Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[CH:6]=1)[CH3:2].Br[C:25]1[CH:26]=[N:27][N:28]([CH2:30][CH2:31][CH3:32])[CH:29]=1>>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:25]3[CH:26]=[N:27][N:28]([CH2:30][CH2:31][CH3:32])[CH:29]=3)[C:13]=2[CH3:22])[CH:6]=1)[CH3:2]
Reactant: CCCn1cc(Br)cn1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: CCCn1cc(-n2c(C)c(Sc3cccc(C(=O)OCC)c3)c3ccc(Cl)cc32)cn1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 4-bromo-1-propylpyrazole.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([CH:12]=[CH:13][CH:14](O)[CH3:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:17]([O-])(=[O:19])C.[Na+]>CN(C)C=O.O>[C:6]1([CH:12]=[CH:13][CH:14]=[CH:15][CH:17]=[O:19])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(O)C=Cc1ccccc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=CC=CC=Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
Dimethylformamide (DMF, anhydrous, 14 mL) was cooled to 0-5 ° C. and phosphorus oxychloride (8.2 mL) was added dropwise over a period of 40 minutes. The resulting solution was added dropwise to a cooled (0-5° C.) solution of 4-phenyl-3-buten-2-ol (10 g) in 32 mL of anhydrous DMF over a period of an hour. The reaction mixture was warmed to room temperature over a 35-minute period and then gradually heated up to 80° C. over a period of 45 minutes. The reaction was stirred at 80° C. for three hours and then cooled to 0-5° C. To the cooled reaction solution was added dropwise a solution of sodium acetate (40 g) in deionized water (100 mL) over a period of one hour. The mixture was then reheated to 80° C., stirred at 80° C. for an additional 10 minutes, cooled down to room temperature and extracted with ether (100 mL) twice. The combined extract was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to yield 8.78 g of the desired 5-phenyl-2,4-pentadienal as a liquid which was used in the next step without further purification. 1H NMR (CDCl3, 300 MHz), δ(ppm) 7.51 (m, 2 H), 7.37 (m, 3 H), 7.26 (m, 1 H), 7.01 (m, 2 H), 6.26 (m, 1 H). The synthesis is summarized in Scheme I.
Reaction SMILES: [CH:1]1([O:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:54][C:55]1[S:56][CH:57]=[CH:58][N:59]=1>ClCCl.O>[CH:1]1([O:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C:9]([NH:54][C:55]2[S:56][CH:57]=[CH:58][N:59]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(OC1C=CCCC1)c1ccc(Cl)c(Cl)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1nccs1)C(OC1C=CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.2 %

Procedure:
A solution of rac-(cyclohex-2-enyloxy)-(3,4-dichloro-phenyl)-acetic acid (89 mg, 0.28 mmol) in dichloromethane (10 mL) was treated with BOP reagent (187 mg, 0.42 mmol), triethylamine (0.12 mL, 0.85 mmol), and 2-aminothiazole (42 mg, 0.42 mmol) at 25° C. The resulting brownish-orange solution was then stirred 16 h at 25° C, then was diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with water (1×10 mL), 1N sodium hydroxide solution (1×10 mL), 1N hydrochloric acid (1×10 mL), and brine (1×10 mL), then were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 95/5 hexanes/ethyl acetate) to provide rac-(cyclohex-2-enyloxy)-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide (99 mg, 92% yield) as a white foam: EI-HRMS m/e calcd for C17H16Cl2O2N2S (M+) 382.0309, found 382.0308.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:19][C@@H:18]([F:20])[CH2:17][C@@H:16]1[CH2:21][OH:22])=[O:14])([CH3:11])([CH3:10])[CH3:9]>CS(C)=O.C(OCC)C>[C:8]([O:12][C:13]([N:15]1[CH2:19][C@@H:18]([F:20])[CH2:17][C@@H:16]1[CH:21]=[O:22])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@@H]1CO
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@@H]1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add triethylamine (1.1 mL, 7.79 mmol) and sulfurtrioxide-pyridine complex (0.63 g, 3.89 mmol) to an ice-cold solution of 4-(S)-fluoro-2-(R)-hydroxymethylpyrrolidine-1-carboxylic acid tert-butyl ester (0.426 g, 1.95 mmol) in DMSO (2 mL). Stir 30 min, warm to room temperature and stir 30 min. Dilute with diethyl ether and wash with 5% aqueous citric acid (3×120 mL), saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound as an oil that was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18](Cl)=[N:17][C:16]([Cl:20])=[CH:15][N:14]=1)(=[O:11])=[O:10].[CH2:21]([OH:25])[CH2:22][CH2:23][CH3:24]>>[CH2:21]([O:25][C:18]1[C:13]([NH:12][S:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])(=[O:11])=[O:10])=[N:14][CH:15]=[C:16]([Cl:20])[N:17]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCO
Reactant: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl
Product: CCCCOc1nc(Cl)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 31 using 1-butanol (0.05 g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.1 g). Yield 0.037 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3I)[NH:11][C:10]=2[CH3:19])=[CH:4][CH:3]=1.F[C:21](F)(F)[C:22]([OH:24])=[O:23].[CH3:27][C:28]#N.N.Cl>ClCCl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:28]3[CH:27]=[CH:4][CH:3]=[CH:2][CH:7]=3)[N:11]([CH2:21][C:22]([OH:24])=[O:23])[C:10]=2[CH3:19])=[CH:4][CH:3]=1
Reactant: Cc1[nH]c2cccc(I)c2c1Sc1ccc(Cl)cc1
Reactant: O=C(O)C(F)(F)F
Reactant: CC#N
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: O
Product: Cc1c(Sc2ccc(Cl)cc2)c2c(-c3ccccc3)cccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from part (i) (0.4 g) in dichloromethane (10 ml) was added trifluoroacetic acid (2 ml), the reaction was stirred at room temperature overnight. The reaction was concentrated in vacuo and the residue dissolved/suspended in water. The pH was adjusted to 2 using 2M HCl(aq) and the solid which precipitated was isolated by filtration. This was purifed using reverse phase preparative HPLC (MeCN/NH3(aq) as eluent) to give a solid. The solid was suspended in water and the pH was adjusted to 2 using 2M HCl(aq), the solid was isolated by filtration, triturated with hexane and dried overnight at 40° C. under vaccum to give the title compound (0.15 g).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13](O)[CH2:14][CH2:15][CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([CH2:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=1)#[N:19].S(=O)(=O)(O)[OH:33]>ClC1C=CC=CC=1Cl>[N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([CH:20]([C:18]([NH2:19])=[O:33])[C:21]2[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=2)[CH2:14][CH2:15][CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(CC#N)cc1
Reactant: O=S(=O)(O)O
Reactant: CCCC(O)c1ccccc1N1CCCCC1
Solvent: Clc1ccccc1Cl
Product: CCCC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)OCC)cc1

Procedure:
Prepared analogously to Example 64 from 1-(2-piperidinophenyl)-1-butanol and ethyl 4-cyanomethyl-benzoate with concentrated sulfuric acid in o-dichlorobenzene at ambient temperature.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[CH:11]=[O:12])([CH3:3])[CH3:2].[CH2:13]([Mg]Br)[CH2:14][CH3:15]>C1COCC1>[CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[CH:11]([OH:12])[CH2:13][CH2:14][CH3:15])([CH3:3])[CH3:2]
Reactant: CCC[Mg]Br
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1C=O
Solvent: C1CCOC1
Product: CCCC(O)[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Temperature: 25 °C

Procedure:
To a solution of (1R,2S,5R)-2-isopropyl-5-methylcyclohexanecarbaldehyde (4.64 g, 27.6 mmol) in THF (120 mL) at 0° C. was slowly added propylmagnesium bromide (2 M in THF, 28 mL). After the reaction was allowed to warm to room temperature over 1 h it was again cooled to 0° C. The reaction was quenched with 1 N HCl and partitioned between brine and MTBE. The organic layer was dried (MgSO4) and concentrated. The residue was purified by silica chromatography to give the desired alcohol (1.65 g).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.CN1CCOCC1.[Br:25][C:26]1[C:31]([F:32])=[CH:30][C:29]([S:33](Cl)(=[O:35])=[O:34])=[C:28]([F:37])[CH:27]=1>ClCCl>[Br:25][C:26]1[C:31]([F:32])=[CH:30][C:29]([S:33]([NH:14][C:13]2[CH:15]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[CH:10]=[CH:11][C:12]=2[O:16][CH3:17])(=[O:34])=[O:35])=[C:28]([F:37])[CH:27]=1
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1N
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1cc(F)c(Br)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)aniline (D4) (500 mg, 2.12 mmol) in dichloromethane (30 ml) was treated with morpholinomethyl-polystyrene HL resin (1 g, 4 mmol/g loading, 4.24 mmol) followed by 4-bromo-2,5-difluorobenzene sulfonyl chloride (930 mg, 3.2 mmol). The resulting solution was stirred room temperature for 18 hours and was then filtered, washing with dichloromethane, and the filtrate concentrated in vacuo. The residue was then purified using an SCX ion exchange cartridge (Varian bond-elute) eluting with methanol followed by ammonia (0.5M to 2M in methanol). The appropriate fractions were combined and reduced in vacuo to afford a crude product which was purified further by trituration with methanol to afford the desired product D37. MS (ES+) m/e 490/492 [M+H]+.
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:16]C1C(I)=C(C=CC=1)C(O)=O.N1C=CN=N1>>[CH3:16][C:4]1[C:5]([N:11]2[N:12]=[CH:13][CH:14]=[N:15]2)=[C:6]([CH:10]=[CH:2][CH:3]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: Cc1cccc(C(=O)O)c1I
Agent: c1c[nH]nn1
Product: Cc1cccc(C(=O)O)c1-n1nccn1

Procedure:
The title compound was prepared following the same general protocol as described for 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A11 using 3-methyl-2-iodobenzoic acid and 1,2,3-triazole. ESI-MS (m/z): 204 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:9]([NH:20][C:21](=[O:27])[O:22]C(C)(C)C)[C@@H:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])O)[C:5]([F:8])=[N:6][CH:7]=1.Cl.C(N(CC)C(C)C)C.C(N1C=CN=C1)(N1C=CN=C1)=O>ClCCl.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[F:19])[O:27][C:21](=[O:22])[NH:20]2)[C:5]([F:8])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](c1cc(Br)cnc1F)[C@H](O)c1cc(F)ccc1F
Agent: CCN(CC)C(C)C
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1N[C@H](c2cc(Br)cnc2F)[C@@H](c2cc(F)ccc2F)O1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of optically-enriched tert-butyl (1R,2R)-1-(5-bromo-2-fluoropyridin-3-yl)-2-(2,5-difluorophenyl)-2-hydroxyethylcarbamate (380 mg, 0.850 mmol) in dichloromethane (6 mL) at room temperature was added hydrochloric acid (4M in dioxane, 10 mL, 40.0 mmol). The resulting solution was placed in a 45° C. bath. After 20 min, the reaction was concentrated. The resulting viscous oil was dissolved in and reconcentrated from tetrahydrofuran (3×) to give a white solid. The resulting residue was suspended in tetrahydrofuran (15 mL), and treated with diethylisopropylamine (0.297 mL, 1.70 mmol). After stirring briefly, the mixture was cooled to 0° C. and treated with carbonyldiimidazole (207 mg, 1.27 mmol) as a solid in one portion. The ice bath was removed and stirring continued for 1.5 h. The reaction was quenched by addition of 2M ammonia in methanol and concentrated. The material was purified by column chromatography (EtOAc/Hex) to give the product as a mixture of regioisomers. The material was re-purified by chiral prep HPLC (Chiralcel OJ, 30% EtOH/heptane/0.1% DEA) to afford 88 mg (25%). 1H NMR (CDCl3) δ: 8.33 (dd, J=2.3, 1.4 Hz, 1H), 8.11 (dd, J=8.2, 2.1 Hz, 1H), 7.21-7.27 (m, 1H), 7.09-7.17 (m, 2H), 6.48 (br. s., 1H), 5.58 (d, J=5.8 Hz, 1H), 5.04 (d, J=5.5 Hz, 1H). 19F NMR (CDCl3) δ: −74.27 (br. s., 1F), −116.97 (d, J=17.3 Hz, 1F), −123.78-123.41 (m, 1F). Mass spec.: 373.0 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:31])[CH:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[CH:23]=3)[CH2:18]2)=[O:11])=[C:4]([N+:32]([O-])=O)[CH:3]=1.O.NN>CO.[Ni]>[NH2:32][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[CH:6][C:5]=1[CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:31])[CH:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[CH:23]=2)[CH2:18]1)=[O:11]
Reactant: COc1cc2c(cc1OC)CC(N(C)CCCNC(=O)Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-])CC2
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1OC)CC(N(C)CCCNC(=O)Cc1cc(Cl)c(Cl)cc1N)CC2

Procedure:
Here, 1-[2-(4,5-dichloro-2-nitro-phenyl)-1-oxo-ethylamino]-3-[N-methyl-N-(6,7-dimethoxy-1,2,3,4-tetrahydronaphth-2-yl)-amino]-propane (15.8 g, 0.031 mol) is dissolved in methanol (300 ml) and mixed with 98% hydrazine hydrate (4.65 ml). Raney nickel (2 g) is added in batches with stirring. Then the mixture is stirred for 2 hours at ambient temperature, the catalyst is filtered off and the filtrate is concentrated by evaporation in vacuo. The viscous residue is purified by column chromatography over alumina N (400 g) [activity II, eluant: methylene chloride and increasing amounts of ethanol (up to 1%]. Yield: 13.9 g. IR spectrum (methylene chloride): 1660 cm-1 (C=O), 1515 cm-1 (Amide-II).
Reaction SMILES: [ClH:1].[CH3:2][S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10]N.C[CH2:13][O:14][C:15]([CH2:17][CH:18]1[C:23](=O)[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:16]>>[Cl:1][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:10]2[C:23]3[CH:18]([CH2:17][C:15]([O:14][CH3:13])=[O:16])[CH2:19][CH2:20][CH2:21][C:22]=3[C:6]3[C:5]2=[C:4]([S:3][CH3:2])[CH:9]=[CH:8][CH:7]=3)=[CH:19][CH:20]=1
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: Cl
Reactant: CSc1ccccc1NN
Product: COC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1c(SC)cccc21

Procedure:
Following the procedure of Example 30, but using 1-(2-methylthiophenyl) hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=2)[N:3]=1.[C:22]1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C[Sn](C)(C)C.C(N(CC)CC)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[CH3:22][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=2)[N:3]=1
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Reactant: Cc1cccc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)n1
Agent: [Pd]
Agent: C[Sn](C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2nc(C)c3c([N+](=O)[O-])cccc32)n1
Temperature: 80 °C
Yield: 394.5 %

Procedure:
A flask equipped with a reflux condenser and a nitrogen line was charged with 3-iodo-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole (Example 89, Steps A-B; 100 mg, 0.254 mmol), trio-tolylphosphine (15.4 mg, 0.051 mmol), and tris(dibenzylideneacetone)dipalladium (0) (23 mg, 0.025 mmol). The flask was purged with nitrogen and anhydrous DMF (30 mL), and tetramethylstannane (0.04 ml, 0.28 mmol) were added, followed by triethylamine (0.04 mL, 0.30 mmol). The flask was degassed under nitrogen and heated at 80° C. for 6 hours. The reaction mixture was cooled to ambient temperature, diluted with water, and extracted with DCM and EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, and concentrated. The crude product was subjected to preparative thin-layer chromatography on silica with 2% MeOH/DCM as eluent to afford 56.8 mg of desired product as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=O)[CH2:10][CH:11]([C:19]2[CH:33]=[CH:32][C:22]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.Cl.[NH2:36][OH:37].C([O-])(O)=O.[Na+].[CH2:43]([OH:45])[CH3:44]>O>[CH2:43]([O:45][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][NH:25][C:23](=[O:24])[C:22]1[CH:21]=[CH:20][C:19]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:10]/[C:9](=[N:36]\[OH:37])/[C:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[CH:33][CH:32]=1)[CH3:44]
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCCCC(=O)O)cc1
Reactant: CCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CCCNC(=O)c1ccc(C(C/C(=N\O)c2ccc(=O)n(C)c2)c2ccccc2C)cc1

Procedure:
In analogy to example 151, step 3, 4-{4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoylamino}-butyric acid was reacted with hydroxylamine hydrochloride in ethanol and water in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=504.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3]1.[OH-].[Na+].Cl[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12]>>[CH:14]([O:13][C:11]([NH:1][C:2]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3]1)=[O:12])([CH3:16])[CH3:15]
Reactant: CC(C)OC(=O)Cl
Reactant: NC1(C(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)OC(=O)NC1(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 54 %

Procedure:
0.2 g (1.98 mmol) of 1-aminocyclopropane-1-carboxylic acid were initially charged in 10 ml of 12% strength aqueous sodium hydroxide solution. After addition of 0.24 g (1.98 mmol) of isopropyl chloroformate, the pH was adjusted to 9 by dropwise addition of 12% strength aqueous sodium hydroxide solution. The mixture was stirred at room temperature for 14 hours and then, for work-up, extracted twice with methyl tert-butyl ether. The pH was subsequently adjusted to 1-2 using phosphoric acid. The mixture was extracted three times using dichloromethane, the extracts were dried with magnesium sulfate and the solvent was removed, after which the title compound was isolated as a white solid (0.2 g; 54% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[N:8]([CH:16]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:7]=1.[NH2:23][C:24]1[N:29]=[CH:28][C:27]([N:30]2[C:34](=[O:35])[C@@H:33]3[CH2:36][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38][C@@H:32]3[CH2:31]2)=[CH:26][CH:25]=1>>[CH:16]1([N:8]2[C:6]3[N:7]=[C:2]([NH:23][C:24]4[N:29]=[CH:28][C:27]([N:30]5[C:34](=[O:35])[C@@H:33]6[CH2:36][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38][C@@H:32]6[CH2:31]5)=[CH:26][CH:25]=4)[N:3]=[CH:4][C:5]=3[CH:10]=[C:9]2[C:11](=[O:12])[N:13]([CH3:15])[CH3:14])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCCCC1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3ccc(N)nc3)C(=O)[C@@H]2C1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@H]5CN(C(=O)OC(C)(C)C)C[C@H]5C4=O)cn3)nc2n1C1CCCCCC1
Yield: 95.1 %

Procedure:
Following general N—C coupling procedure 1, 2-chloro-7-cycloheptyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (50.4 mg, 0.157 mmol) was combined with cis-tert-butyl 5-(6-aminopyridin-3-yl)-4-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (50 mg, 0.157 mmol, 1.0 eq), gave after silica gel chromatography, cis-tert-butyl 5-(6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-4-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (90 mg) in 94% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.76 (s, 1H), 8.65 (d, J=9.6 Hz, 1H), 8.54 (s, 1H), 8.34 (s, 1H), 8.18 (s, 1H), 6.46 (s, 1H), 4.54 (m, 1H), 4.13 (dd, J1=9.85 Hz, J2=6.82 Hz, 1H), 3.97 (d, J=10.61 Hz, 1H), 3.89 (t, J=9.85 Hz, 1H), 3.62-3.76 (m, 2H), 3.06-3.40 (m, 9H), 2.65 (q, J=10.95 Hz, 2H), 2.02 (m, 2H), 1.89 (m, 2H), 1.74 (m, 4H), 1.60 (m, 2H), 1.49 (m, 9H). MS m/z 603.6 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C@H:7]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]#N)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].C([O:28][C:29]([NH:31][C@H](C(O)=O)CCCCNC=NOCC)=O)(C)(C)C.CO.[Cl:48]CCl>>[ClH:48].[C:1]([O:5][C:6](=[O:23])[C@H:7]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:21][O:28][CH:29]=[NH:31])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCON=CNCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC#N)C(=O)OC(C)(C)C
Reactant: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNCOC=N)C(=O)OC(C)(C)C
Product: Cl

Procedure:
From 1.6 g (4.89 mmol) N2-(tert-butoxycarbonyl)-N6-(cyano)-L-lysine tert-butyl ester was prepared 1.5 g (75%) of foamy solid N2-(tert-butoxycarbonyl)-N6-(ethoxyiminomethyl)-L-lysine tart-butyl ester hydrochloride by the method described for N2-(tert-butoxycarbonyl)-N5-(imonomethoxymethyl)-L-ornithine tert-butyl ester hydrochloride. TLC (methanol:dichloromethane/1:9) Rf=0.36. Mass spectrum (CI) 360 (MH+, 60%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[C:26]1([NH2:33])[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([NH2:33])=[CH:27][CH:28]=3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: Nc1ccc(N)cc1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Nc3ccc(N)cc3)c2c1

Procedure:
The title compound was prepared in analogy to Example 15-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1 1) and benzene-1,4-diamine. MS obsd. (ESI+) [(M+H)+] 445, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.21 (s, 1 H), 7.92-7.83 (m, 2 H), 7.63-7.55 (m, 1 H), 7.53-7.46 (m, 1 H), 7.34 (d, J=8.34 Hz, 1 H), 7.27 (dd, J=8.59, 1.52 Hz, 1 H), 7.15 (d, J=7.58 Hz, 1 H), 6.91 (m, J=8.34 Hz, 2 H), 6.77 (m, J=8.59 Hz, 2 H), 5.97 (s, 1 H), 5.20-5.12 (m, 2 H), 4.76 (brs, 2 H), 3.57 (brs, 2 H), 2.37 (s, 3 H).