Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:12]=1[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+]>[Cu]Br.CCCCCCC.C(Cl)Cl>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:9][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]=2[CH3:27])=[CH:20][CH:21]=1
Reactant: Oc1ccccc1
Reactant: COc1ccc(COc2cccc(Br)c2C)cc1
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CCCCCCC
Product: COc1ccc(COc2cccc(Oc3ccccc3)c2C)cc1
Temperature: 180 °C
Yield: 91 %

Procedure:
Sodium hydride as a 60% dispersion in mineral oil (56 mg, 1.4 mmol) was added portionwise to a solution of phenol (0.35M in DMF, 2 mL). The resultant solution was added to a mixture of 1-bromo-3-(4-methoxybenzyloxy)-2-methylbenzene (215 mg, 0.7 mmol) and cesium carbonate (228 mg, 0.7 mmol) in a microwave vessel. Copper (I) bromide (10 mg) was added, the vessel was sealed and the reaction heated at 180° C. for 900 s. 1N NaOH (aq) (2 mL) and DCM (5 mL) were added to the cooled reaction mixture and the organic layer was separated and concentrated in vacuo. The crude material was then purified by chromatography on silica gel. Elution with 5:95 ethyl acetate:heptane afforded 1-(4-methoxybenzyloxy)-2-methyl-3-phenoxybenzene (205 mg, 0.64 mmol, 91%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:4]([CH3:18])=[N:3]1.[OH-].[Na+].[Cl-].[Ca+2:22].[Cl-]>O>[Ca:22].[CH3:1][N:2]1[C:6]([OH:7])=[C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:4]([CH3:18])=[N:3]1
Reactant: [Ca+2]
Agent: Cc1nn(C)c(O)c1C(=O)c1ccc(Cl)cc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: [Ca]

Procedure:
In 50 ml. of water is suspended 2.85 g. of 1,3-dimethyl-4-(2,4-dichlorobenzoyl)-5-hydroxypyrazole and the suspension is dissolved in about 5 ml. of a 2N aqueous solution of sodium hydroxide. A solution of 1.11 g. of calcium chloride in 10 ml. of water is added and the resulting mixture is stirred. The so separated precipitates are recovered by filtration and dried to give 2.4 g. of the desired product as white powder melting at about 260° C. Yield 79.0%.
Reaction SMILES: Cl.C(O[C@H](C)C([N:13]1[C:21]2[C:16](=[C:17]([F:22])[CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]1[CH3:23])=O)C1C=CC=CC=1>C(O)C>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[CH2:15][CH:14]([CH3:23])[NH:13]2
Reactant: CC1Cc2c(F)cccc2N1C(=O)[C@@H](C)OCc1ccccc1
Agent: Cl
Solvent: CCO
Product: CC1Cc2c(F)cccc2N1
Temperature: 25 °C
Reaction time: 40 h
Yield: 68.7 %

Procedure:
8.2 ml of concentrated hydrochloric acid are added to a solution of 1.69 g of (R)-2-benzyloxy-1-(4-fluoro-2-methyl-2,3-dihydroindol-1-yl)propan-1-one diastereoisomer (B) in 200 ml of absolute ethanol. The reaction mixture is refluxed with stirring for 40 hours and is then cooled to ambient temperature and concentrated to dryness under reduced pressure. The residue is taken up in 200 ml of water, alkalinized with concentrated sodium hydroxide to pH 14, and the mixture is then extracted with 3×200 ml of dichloromethane. The organic phases are combined, washed with water, dried over magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 70 g cartridge of 15-40 μm silica, elution being carried out with pure cyclohexane and then with a 70/30 cyclohexane/dichloromethane mixture, at a flow rate of 50 ml/min. 0.56 g of (−)-4-fluoro-2-methylindoline is thus obtained in the form of a very pale yellow oil, the characteristics of which are the following:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].C([O-])(=O)C.[K+].[CH3:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1>CN(C)C(=O)C.[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>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[C:21]1[S:20][C:19]([CH3:18])=[N:23][CH:22]=1
Reactant: Cc1nccs1
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc([N+](=O)[O-])ccc1-c1cnc(C)s1
Yield: 42.6 %

Procedure:
In a microwave vial a mixture of 2-bromo-5-nitroanisole (800 mg, 3.38 mmol), potassium acetate (503 mg, 5.07 mmol) and tetrakis(triphenylphosphine)-palladium(0) (197 mg, 0.17 mmol) in N,N-dimethylacetamide (12 mL) were flushed with argon while 2-methylthiazole (1.71 g, 16.9 mmol) was added. The tube was sealed and the mixture irradiated two times for 30 minutes at 160° C. The red-brown mixture was partitioned between ethyl acetate and water. The water layer was re-extracted with ethyl acetate. The combined organic phases were washed three times with water, once with brine, dried with magnesium sulfate and evaporated to dryness. Column chromatography (70 g silica, heptane/ethyl acetate 7:3 v/v) afforded the title compound (360 mg, 42%) as a yellow solid. MS ISP (m/e): 251.1 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.15 (s, 1H), 7.90 (dd, 1H), 7.84 (s, 1H), 7.72 (d, 1H), 4.05 (s, 3H), 2.76 (s, 3H). Mp 114-117° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C@H:9]1[CH2:13][C@@H:12]([C:14]([OH:16])=O)[C@H:11]([CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[CH2:10]1.[NH2:31][C:32]1([C:35]#[N:36])[CH2:34][CH2:33]1>>[C:35]([C:32]1([NH:31][C:14]([C@@H:12]2[CH2:13][C@H:9]([S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH2:10][C@H:11]2[CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[CH2:20][CH2:19]2)=[O:16])[CH2:34][CH2:33]1)#[N:36]
Reactant: N#CC1(N)CC1
Reactant: O=C(O)[C@@H]1C[C@H](Sc2ccccc2Cl)C[C@H]1CN1CCC(c2ccc(F)cc2)CC1
Product: N#CC1(NC(=O)[C@@H]2C[C@H](Sc3ccccc3Cl)C[C@H]2CN2CCC(c3ccc(F)cc3)CC2)CC1

Procedure:
The title compound was prepared in analogy to example 68 step 11 using (1R,2R,4R)-4-(2-Chloro-phenylsulfanyl)-2-[4-(4-fluoro-phenyl)-piperidin-1-ylmethyl]-cyclopentanecarboxylic acid (example 148 step 5) and 1-amino-cyclopropanecarbonitrile. Light yellow foam (52%). MS (EI): 512.3 (M+H)+.
Reaction SMILES: Cl.C([NH:5][C:6]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([O:19][CH2:20][CH3:21])[CH:7]=1)(=O)C>>[NH2:5][C:6]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([O:19][CH2:20][CH3:21])[CH:7]=1
Reactant: CCOc1cc(NC(C)=O)c([N+](=O)[O-])cc1C(=O)OC
Agent: Cl
Product: CCOc1cc(N)c([N+](=O)[O-])cc1C(=O)OC
Yield: 42.2 %

Procedure:
To 100 parts of a hydrochloric acid solution 6N were added 5.65 parts of methyl 4-(acetylamino)-2-ethoxy-5-nitrobenzoate and the whole was stirred and refluxed for 30 minutes. After cooling, the precipitated product was filtered off and crystallized from 80 parts of 2-propanol at 0° C. The product was filtered off and dried, yielding 1.9 parts (42.2%) of methyl 4-amino-2-ethoxy-5-nitrobenzoate; mp. 210° C.;(intermediate 33).
Reaction SMILES: [Li].C[Si]([NH-])(C)C.Br[CH2:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[NH:34][CH:35]=2)=[CH:27][CH:26]=1>C1COCC1.CN(C=O)C>[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[N:32]=[C:33]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:34]([CH2:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)=[O:10])[CH:35]=2)=[CH:29][CH:30]=1
Reactant: COc1ccc(-c2c[nH]c(-c3ccccc3)n2)cc1
Reactant: O=C(CBr)N1CCN(c2ccccn2)CC1
Agent: C[Si](C)(C)[NH-]
Agent: [Li]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(-c2cn(CC(=O)N3CCN(c4ccccn4)CC3)c(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.8 %

Procedure:
250 μl 1 mol/L lithium his (trimethylsilyl) amide solution in THF was added to 29 mg 2-bromo-1-(4-pyridin-2-yl-piperazin-1-yl)-ethanone in 1 mL DMF. The mixture was stirred 10 min at RT and 28 mg 4-(4-methoxy-phenyl)-2-phenyl-1H-imidazole was added. The reaction was stirred 2 h at 60° C. The mixture was purified by HPLC to give 30 mg desired product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][N:22]1[C:26]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[C:25]([CH:33]=O)[C:24]([CH3:35])=[N:23]1.C([O-])(=O)C.[NH4+]>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:33]([C:25]3[C:24]([CH3:35])=[N:23][N:22]([CH3:21])[C:26]=3[N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: Cc1nn(C)c(N2CCOCC2)c1C=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: Cc1nn(C)c(N2CCOCC2)c1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 35 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.00 mg, 0.1702 mmol), 1,3-Dimethyl-5-morpholin-4-yl-1H-pyrazole-4-carbaldehyde (39.2 mg, 0.187 mmol), and Ammonium acetate (26.2 mg, 0.340 mmol) were reacted to produce 28.80 mg (35%) of the title compound. (300 MHz, DMSO-d6) 12.67 (s, 1H), 7.93 (s, 1H), 7.68 (m, 1H), 7.18 (s, 1H), 6.98 (d, J=8.5 Hz, 1H), 6.31 (d, J=15 Hz, 2H), 5.28 (t, J=17 Hz, 9 Hz, 1H), 3.65 (m, 7H), 3.04 (m, 4H), 2.94 (m, 2H), 2.84 (s, 1H), 2.74 (s, 1H), 2.57 (d, J=9 Hz, 1H), 2.27 (d, J=9 Hz, 1H), 2.18 (s, 3H), 1.40 (d, J=8 Hz, 1H). MS=483 (M+H), HPLC: 1.99 min. (G Method)
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=2[N:5]=[CH:6][N:7]=1.[N+:19]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N+:19]([C:22]1[CH:27]=[C:26]([C:2]2[C:3]3[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH:25]=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cccc([N+](=O)[O-])c3)ncnc21
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A solution of 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (15.0 g, 52.9 mmol) in N,N-dimethylformamide (200 mL) was added to Pd(dppf)Cl2 (2.2 g, 2.7 mmol), (3-nitrophenyl)boronic acid (13.3 g, 79.7 mmol) under nitrogen. A solution of sodium carbonate (6.00 g, 56.6 mmol) in water (60.0 mL) was then added and the reaction was stirred for 3 hours at 100° C. The resulting mixture was concentrated in vacuo, and the solids were filtered and extracted with dichloromethane (×3). The combined organic layers were washed with H2O, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The reaction was then purified by chromatography using silica gel, eluting with 0-33% EtOAc/petroleum ether. The product was collected and concentrated in vacuo to afford 4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine as a yellow solid. LRMS (ESI) calc'd for C18H23N4O3Si [M+H]+: 371, found 371.
Reaction SMILES: [Br:1][C:2]1[C:9]([CH3:10])=[C:8]([F:11])[CH:7]=[C:6]([Br:12])[C:3]=1[C:4]#[N:5]>C1COCC1>[Br:1][C:2]1[C:9]([CH3:10])=[C:8]([F:11])[CH:7]=[C:6]([Br:12])[C:3]=1[CH2:4][NH2:5]
Reactant: Cc1c(F)cc(Br)c(C#N)c1Br
Solvent: C1CCOC1
Product: Cc1c(F)cc(Br)c(CN)c1Br
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred solution of 2,6-dibromo-4-fluoro-3-methylbenzonitrile (1.145 g, 3.91 mmol) in THF (7 mL) was added 2M borane-methylsulfide complex (8 mL, 16.00 mmol) over 5 min at room temperature. After 30 min, the reaction mixture was warmed to 60° C. and stirred for an additional 1.6 h. The mixture was cooled then quenched by the careful addition of methanol (10 mL) and 4M HCl/dioxane (2 mL). After 30 min, the reaction mixture was heated to 50° C. for 45 min and concentrated. The residue was taken up in sat. Na2CO3 (20 mL) and extracted with CH2Cl2 (3×25 mL). The combined CH2Cl2 extracts were washed with water (20 mL) followed by brine (20 mL), then dried (Na2SO4), filtered and concentrated to afford (2,6-dibromo-4-fluoro-3-methylphenyl)methanamine (1.16 g, 3.91 mmol, 100% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ: 7.31 (1 H, d, J=8.9 Hz), 4.19 (2 H, s), 2.34 (3 H, d, J=2.4 Hz), 1.59 (2 H, brs). LCMS (M+H) calcd for C15H21N2O3: 297.91; found: 297.85.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][CH2:9][CH2:10][CH3:11])=[C:6]([O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl>[Cl:22][CH2:23][C:24]([N:8]([CH2:9][CH2:10][CH3:11])[C:7]1[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=1[O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])=[O:25]
Reactant: O=C(Cl)CCl
Reactant: CCCNc1c(C)cccc1OCCOCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCN(C(=O)CCl)c1c(C)cccc1OCCOCCOC
Reaction time: 0.17 h
Yield: 39 %

Procedure:
A mixture containing a portion of the 6-methyl-2-[2-(2-methoxyethoxy)ethoxy]-N-2-methylethyl aniline (5.34 g; 0.02 mole) and sodium hydroxide (0.88 g; 0.22 mole) in 150 ml. of methylene chloride was cooled to 10° C. To the reaction mixture was added dropwise chloroacetyl chloride (2.5 g; 0.022 mole) and the resulting mixture was stirred for 10 minutes. The layers were separated and the organic methylene chloride layer was washed with water, dried over magnesium sulfate and concentrated in vacuo to yield a crude product. The crude product was separated on a silica gel column using a 2:5 ethyl acetate:cyclohexane mixture as the eluant to yield 2-chloro-N-2-methylethyl-N-[6-methyl-2-(2-(2-methoxyethoxy)ethoxy)phenyl]acetamide (Compound No. 102) (2.7 g; 39% yield) as a clear yellow oil having a boiling point of 163° C. (0.13 mmHg) and the following analysis:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([F:18])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CN(C)[CH:26]=[O:27]>C1COCC1>[Si:11]([O:10][CH2:9][CH:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:26]=[O:27])[F:18])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OCC(F)c1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC(F)c1cccc(C=O)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of (2-(3-bromophenyl)-2-fluoroethoxy)(tert-butyl)dimethylsilane (example 39, step c) (1.8 g) in THF (36 mL) was cooled to −78° C. under an atmosphere of nitrogen and treated with butyllithium (1.8M in hexanes, 3.3 mL), added dropwise over 5 minutes. The solution was stirred at −78° C. for 30 minutes, treated with N,N-dimethylformamide (0.63 mL), stirred at −78° C. for a further 30 minutes, then removed from the cooling bath and allowed to warm to room temperature over 140 minutes. The solution was quenched by the addition of 10% aqueous ammonium chloride, and the resulting mixture was extracted twice with diethyl ether. The combined organic phases were washed with brine, dried over anhydrous magnesium sulphate and purified by flash chromatography on silica eluted with 50% dichloromethane in isohexane to afford the subtitled compound as a colourless oil. Yield 1.26 g.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N+:14]([O-])=O)=[C:11]([CH:13]=2)[NH2:12])=[C:4]([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH:3]=1>C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([NH2:14])=[C:11]([NH2:12])[CH:13]=2)=[C:4]([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH:3]=1
Reactant: Nc1cc(Oc2ccc(Cl)cc2Cn2cncn2)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1ccc(Oc2ccc(Cl)cc2Cn2cncn2)cc1N
Yield: 49.6 %

Procedure:
5-[4-Chloro-2-(1H-1,2,4-triazol-1-ylmethyl)phenoxy]-2-nitroaniline (11 g) from Example 37 was dissolved in acetic acid (100 ml), followed by gradual addition of zinc powder (12.5 g) under water cooling. After the addition, insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate, and to the resulting solution was added carefully saturated sodium hydrogen carbonate solution to make the solution alkaline. The organic phase was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the residue was crystallized from chloroform (100 ml) and ethanol (10 ml), and the deposited crystal was filtered to give the title compound (4.98 g; 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:14]([NH:15][C@H:16]([CH:21]4[CH2:23][CH2:22]4)[C:17]([F:20])([F:19])[F:18])=[N:13][CH:12]=[C:11]([C:24]#[N:25])[C:7]=3[NH:8][C:9]=2[CH:10]=1.C(=O)([O-])[O-:27].[K+].[K+].CS(C)=O.OO>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:14]([NH:15][C@H:16]([CH:21]4[CH2:22][CH2:23]4)[C:17]([F:18])([F:20])[F:19])=[N:13][CH:12]=[C:11]([C:24]([NH2:25])=[O:27])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cnc(N[C@H](C2CC2)C(F)(F)F)c2c1[nH]c1cc(Cl)ccc12
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: NC(=O)c1cnc(N[C@H](C2CC2)C(F)(F)F)c2c1[nH]c1cc(Cl)ccc12
Temperature: 80 °C

Procedure:
7-Chloro-1-{[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]amino}-5H-pyrido[4,3-b]indole-4-carbonitrile (4.48 g, 12.3 mmol) and potassium carbonate (8.49 g, 61.4 mmol) were placed in a flask. DMSO (246 ml) and 30% hydrogen peroxide (12.55 ml, 123 mmol) were added and the solution heated at 80° C. for 2 h. Additional 30% hydrogen peroxide (12.55 mL, 123 mmol) and potassium carbonate (8.49 g, 61.4 mmol) were added. The resultant mixture was heated to 80° C. for 2 h, cooled to room temperature, and diluted with EtOAc. The mixture was washed with water and brine, dried (magnesium sulfate), concentrated, and purified by flash chromatography to give the title compound. 1H NMR (600 MHz, CD3SOCD3) δ 11.81 (s, 1H); 8.54 (s, 1H); 8.50 (d, 1H); 7.96 (br s, 1H); 7.80 (d, 1H); 7.33 (br s, 1H); 7.30 (dd, 1H); 7.07 (d, 1H); 4.86 (m, 1H); 1.59 (m, 1H); 0.76 (m, 1H); 0.64 (m, 1H); 0.54 (m, 1H); 0.33 (m, 1H). LRMS (APCI) calc'd for (C17H14ClF3N4O) [M+H]+, 383.1. found 383.0.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[N:23]=[CH:24][C:25]4[C:48](=[O:49])[N:29]5[N:30]([C:42]6[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=6)[C:31]6[CH:32]=[C:33]([O:37][CH2:38][C:39](O)=[O:40])[CH:34]=[CH:35][C:36]=6[C:28]5=[N:27][C:26]=4[N:50]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Cl-].[NH4+].Cl.C[N:55](C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>C(N(CC)CC)C.CN(C)C=O>[CH3:8][N:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[N:23]=[CH:24][C:25]4[C:48](=[O:49])[N:29]5[N:30]([C:42]6[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=6)[C:31]6[CH:32]=[C:33]([O:37][CH2:38][C:39]([NH2:55])=[O:40])[CH:34]=[CH:35][C:36]=6[C:28]5=[N:27][C:26]=4[N:50]=3)=[CH:17][CH:16]=2)[CH2:13][CH2:14]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CN1CCN(c2ccc(Nc3ncc4c(=O)n5c(nc4n3)c3ccc(OCC(=O)O)cc3n5-c3ccccn3)cc2)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2ccc(Nc3ncc4c(=O)n5c(nc4n3)c3ccc(OCC(N)=O)cc3n5-c3ccccn3)cc2)CC1
Yield: 50.4 %

Procedure:
An N,N-dimethylformamide (1 mL) solution of the compound (10 mg) obtained in Example 157, ammonium chloride (5 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10 mg), 1-hydroxybenzotriazole monohydrate (7 mg) and triethylamine (0.05 mL) was stirred for 16 hours. The reaction liquid was concentrated under reduced pressure, and the precipitated solid was collected through filtration, washed with distilled water and ethyl acetate in that order, and dried to give the title compound as a yellow solid (4.2 mg).
Reaction SMILES: N[C@H](C1C=CC=CC=1)[C@H](NS(C1C(C)=CC(C)=CC=1C)(=O)=O)C1C=CC=CC=1.[CH2:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][NH:30]1.C([O-])(O)=O.[Na+]>C(#N)C.ClCCl.CC1C=CC(C(C)C)=CC=1.CC1C=CC(C(C)C)=CC=1.Cl[Ru]Cl.Cl[Ru]Cl.C(N(CC)CC)C.C(O)=O>[CH2:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][NH:30]1
Reactant: C1=Cc2ccccc2CN1
Agent: Cl[Ru]Cl
Agent: Cc1cc(C)c(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)c(C)c1
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O=CO
Solvent: CCN(CC)CC
Product: c1ccc2c(c1)CCNC2
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Dichloro-(p-cymene)ruthenium (II) dimer (0.20 mmol) is added to a solution of N-((1R,2R)-2-amino-1,2-diphenyl-ethyl)-2,4,6-trimethylbenzene-sulfonamide (0.40 mmol) and triethylamine (0.80 mmol) in acetonitrile (3.0 mL). The mixture is stirred for 1 h at 80° C. and added to a solution of the respective dihydroisoquinoline (28.0 mmol) in dichloromethane (30 mL). An azeotropic mixture of formic acid and triethylamine (5:2, 14 mL) is added (gas evolution). After 90 min a sat. aqueous NaHCO3 solution (200 mL) is added to the dark red solution. The layers are separated, the aqueous layer is extracted twice with DCM (2×200 mL) and the combined organic extracts are concentrated in vacuo. The residue is dissolved in isopropanol (1600 mL) and treated with a solution of HCl in isopropanol (5-6 M, 10 mL). The obtained hydrochloride salt is recrystallized to give the respective 1,2,3,4-tetrahydroisoquinoline with high enantiomeric excess as determined by chiral HPLC. The hydrochloride salt is converted to the free base by extraction with sat. NaHCO3 solution/dichloromethane. The absolute configuration of the respective product is assigned in analogy to the literature (N. Uematsu, A. Fujii, S. Hashiguchi, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 1996, 118, 4916-4917).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4](=O)[C:5](=O)[NH:6]2.[F:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][C:20]2[N:21]([NH2:26])[C:22]([NH2:25])=[N:23][N:24]=2)=[CH:17][CH:16]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4]1[C:5]([NH:6]2)=[N:25][C:22]2=[N:23][N:24]=[C:20]([CH2:19][C:18]3[CH:27]=[CH:28][C:15]([F:14])=[CH:16][CH:17]=3)[N:21]2[N:26]=1
Reactant: Nc1nnc(Cc2ccc(F)cc2)n1N
Reactant: Cc1ccc(Cl)c2c1NC(=O)C2=O
Product: Cc1ccc(Cl)c2c1[nH]c1nc3nnc(Cc4ccc(F)cc4)n3nc12

Procedure:
According to the general cyclization procedure (for Example 27), 0.60 mmol of 4-chloro-7-methyl-1H-indole-2,3-dione (117.5 mg) and 0.70 mmol of 5-(4-fluoro-benzyl)-[1,2,4]triazole-3,4-diamine (145 mg) was used for the preparation.
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.[CH2:9]([N:16]1[CH:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31](=[NH:33])[NH2:32])=[CH:27][CH:26]=2)=[O:22])[CH:18]=[N:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:41]([O:43][CH2:44][CH3:45])=[O:42]>O.O1CCCC1>[NH2:33]/[C:31](=[N:32]\[C:41](=[O:42])[O:43][CH2:44][CH3:45])/[C:28]1[CH:27]=[CH:26][C:25]([CH2:24][NH:23][C:21]([C:19]2[CH:18]=[N:17][N:16]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:20]=2)=[O:22])=[CH:30][CH:29]=1
Reactant: N=C(N)c1ccc(CNC(=O)c2cnn(Cc3ccccc3)c2)cc1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/N=C(\N)c1ccc(CNC(=O)c2cnn(Cc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
65 mg of 1-benzyl-N-[(4-carbamimidoylphenyl)methyl]pyrazole-4-carboxamide diacetate and 65 mg of potassium carbonate were dissolved in 0.75 ml of water and 3.75 ml of tetrahydrofuran. The mixture was stirred at room temperature, and 0.015 ml of ethyl chloroformate (Sigma-Aldrich) added. Stirring was continued for 1 h, following which the organic layer was removed, and dried in vacuo to obtain the synthetic target. The mass of the compound was verified using LC/MS/MS.