br, 2H), 1.98 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)C>[CH3:19][S:20]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)C(=O)CCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
To a solution of 7-amino-1-tetralone in 30 ml CH2Cl2 was added 1.03 g (0.013 mole) pyridine and 1.33 g (0.0116 mole) methanesulfonyl chloride. The solution was stirred at room temperature for 3 hours, saturated NaHCO3 solution was added. The CH2Cl2 solution was separated and washed with H2O. The resulting solution was dried over Na2SO4 (anhydrous), filtered, concentrated in vacuo and recrystallized from abs. ethanol to give 1.45 g (58% yield) of 7-methanesulfonamido-1-tetralone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6](O)=[O:7].S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6]([Cl:16])=[O:7]
Reactant: COc1cc(OC)cc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc(OC)cc(C(=O)Cl)c1
Reaction time: 2 h

Procedure:
72.9 g of 3,5-dimethoxybenzoic acid are suspended in 320 ml of toluene, and 2 drops of dimethylformamide are added thereto. The suspension is heated to 50°. 40 ml of thionyl chloride are added dropwise at that temperature within a period of 10 minutes. The whole is then heated to 90° (vigorous evolution of gas) and stirred for 2 hours. The reaction mixture is cooled and concentrated by evaporation in a rotary evaporator. After the addition of toluene, the whole is again concentrated by evaporation. The oily residue is dried for 15 minutes under a high vacuum. 3,5-dimethoxybenzoyl chloride is thus obtained.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH:8]1[C:16]([NH2:18])=O>C1COCC1>[NH2:18][CH2:16][CH:8]1[CH2:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7]1
Reactant: NC(=O)C1Cc2ccccc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC1Cc2ccccc2N1
Reaction time: 6 h
Yield: 50.6 %

Procedure:
LAH (20 mL, 1M solution in THF) was added dropwise through a syringe to a solution of (±)-indoline-2-carboxamide (2.2 g, 13.6 mmol) in anhydrous THF (20 mL) with cooling, and the resulting solution was refluxed under argon for 5 h. More LAH (20 mL) was added, and reflux was continued for another 6 h. 10% aqueous THF was added dropwise with cooling to destroy excess LAH, and then Et2O was added. After stirring for 10 min, the colorless precipitate was removed by filtration and washed with THF. The filtrate was dried (K2CO3), concentrated, and purified by silica gel flash chromatography (90:10:0.2 CH2Cl2 /MeOH/Et3N). The title compound (1.02 g, 51%) was obtained as an amber oil: MS (ES) m/e 149.0 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[Cl:13][C:14]1[CH:15]=[C:16]([C:20]2[O:24][N:23]=[C:22]([CH2:25][OH:26])[CH:21]=2)[CH:17]=[CH:18][CH:19]=1>ClCCl>[Cl:13][C:14]1[CH:15]=[C:16]([C:20]2[O:24][N:23]=[C:22]([CH2:25][O:26][S:9]([CH3:8])(=[O:11])=[O:10])[CH:21]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cc(-c2cccc(Cl)c2)on1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cc(-c2cccc(Cl)c2)on1
Reaction time: 1 h
Yield: 101.4 %

Procedure:
Triethyl amine (965 mg, 9.5 mmol) and methanesulfonyl chloride (820 mg, 7.2 mmol) were added to a solution of [5-(3-chloro-phenyl)-isoxazol-3-yl]-methanol (1.0 g, 4.8 mmol) in dichloromethane (50 mL) at 0° C. After 1 hour, the reaction mixture was quenched with cold saturated sodium bicarbonate and then the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford methanesulfonic acid 5-(3-chloro-phenyl)-isoxazol-3-ylmethyl ester (1.4 g, 100%, light brown solid). 1H NMR (CDCl3) δ (ppm): 7.80 (s, 1H), 7.70 (m, 1H), 7.45 (m, 2H), 6.73 (s, 1H), 5.37 (s, 2H), 3.16 (s, 3H).
Reaction SMILES: [NH2:1][NH2:2].[O:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]([O:13]C)=O)[CH2:5][CH2:4]1>>[N:6]1([CH2:9][CH2:10][C:11]([NH:1][NH2:2])=[O:13])[CH2:7][CH2:8][O:3][CH2:4][CH2:5]1
Reactant: NN
Reactant: COC(=O)CCN1CCOCC1
Product: NNC(=O)CCN1CCOCC1
Reaction time: 16 h
Yield: 61.4 %

Procedure:
Hydrazine (64.1 g, 2 mol) was added dropwise, over 8-10 min, to methyl 3-morpholinopropionate (35 g, 0.202 mol) and the reaction mixture was refluxed for 16 h. The excess hydrazine was removed under reduced pressure and the material was dried in vacuo at room temperature for 16 h to give the crude product as an oil. The 1H NMR showed the presence of hydrazine, so the crude material was dried using a lyophilizer. Then the oil was refluxed in benzene/water (using a Dean-Stark distilling receiver). The benzene was then removed under reduced pressure, and the product was triturated with petroleum ether. After sitting in petroleum ether at room temperature for 16 h, the oil solidified. The petroleum ether was decanted and the solid was dried under house vacuum at room temperature to give the desired product (21.5 g, 61.4%), which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([N:8](COCCOC)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[O:25][CH:26]=[CH:27][N:28]=3)=[CH:20][C:19]=2[CH2:29][CH2:30][N:31]([CH3:41])[C:32](=[O:40])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:11])=[O:10])[O:4][N:3]=1.[Si](Cl)(C)(C)C.[Na+].[I-].O>CC#N.CCOC(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[O:25][CH:26]=[CH:27][N:28]=3)=[CH:20][C:19]=2[CH2:29][CH2:30][N:31]([CH3:41])[C:32](=[O:40])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:10])=[O:11])[O:4][N:3]=1
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CCN(C)C(=O)Cc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CCN(C)C(=O)Cc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the title compound of Step (B) in 1.5 ml of CH3CN, Me3SiCl (34 mg, 0.32 mmol) was added and followed by NaI (48 mg, 0.32 mmol). The mixture was stirred at room temperature for 0.5 hr. Additional Me3SiCl (46 mg, 0.42 mmol) and NaI (63 mg, 0.42 mmol) were added in three portions and the reaction mixture was stirred for additional 1 hr and 45 min. The mixture was then added to 2 ml H2O and 20 ml EtOAc. The organic layer was washed with 1 ml sat. Na2 S2O3, brine, dried and concentrated. The residue was purified by preparative HPLC on an ODS S10 column using 30% solvent A (10% MeOH, 90% H2O, 0.1% TFA) and 70% solvent B (90% MeOH, 10% H2O, 0.1% TFA) to provide the title compound of this Example (7 mg, 23% for two steps) as a white solid, m.p. 98°-106° C. (amorphous).
Reaction SMILES: O=[C:2]1[O:8][C@H:7]([C@H](CO)O)[C:5]([O-])=[C:3]1O.[Na+].C(OC([N:21]1[CH2:26][CH2:25][CH:24]([O:27][C:28]2[C:29]([N:38]=[N+:39]=[N-:40])=[C:30]3[C:35](=[CH:36][CH:37]=2)[CH:34]=[N:33][CH:32]=[CH:31]3)[CH2:23][CH2:22]1)=O)(C)(C)C.C(OC)C#C.FC(F)(F)C([O-])=O>CCCCCCC.C(OCC)(=O)C.O.S([O-])([O-])(=O)=O.[Cu+2].C(OCC)(=O)C>[CH3:2][O:8][CH2:7][C:5]1[N:40]=[N:39][N:38]([C:29]2[C:28]([O:27][CH:24]3[CH2:23][CH2:22][NH:21][CH2:26][CH2:25]3)=[CH:37][CH:36]=[C:35]3[C:30]=2[CH:31]=[CH:32][N:33]=[CH:34]3)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnccc3c2N=[N+]=[N-])CC1
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Cu+2]
Agent: C#CCOC
Agent: O=C([O-])C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: O
Product: COCc1cn(-c2c(OC3CCNCC3)ccc3cnccc23)nn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.9 %

Procedure:
4 mg (0.1 eq.) of sodium ascorbate and 0.5 mg (0.01 eq.) of Copper(II) sulfate-hydrate were added to a solution of 73 mg (0.2 mmol) of 4-(5-Azido-isoquinoline-6-yloxy)-piperidin-1-carboxylic acid tert-butyl ester (17) and 14 mg (0.2 mmol) of methyl propargyl ether in 4 ml of water/tert-butanol (1/1). The mixture was stirred for 18 h at room temperature. Then ethyl acetate was added and the mixture was filtered through a Celite cartridge. After removal of the solvents the remainder was subjected to preparative HPLC. The N-Boc-protected intermediate was deprotected by treatment with 2 mL 5-6 N HCl in isopropanol for 2 h at room temperature. Then the solvent was evaporated and the product was isolated by preparative HPLC to yield 2.8 mg compound 33 as trifluoroacetate.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:23]4[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][C:24]=4[Cl:26])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(Cl)cc4Cl)cc3CC[C@@H]12
Yield: 64.5 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 2,4-dichlorophenylboronic acid (149 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 1.5 mL of toluene fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with dichloromethane (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), followed by recrystallization from ethyl acetate to give 157 mg (65%) of the title compound as an amorphous foam. mp 45°-48°. FDMS: m/e=374.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8]2.[C:24]([O:29][CH2:30][CH3:31])(=[O:28])[C:25]#[C:26][CH3:27].C(P(CCCC)CCCC)CCC.ClCCl>O1CCCC1>[CH2:30]([O:29][C:24](=[O:28])[CH2:25][CH:26]1[S:14][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[S:15]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])=[N:13][CH2:27]1)[CH3:31]
Reactant: CN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccnc1
Reactant: CC#CC(=O)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccnc4)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 15 h
Yield: 30.2 %

Procedure:
A mixture of 7-[methyl(pyridin-3-ylsulfonyl)amino]-1H-indole-2-carbothioamide (150 mg), ethyl but-2-ynoate (120 mg), tributylphosphine (90 mg), dichloromethane (20 mL) and tetrahydrofuran (40 mL) was stirred at room temperature for 15 hr, and the mixture was stirred at 50° C. for 3 hr. The reaction mixture was concentrated, and the residue was subjected to basic silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-1:4, volume ratio). The obtained crystals were further subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-1:4, volume ratio) to give pale-yellow crystals. The crystals were recrystallized from ethyl acetate-hexane to give the title compound (60 mg, yield 30%) as pale-yellow prism crystals. melting point 146-147° C.
Reaction SMILES: COC(=O)CN(C(C1C2C(=C(Br)C=CC=2)C=CC=1)=S)C.C([O:23][C:24](=[O:42])[CH2:25][NH:26][C:27]([C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([O:39][CH3:40])=[C:31]([Cl:41])[CH:30]=1)=[S:28])C>>[Cl:41][C:31]1[CH:30]=[C:29]([C:27](=[S:28])[NH:26][CH2:25][C:24]([OH:42])=[O:23])[C:38]2[C:33]([C:32]=1[O:39][CH3:40])=[CH:34][CH:35]=[CH:36][CH:37]=2
Reactant: CCOC(=O)CNC(=S)c1cc(Cl)c(OC)c2ccccc12
Agent: COC(=O)CN(C)C(=S)c1cccc2c(Br)cccc12
Product: COc1c(Cl)cc(C(=S)NCC(=O)O)c2ccccc12

Procedure:
In the same manner, but replacing N-[(5-bromo-1-naphthalenyl)thioxomethyl]-N-methylglycine methyl ester with an equivalent amount of N-[(3-chloro-4-methoxy-1-naphthalenyl)thioxomethyl]glycine ethyl ester, described in Example 31, N-[(3-chloro-4-methoxy-1-naphthalenyl)thioxomethyl]glycine [mp 217° C.(dec); NMR (DMSO-d6) δ 3.96 (s, 3H), 4.42 (d, J=6 Hz, 2H), 7.40 (s, 1H), 7.65 (m, 2H), 8.18 (m, 2H); IR (Nujol*) 3150, 2900, 1720, 1140 cm-1 ; UVλmax (EtOH) 277 nm (ε11,400), 224 (51,300); Anal Calcd: C, 54.28% H, 3.91% N, 4.52%; Found: C, 54.26% H, 4.06% N, 4.62%] was obtained.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1.[CH3:16][C:17]1[NH:21][N:20]=[C:19]([C:22](O)=O)[N:18]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH3:16][C:17]1[NH:21][N:20]=[C:19]([C:22]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[CH:6][C:7]([O:10][C:11]([F:13])([F:12])[F:14])=[CH:8][CH:9]=3)[N:15]=2)[N:18]=1
Reactant: NC(=NO)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1nc(C(=O)O)n[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.2 %

Procedure:
To a solution of N′-hydroxy-4-(trifluoromethoxy)benzimidamide (1.3 g, 5.1 mmol) and 5-methyl-1H-1,2,4-triazole-3-carboxylic acid (650 mg, 5.1 mmol) in DMF (15 mL), EDC.HCl (980 mg, 5.1 mmol) and HOBT (690 mg, 5.1 mmol) were added at RT. The mixture was stirred at RT for 1 h, and then heated to 140° C. for 3 h. The resulting mixture was cooled, diluted with H2O (20 mL) and extracted with EtOAc (4×40 mL). The combined organic layers were washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure, and the residue was purified by Combiflash reverse phase chromatography (50%˜60% MeCN/H2O containing 0.01% trifluoroacetic acid) to give 5-(5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole as a white solid (590 mg, 37%). MS (ES+) C12H8F3N5O2 requires: 311. found: 312[M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([N:9]1[C:15](=[O:16])[CH2:14][CH2:13][N:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH2:11][CH2:10]1)[CH2:5][CH2:6][CH2:7]Br.[CH3:28][C:29]1([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:1][O:2][C:3](=[O:27])[CH:4]([N:9]1[C:15](=[O:16])[CH2:14][CH2:13][N:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH2:11][CH2:10]1)[CH2:5][CH2:6][CH2:7][N:32]1[CH2:33][CH2:34][C:29]([OH:35])([CH3:28])[CH2:30][CH2:31]1
Reactant: CC1(O)CCNCC1
Reactant: COC(=O)C(CCCBr)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Product: COC(=O)C(CCCN1CCC(C)(O)CC1)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Yield: 73 %

Procedure:
In analogy to the procedure described in example 25B, (rac)-5-bromo-2-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-pentanoic acid methyl ester (example 26A) and 4-methyl-piperidin-4-ol (intermediate 8) gave the title compound in 73% yield as colorless oil. MS: 486.3 (MH+).