Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH:11][CH3:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.[O:14]=[C:15]1[NH:24][C:23]2[N:22]=[CH:21][C:20](/[CH:25]=[CH:26]/[C:27]([OH:29])=O)=[CH:19][C:18]=2[CH2:17][CH2:16]1>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][N:11]([CH3:12])[C:27](=[O:29])/[CH:26]=[CH:25]/[C:20]3[CH:21]=[N:22][C:23]4[NH:24][C:15](=[O:14])[CH2:16][CH2:17][C:18]=4[CH:19]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CNCc1ccc2[nH]ccc2c1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: Cl
Product: CN(Cc1ccc2[nH]ccc2c1)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Yield: 38.8 %

Procedure:
According to the procedure of Example 35g (1H-indol-5-yl-methyl)-methyl-amine (257 mg, 1.62 mmol) and (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)acrylic acid hydrochloride (312 mg, 1.23 mmol), were coupled to give crude product. Purification by column chromatography (silica gel, 5% MeOH/CH2Cl2) gave the title compound (172 mg, 39%) as a white solid and a mixture of amide rotomers: 1H NMR (300 MHz, DMSO-d6) δ 11.06-11.05 (m, 1H), 10.63-10.61 (m, 1H), 8.36-8.34 (m, 1H), 8.06 (s, 1H), 7.56-7.19 (m, 5H), 7.02-6.96 (m, 1H), 6.38 (s, 1H), 4.84-4.65 (m, 2H), 3.06-2.85 (m, 5H), 2.55-2.52 (m, 2H); ESI MS m/e 361 [C21H20N4O2+H]+.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:34]=[CH:33][CH:32]=[CH:31][C:8]=2[C:9]=1[C:10]1[O:11][C:12]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20]([O:25][CH2:26][C:27]([O:29]C)=[O:28])[CH:19]=[CH:18]3)=[CH:13][N:14]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>C1COCC1.O>[CH2:1]([C:5]1[O:6][C:7]2[CH:34]=[CH:33][CH:32]=[CH:31][C:8]=2[C:9]=1[C:10]1[O:11][C:12]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20]([O:25][CH2:26][C:27]([OH:29])=[O:28])[CH:19]=[CH:18]3)=[CH:13][N:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3cc(OCC(=O)OC)ccc3c2)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3cc(OCC(=O)O)ccc3c2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A mixture of methyl ({6-[2-(2-butyl-1-benzofuran-3-yl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)acetate (295 mg, 0.647 mmol), prepared in the previous step, and 1N NaOH (1.3 mL, 1.3 mmol) in 35 mL of THF and 20 mL of H2O was stirred under nitrogen at room temperature for 14 h (overnight). The reaction was acidified by the addition of 1.4 mL of 1N HCl and then concentrated under reduced pressure to remove the THF. The yellow solid that formed was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (237 mg, 93%) as a yellow solid, mp 214-216° C. Elemental Analysis for C27H23NO5 Calc'd: C, 73.46; H, 5.25; N, 3.17. Found: C, 73.00; H, 5.49; N, 3.02.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:19]1[C:20](=[O:27])[N:21]([CH3:26])[N:22]=[C:23]([Cl:25])[CH:24]=1>CN(C)C=O>[Cl:25][C:23]1[CH:24]=[C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[O:9])=[CH:6][N:7]=2)[C:20](=[O:27])[N:21]([CH3:26])[N:22]=1
Reactant: Cn1nc(Cl)cc(Cl)c1=O
Reactant: Nc1ccc(C(=O)N2CCOCC2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc(Cl)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.6 %

Procedure:
(6-Amino-pyridin-3-yl)-morpholin-4-yl-methanone (2.921 g, 14.11 mmol) was suspended in 50 mL dimethylformamide and cooled to 0° C. Sodium hydride 60% suspension in mineral oil (847 mg, 21.2 mmol) was added. This was stirred at room temperature for 30 minutes and was cooled to 0° C. 4,6-Dichloro-2-methyl-2H-pyridazin-3-one (1.256 g, 7.056 mmol) was added. After 2 hours, this was partitioned between saturated aqueous ammonium chloride solution and ethylacetate. The ethylacetate layer was dried over anhydrous MgSO4, concentrated in vacuo, and purified by flash chromatography (2% MeOH/CH2Cl2) to yield 6-Chloro-2-methyl-4-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-2H-pyridazin-3-one (732 mg, 2.09 mmol). MS (ESI) 350.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[CH3:10][NH:11][S:12](Cl)(=[O:14])=[O:13]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][S:12](=[O:14])(=[O:13])[NH:11][CH3:10]
Reactant: COc1ccccc1O
Reactant: CNS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: CNS(=O)(=O)Oc1ccccc1OC
Yield: 65.8 %

Procedure:
A solution of 12.4 g (0.1 mole) of 2-methoxyphenol (guaiacol; Aldrich) and 13.1 g (0.1 mole) of methylsulfamoyl chloride (Preparation 20) in 150 ml of toluene was stirred and treated at reflux for 2 hr. The solvent was evaporated under reduced pressure and the only residue was purified by high pressure liquid chromatography (Waters Associates Prep LC/System 500A, PrePAK 500A silica, ethyl acetate-hexanes, 1:2; flow rate 150 ml/min). Fractions containing the product were combined and the solvents evaporated under reduced pressure to yield an oil that solidified upon standing. The solid was recrystallized from benzene-petroleum-ether (30°-60° C.) to give 14.3 g (66%) of the title compound as a white solid, mp 68°-71° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([O:26][C:27]4[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=4)[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)=[O:5])[CH3:2].O[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:10]=[CH:11][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([O:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:35][CH2:36][N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)=[CH:29][CH:28]=4)[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(Oc4ccc(O)cc4)ccc(F)c32)cc1
Reactant: OCCN1CCOCC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(Oc4ccc(OCCN5CCOCC5)cc4)ccc(F)c32)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(1S,2S)-2-{4-[(R)-7-Fluoro-4-(4-hydroxy-phenoxy)-indan-1-yloxy]-phenyl}-cyclopropanecarboxylic acid ethyl ester (Intermediate 7, 140 mg, 0.29 mmol), N-(2-hydroxyethyl)morpholine (42 mg, 0.32 mmol), and triphenylphosphine (84 mg, 0.32 mmol) are suspended in dry tetrahydrofuran (5 mL) and cooled to 0° C. Di-tert-butyl azodicarboxylate (74 mg, 0.32 mmol) is added, the mixture is stirred for 2 hours at 0° C. then 2 h at room temperature. The solvent is removed under vacuum and residue is purified by flash chromatography (0-20% ethyl acetate in cyclohexane) to give the title compound. (Yield 175 mg, 55% content). LC (METHOD 6): tR=0.57 min; Mass spectrum (ES+): m/z=562 [M+H]+.
Reaction SMILES: Cl[CH2:2][C@H:3]([C:5]([OH:7])=[O:6])[NH2:4].O.[OH-].[Li+].[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21])([O-:13])=[O:12].Cl>O.C(OCC)(=O)C.CC(C)=O>[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N@:4]1[CH2:2][CH:3]1[C:5]([OH:7])=[O:6])(=[O:22])=[O:21])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: N[C@H](CCl)C(=O)O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)C1C[N@@]1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
200 mg (1.62 mmol) of (S)-3-chloroalanine was dissolved in 4.0 mL of water. After adding 136 mg (3.24 mmol) of lithium hydroxide monohydrate, the resulting mixture was slowly heated to 50° C. and then stirred for 3 hours. The reaction container was ice-cooled and 6.4 mL of acetone, 431 mg (1.94 mmol) of 2-nitrobenzenesulfonyl chloride and 68 mg (1.62 mmol) of lithium hydroxide monohydrate were successively added thereto at an internal temperature of 5° C. After 1 hour, 30 mL of ethyl acetate was added. Further, 6 N hydrochloric acid was added to adjust to pH 2.0. Then the reaction mixture was divided into layers and the organic layer was collected. The aqueous layer was extracted with 50 mL portions of ethyl acetate twice to give an organic layer. The organic layers thus obtained were combined, washed successively with 50 mL of water and 50 mL of a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and filtered. After distilling off the solvent under reduced pressure, 265 mg of (S)-N-2-nitrobenzenesulfonyl-aziridine-2-carboxylic acid was obtained. Yield: 60%.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13].Cl[CH2:16][S:17]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)(=[O:19])=[O:18].CC(C)([O-])C.[K+].Cl>C1COCC1>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([N+:12]([O-:14])=[O:13])=[C:8]([CH2:16][S:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)(=[O:18])=[O:19])[CH:9]=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1ccccc1OCCCCl
Reactant: O=S(=O)(CCl)c1cccc2ccccc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(CS(=O)(=O)c2cccc3ccccc23)cccc1OCCCCl
Reaction time: 5 h
Yield: 75 %

Procedure:
A mixture of 1-(3-chloro-propoxy)-2-nitrobenzene (1.2 g, 6 mmoles) and 1-chloromethane-sulfonyl-naphthalene (2.16 g, 9 mmoles) was stirred in THF (50 mL) at −78° C., in a round bottom flask under nitrogen. A solution of 1M potassium t-butoxide was added dropwise (18 mL, 18 mmoles) over a half hour period. Temperature was allowed to rise to 40° C., and the reaction mixture was stirred at this temperature for 5 hours. The reaction mixture was poured into cold 2N HCl, extracted with EtOAc, dried over Na2SO4, and concentrated under vacuum. Compound was recrystallized from CH2Cl2/hexane to afford the title compound as an off-white solid (1.9 g, 4.5 mmoles).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([CH3:12])[CH2:8][N+:9]([O-])=O)[CH:2]=1>C(O)C.Cl.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([CH3:12])[CH2:8][NH2:9])[CH:2]=1
Reactant: CC(C[N+](=O)[O-])c1cccnc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(CN)c1cccnc1

Procedure:
To a solution of 2-(3-pyridyl)-1-nitropropane (0.91 g, 5.48 mmol) in 20 mL of ethanol and 0.1 mL of 12N HCl was added 10% Pd/C (1.00 g) under argon. The solution was evacuated and flushed with hydrogen several times, place under an atmosphere of hydrogen and vigorously stirred. After 14 h the mixture was evacuated and flushed with argon several times, filtered through celite and washed with 200 mL of ethanol. The volatiles were removed in vacuo to provide a residue which was partitioned between methylene chloride (100 mL) and NaOH (50 mL, 10%) and the aqueous layer was extracted with methylene chloride (2×100 mL). The combined organic layers were dried over MgSO4, filtered, concentrated in vacuo and the residue was purified by flash column chromatography (20×150 mm column of SiO2, CH2Cl2 /CH2Cl2 saturated with NH3 /MeOH 60:39:1) to give the title compound as an oil:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10](=[O:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:27][C:28]#[N:29]>CC(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:27][C:28]#[N:29])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10](=[O:19])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCBr
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(CC#N)CCN(Cc2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a flask charged with ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (1.0 g, 3.8 mmol) and a stir bar was added K2CO3 (1.06 g, 7.6 mmol), bromoacetonitrile (0.92 g, 7.6 mmo0, and acetone (15 mL). The reaction was allowed to stir at RT for 2 hours. LC showed slow reaction. It was then heated to 45° C. for 3 hours. LC showed complete reaction at that point. The reaction was quenched with NH4Cl, extracted with EtOAc, dried over Na2SO4, filtered and concentrated. The crude product was purified by MPLC to furnish the title compound. LCMS: m/z 301 (M+H)+.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:10]([Cl:11])[C:4]=2[N:3]=1.[CH3:16][C@@H:17]1[CH2:22][NH:21][CH2:20][CH2:19][NH:18]1.C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1.O>[Cl:11][C:10]1[C:4]2[NH:3][C:2]([N:21]3[CH2:20][CH2:19][NH:18][C@H:17]([CH3:16])[CH2:22]3)=[N:6][C:5]=2[CH:7]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=1
Reactant: C[C@@H]1CNCCN1
Reactant: FC(F)(F)c1cc(Cl)c2nc(Cl)[nH]c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: C[C@@H]1CN(c2nc3cc(C(F)(F)F)cc(Cl)c3[nH]2)CCN1
Temperature: 120 °C

Procedure:
A mixture of 2,4-dichloro-6-trifluoromethyl-1H-benzoimidazole (0.51 g, 2 mmol, Example 5b), (R)-(−)-2-methylpiperazine (0.25 g. 2.5 mmol) and N,N-diisopropylethylamine (0.5 mL, 2.9 mmol) in NMP (5 mL) was heated at 120° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 10% MeOH in dichloromethane to give the title compound as a light-yellow solid. MS (ESI, pos. ion) m/z: 319 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:5]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17].[CH3:26][C:27]1[NH:31][N:30]=[N:29][N:28]=1>>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH:6]2[N:5]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)(=[O:17])=[O:18])[CH:4]([CH2:3][CH2:2][N:28]3[C:27]([CH3:26])=[N:31][N:30]=[N:29]3)[CH2:8][CH2:7]2)=[CH:14][CH:13]=1
Reactant: Cc1nnn[nH]1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCl)CCC2c2ccc(F)cc2)cc1
Product: Cc1ccc(S(=O)(=O)N2C(CCn3nnnc3C)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=430.4 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(2-chloro-ethyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 5-methyl-1H-tetrazole.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29].C(N(C(C)C)C(C)C)C>O1CCCC1>[CH2:28]([N:30]([CH2:31][CH3:32])[C:25]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([NH:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[N:17]=[C:11]2[CH:10]=1)=[O:24])=[O:26])[CH3:29]
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Reactant: CCNCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Temperature: 70 °C
Reaction time: 22 h
Yield: 81.3 %

Procedure:
A mixture of 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (150 mg, 0.404 mmole), diethylamine (250 ul, 2.42 mmole), N-ethyldiisopropylamine (282 ul, 1.62 mmole) and propylphosphonic acid cyclic anhydride (50% in ethyl acetate, 606 ul, 1.01 mmole) in tetrahydrofurane (5 ml) is stirred for 22 h at 70° C. The solvent is removed under reduced pressure and the residue is triturated for 1 hr with sat. aqueous sodium bicarbonate solution (30 ml). The solid is collected by filtration, washed with water and dried affording N4,N4-diethyl-1-methyl-N5-(2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (140 mg, 81.3%) as a white solid. Mp.: 165-7° C. MS: m/z=427.4 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[NH:37]1[CH2:42][CH2:41][CH:40]([N:43]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH2:39][CH2:38]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH2:11][C@@H:12]([NH:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[NH:27][C:26]2=[O:36])[CH2:21][CH2:20]1)=[O:18])[C:13](=[O:14])[N:37]1[CH2:42][CH2:41][CH:40]([N:43]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH2:39][CH2:38]1)[CH3:2]
Reactant: C1CCCN(C2CCNCC2)CC1
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCCCCC3)CC2)cc1CC

Procedure:
Prepared analogously to Example 9i) from 400 mg (0.81 mmol) (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 180 mg (0.99 mmol) 1-piperidin-4-yl-azepan.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:23]([O-])=O)[CH:5]=[C:6]([Cl:22])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[Pt].C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:22])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[NH2:23]
Reactant: O=[N+]([O-])c1cc(Cl)c(OCc2ccccc2-c2ccccc2)c(Cl)c1
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Nc1cc(Cl)c(OCc2ccccc2-c2ccccc2)c(Cl)c1
Yield: 82.5 %

Procedure:
A 500 milliliter rocking Parr hydrogenator was charged with a solution of 12 grams (0.032 moles) of 3,5-dichloro-4-(2-phenylphenylmethoxy) nitrobenzene prepared in Part A and 100 milliliters of toluene. To this solution was added 1.0 gram of a catalyst of 5% platinum on carbon and the reactor was sealed. The reactor was purged twice with nitrogen and then twice with hydrogen. Hydrogen was then introduced to a pressure of 26 psi and this pressure was maintained until the hydrogen up-take ceased, i.e., about 20 minutes. The material was removed from the reactor, filtered through celite and concentrated (toluene removed under vacuum) to give an oil. Crystallization from a hexane-ethyl acetate mixture (5:2 volume ratio) afforded 9.09 grams of an ivory powder having a melting point of 67.0° C.-69.0° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[S:15][CH2:14][CH2:13][NH:12][C:11]2[N:16]([CH3:25])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[C:10]1=2.[CH2:26]([Sn](CCCC)(CCCC)C=C)[CH2:27]CC.[F-].[Cs+]>CN(C=O)C.C(Cl)Cl.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([CH:9]2[S:15][CH2:14][CH2:13][NH:12][C:11]3[N:16]([CH3:25])[N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[C:10]2=3)=[C:2]([CH:26]=[CH2:27])[CH:7]=1
Reactant: Cn1nc(-c2ccccn2)c2c1NCCSC2c1ccc(Cl)cc1Br
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=Cc1cc(Cl)ccc1C1SCCNc2c1c(-c1ccccn1)nn2C
Temperature: 45 °C
Yield: 60.8 %

Procedure:
To a degassed mixture of 4-(2-bromo-4-chloro-phenyl)-1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (0.50 g, 1.2 mmol, Example #D.37) and tributyl(vinyl)stannane (0.37 mL, 1.3 mmol) in DMF (5 mL) was added cesium fluoride (0.35 g, 2.3 mmol), copper(I) iodide (0.022 g, 0.12 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.066 g, 0.058 mmol). The resulting mixture was heated at about 45° C. overnight; then diluted with DCM (50 mL), washed with water (20 mL) and brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, ethyl acetate/hexanes 1:1) to give 4-(4-chloro-2-vinyl-phenyl)-1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (0.28 g, 0.73 mmol, 63%) as an off white solid: LC-MS (Table 1, Method a) Rt=4.07 min; m/z 383 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) 2.69-2.78 (1 H, m) 2.81-2.89 (1 H, m) 3.19-3.28 (1 H, m) 3.52-3.61 (1 H, m) 3.77-3.86 (1 H, m) 3.84 (3 H, s) 5.47 (1 H, dd, J=11.0, 1.5 Hz) 5.73 (1 H, dd, J=17.5, 1.5 Hz) 6.79 (1 H, s) 7.02-7.08 (2 H, m) 7.14 (1 H, d, J=8.5 Hz) 7.38 (1 H, dd, J=17.5, 11.0 Hz) 7.45 (1 H, d, J=2.0 Hz) 7.58 (1 H, td, J=7.5, 2.0 Hz) 7.77 (1 H, br.d, J=8.0 Hz) 8.42 (1 H, br.d, J=5.0 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Cl:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Cl:15][CH2:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cccc(C)c1C(=O)OC(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cccc(CCl)c1C(=O)OC(C)C
Yield: 96.5 %

Procedure:
19.2 g of isopropyl 2,6-dimethylbenzoate are initially charged in 100 ml of carbon tetrachloride admixed at room temperature with 13.3 g of N-chlorosuccinimide and 200 mg of AIBN. The mixture is heated to reflux for 3 h. After the mixture has been cooled, it is filtered with suction, and the succinimide is washed with 20 ml of carbon tetrachloride. The filtrates are combined, and carbon tetrachloride is distilled off in vacuo. 21.8 g of colorless liquid are obtained. The product is distilled under high vacuum (0.05 mbar, 94–97° C.). Yield: 13.9 g (61% of theory; 93.6 area %).
Reaction SMILES: [Na].Cl.[F:3][C:4]1[CH:5]=[C:6]([NH:10][NH2:11])[CH:7]=[CH:8][CH:9]=1.[C:12](#[N:15])[CH:13]=[CH2:14]>C(O)C>[NH2:15][C:12]1[CH2:13][CH2:14][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[CH:5]=2)[N:11]=1
Reactant: C=CC#N
Reactant: NNc1cccc(F)c1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: NC1=NN(c2cccc(F)c2)CC1
Reaction time: 0.25 h

Procedure:
A 1.38 g. amount of sodium metal is dissolved in 150 ml. of absolute ethanol, then 8.1 g. of m-fluorophenylhydrazine hydrochloride is added followed in 15 minutes by 2.75 g. of acrylonitrile. The reaction mixture is refluxed for 5 hours, then is evaporated to dryness in vacuo. Water is added and the separated solid is collected by filtration. The solid is dissolved in dichloromethane and the solution is passed through a short column of a hydrous magnesium silicate. The effluent is heated to reflux on a steam bath and hexane is added to precipitate a product. The solid is collected, dissolved in acetone, treated with activated charcoal and filtered. Hexane is added to the filtrate to crystallize 2.95 g. of the product of the Example as off-white needles, m.p. 146°-147° C.