Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][NH2:12])=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[C:13]([O:17][C:18]([N:20]([CH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)[CH3:21])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>CN(C)C=O>[NH2:1][C:2]1[C:3]([C:9]([NH:11][NH:12][C:27]([C:26]2[CH:25]=[CH:24][C:23]([CH2:22][N:20]([CH3:21])[C:18](=[O:19])[O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[CH:31][CH:30]=2)=[O:28])=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: CN(Cc1ccc(C(=O)O)cc1)C(=O)OC(C)(C)C
Reactant: NNC(=O)c1nc(Br)cnc1N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(Cc1ccc(C(=O)NNC(=O)c2nc(Br)cnc2N)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
3-amino-6-bromo-pyrazine-2-carbohydrazide (12.91 g, 55.64 mmol), 4-[[tert-butoxycarbonyl(methyl)amino]methyl]benzoic acid (14.76 g, 55.64 mmol) and triethylamine (12.39 g, 17.07 mL, 122.4 mmol) were suspended in N,N-dimethylformamide (200 mL) and stirred at ambient temperature for 30 minutes. A further 3-amino-6-bromo-pyrazine-2-carbohydrazide (3 g, 12.93 mmol) was added and left to stir for 18 hours at ambient temperature. The reaction mixture was concentrated in vacuo to remove most of the N,N-dimethylformamide. The residue was then diluted with ethyl acetate and water. The organic layer was separated and washed with saturated aqueous sodium bicarbonate solution followed by a brine wash. The organic extracts were dried over MgSO4, filtered and concentrated in vacuo to a yellow sticky solid. The solid was triturated with ethyl acetate to give a beige solid (this is the hydrazide starting material), the crude mother liquors were concentrated and purified by column chromatography (ISCO Companion XL, 330 g gold column) dry loaded and eluted with 30 to 70% ethyl acetate/petroleum ether to give a yellow sticky gum. This gum was then crystallised from petroleum ether to give tert-butyl 4-(2-(3-amino-6-bromopyrazine-2-carbonyl)hydrazinecarbonyl)benzyl(methyl)carbamate as a yellow powder (14.16 g, 53% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.16-1.20 (m, 1H), 1.38-1.45 (br d, 9H), 2.80 (br s, 3H), 4.02-4.04 (m, 1H), 4.45 (s, 2H), 7.34 (d, 2H), 7.69 (br s, 2H), 7.89 (d, 2H), 8.44 (s, 1H) ppm.
Reaction SMILES: COC(C1CC(=O)[N:7](C2C=CC(O)=CC=2)[CH2:6]1)=O.FC1C=C(F)C=C(F)C=1CBr.C[O:30][C:31]([CH:33]1[CH2:37][C:36](=[O:38])[N:35]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]3[C:52]([F:53])=[CH:51][C:50]([F:54])=[CH:49][C:48]=3[F:55])=[CH:41][CH:40]=2)[CH2:34]1)=O>>[CH3:6][NH2:7].[CH3:6][NH:7][C:31]([CH:33]1[CH2:37][C:36](=[O:38])[N:35]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]3[C:52]([F:53])=[CH:51][C:50]([F:54])=[CH:49][C:48]=3[F:55])=[CH:41][CH:40]=2)[CH2:34]1)=[O:30]
Reactant: COC(=O)C1CC(=O)N(c2ccc(O)cc2)C1
Reactant: COC(=O)C1CC(=O)N(c2ccc(OCc3c(F)cc(F)cc3F)cc2)C1
Agent: Fc1cc(F)c(CBr)c(F)c1
Product: CN
Product: CNC(=O)C1CC(=O)N(c2ccc(OCc3c(F)cc(F)cc3F)cc2)C1

Procedure:
The title compound is prepared by alkylation of the (RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester with 2,4,6-trifluorobenzyl bromide giving the (RS)-5-oxo-1-[4-(2,4,6-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid methyl ester which, thereupon, by treatment with methylamine yields the (RS)-5-oxo-1-[4-(2,4,6-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid methylamide. Yield: 97% of theory as a white solid. MS: m/e=379 (M+H)+.
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.[NH2:13][C@@H:14]1[C:32](=[O:33])[N:16]2[C:17]([C:29]([OH:31])=[O:30])=[C:18]([CH:21]([S:23][C:24]3[NH:28][N:27]=[N:26][N:25]=3)[CH3:22])[CH2:19][S:20][C@H:15]12>CO>[C:2]1([CH:12]([O:30][C:29]([C:17]2[N:16]3[C:32](=[O:33])[C@@H:14]([NH2:13])[C@H:15]3[S:20][CH2:19][C:18]=2[CH:21]([S:23][C:24]2[NH:25][N:26]=[N:27][N:28]=2)[CH3:22])=[O:31])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.09 g of p-toluenesulphonic acid monohydrate are added to a suspension of 5.0 g of 7β-amino-3-(1-methyl-5-tetrazolylthiomethyl)-3-cephem-4-carboxylic acid (U.S. Pat. No. 3,516,997) in 200 ml of methanol, whilst stirring; this slowly produces a clear solution, which is concentrated under reduced pressure. Diethyl ether is added and the p-toluenesulphonic acid salt of 7β-amino-3-(1-methyl-5-tetrazolylthiomethyl)-3-cephem-4carboxylic acid is filtered off. The salt is dissolved in 100 ml of dioxane and 2.5 g of diphenyldiazomethane are added in portions to the solution. The mixture is stirred for 18 hours at room temperature and concentrated under reduced pressure; 100 ml of an 0.1 N aqueous sodium bicarbonate solution are added to the residue and the mixture is extracted with twice 100 ml of ethyl acetate. The organic extracts are washed successively with water and with a saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. The crystallisation from diethyl ether gives 7β-amino-3-(1-methyl-5-tetrazolylthiomethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester, thin layer chromatogram (silica gel): Rf=0.21 (system: chloroform/ethyl acetate/acetic acid, 80:19:1); ultraviolet absorption spectrum (ethanol): λmax =269 mμ (ε=6,400); infrared absorption spectrum (in methylene chloride); characteristic bands at 2.93μ, 5.60μ and 6.15μ.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31].C(=O)(O)[O-].[Na+]>CN(C=O)C.C1COCC1>[Cl:21][C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:29](=[O:32])[CH:30]=[CH2:31])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]#[N:13])[CH:20]=[CH:19][CH:18]=1
Reactant: C=CC(=O)Cl
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Cl)c3)c2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 39.3 %

Procedure:
Dissolved 430 mg (1.46 mmol) 6-amino-4-[(3-chlorophenyl)amino]-3-quinolinecarbonitrile in 4 ml DMF, added 10 ml THF and chilled to 0° C. under N2. Added 224 μl (1.60 mmol) triethylamine and 133 μl (1.60 mmol) acryloyl chloride. Removed ice bath at 15 minutes, reaction complete at this time, but stirred overnight at 25° C. Stripped solvent, added a dilute sodium bicarbonate to the residue and collected solids. Washed with water and dried in vacuo. Boiled in ethyl acetate, collected solids and dried in vacuo, giving 200 mg of orange solid: mass spectrum (electrospray m/e): M+H=349.0, 351.0.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:15][CH2:14][CH2:13][CH2:12][N:5]1[CH:6]=[N:7][C:8]2[C:4]1=[N:3][CH:2]=[N:1][C:9]=2[NH2:10]
Reactant: Nc1ncnc2nc[nH]c12
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2CCCCl
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of adenine, 1-bromo-3-chloropropane, and potassium carbonate in DMF was stirred at room temperature under argon for 4 days, filtered and evaporated to dryness. The crude product was washed with water and dried. Recrystallization from ethanol gave 9-(3-chloropropyl)adenine.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH2:11][CH2:12][CH2:13][CH3:14])=[N:8][O:9][CH:10]=1)=[O:5])C.O.[OH-].[Li+].CO.Cl>C1COCC1.O>[CH2:11]([C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:10][O:9][N:8]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCc1nocc1C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCCc1nocc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To a suspension of (E and/or Z)-3-butyl-isoxazole-4-carboxylic acid ethyl ester (10.0 g, 51 mmol) in THF (100 mL) was added a solution of lithium hydroxide monohydrate (4.25 g, 101 mmol) in water (100 mL) and then methanol (100 mL) added and the resulting mixture stirred at room temperature for 1 h. The mixture was acidified to pH 1 with HCl (2 N) and the resulting mixture extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulphate, filtered and evaporated to afford the title compound (8.33 g, 97%) which was obtained as an off white solid. MS: m/e=168.1 [M−H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][CH:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20].Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])[C:25]([Cl:41])=[CH:24][N:23]=1>>[Cl:41][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])=[N:27][C:22]([NH:20][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH:12]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH2:11][CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:23][CH:24]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1c(N)ccc2c1CCCC(N1CCOCC1)C2
Product: COc1c(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n2)ccc2c1CCCC(N1CCOCC1)C2

Procedure:
The title compound was prepared from 1-methoxy-6-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (50 mg, 0.2 mmol) and 2-(2,5-dichloropyrimidin-4-ylamino)-N,N-dimethylbenzenesulfonamide (70 mg, 0.2 mmol) in an analogous manner to Example 936 to afford an off white foam (81 mg, 80%). Mp: 171-4° C. LCMS (m/e) 587 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 9.42 (s, 1H), 8.57 (d, J=8 Hz, 1H), 8.17 (s, 1H), 8.02 (d, J=8 Hz, 1H), 7.90 (d, J=8 Hz, 1H), 7.63 (m, 1H), 7.50 (s, 1H), 7.29 (m, 1H), 6.88 (d, J=8 Hz, 1H), 3.74 (s, 7H), 3.23 (m, 1H), 2.89 (m, 2H), 2.77 (s, 6H), 2.70 (m, 2H), 2.60 (m, 2H), 2.41 (m, 2H), 2.12 (d. J=1 Hz, 2H), 1.77 (m, 1H), 1.36 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:10]([NH:17][CH2:18][CH2:19][CH2:20][NH2:21])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[C:13]([O:12][C:10](=[O:11])[NH:17][CH2:18][CH2:19][CH2:20][NH:21][C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCNc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of 6.1 g (26.6 mmol) of 5-bromo-2,4-dichloro-pyrimidine in 100 ml of acetonitrile is mixed successively with 5.0 g (28.7 mmol) of N-boc-1,3-diaminopropane and 4.5 ml (32.4 mmol) of triethylamine and stirred for 3.5 hours at room temperature. The batch is diluted with 200 ml of ethyl acetate. It is washed with saturated NaCl solution, citric acid (10%), saturated NaHCO3 solution as well as saturated NaCl solution. The combined organic phases are dried (Na2SO4), filtered and concentrated by evaporation. 9.7 g (26.6 mmol, corresponding to 100% of theory) of the product is obtained.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][CH2:19][C:20]2[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=2[C:22]([OH:24])=[O:23])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][C:30](=[CH2:32])[CH3:31].S(=O)(=O)(O)O>C(Cl)Cl>[C:1]1([CH2:7][O:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][CH2:19][C:20]2[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=2[C:22]([O:24][C:30]([CH3:32])([CH3:31])[CH3:29])=[O:23])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccccc1CCc1ccccc1C(=O)O)OCc1ccccc1
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccccc1CCc1ccccc1NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 31 %

Procedure:
A solution of 2-[2-(2-(phenylmethoxycarbonylamino)phenyl)ethyl]benzoic acid (5.2 g, 0.014 mol) in methylene chloride (100 mL) was treated with isobutylene (15 mL) and sulfuric acid (0.14 mL) and stirred at room temperature. Isobutylene was added over the period of several days until the reaction was complete. The reaction mixture was washed with 5% aqueous sodium carbonate and with water. The organic phase was dried with magnesium sulfate and concentrated in vacuo to give an oil which was purified by chromatography (silica gel, hexane:ethyl acetate 95:5) to give t-butyl 2-[2-(2-(phenylmethoxycarbonylamino)phenyl)-ethyl]-benzoate (1.8 g, 31%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[C:3]=1[CH2:10][OH:11].C([Cu])#N.CN([CH:18]=[O:19])C.O>C(Cl)Cl>[Cl:9][C:4]1[C:3]2[CH2:10][O:11][C:18](=[O:19])[C:2]=2[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: OCc1c(Br)ccc(O)c1Cl
Reactant: CN(C)C=O
Agent: N#C[Cu]
Solvent: O
Solvent: ClCCl
Product: O=C1OCc2c1ccc(O)c2Cl
Temperature: 145 °C
Reaction time: 24 h

Procedure:
To a flask charged with 4-bromo-2-chloro-3-(hydroxymethyl)phenol (2.44 g, 10.3 mmol) and a stir bar was added CuCN (2.76 g, 30.8 mmol) and DMF (25 mL). The flask was fitted with a condenser and purged three times with Nitrogen. The solution was then heated to 145° C. for 2 hours. At that point, water (0.555 mL, 30.8 mmol) was added to the reaction via a syringe, and the reaction was kept at 100° C. for another 24 hours. The reaction was cooled to RT, diluted with DCM (100 mL), and filtered through a pad of celite to remove the solids. The filtrate was washed with saturated NH4OAc, dried over sodium sulfate, concentrated and purified by silica gel flash chromatography. 4-Chloro-5-hydroxy-2-benzofuran-1(3H)-one was collected after removal of solvents.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[CH2:10][C:9](=O)[NH:8][CH2:7]1)C.O.[OH-].[Na+]>C1COCC1.ClCCl>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([C:6]2([CH2:5][CH2:4][OH:3])[CH2:10][CH2:9][NH:8][CH2:7]2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: CCOC(=O)CC1(c2ccc(OC)c(OC)c2)CNC(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(C2(CCO)CCNC2)cc1OC

Procedure:
Combined LiA1H4 (4.80 g, 127 mmol, 4 eq) and anhydrous THF (200 mL). Added portionwise, a slurry of [3-(3,4-dimethoxy-phenyl)-5-oxo-pyrrolidin-3-yl]-acetic acid ethyl ester (9.72 g, 31.6 mmol) in THF (100 mL). After the addition was complete, the reaction was heated at reflux overnight. Cooled in an ice/NaCl bath. Cautiously added H2O (4.8 mL), NaOH (4.8 mL, 15%), and H2O (19.2 mL). Filtered. Concentrated the filtrate to obtain a residue. Dissolved the residue in dichloromethane and dried over MgSO4, filtered, and concentrated the filtrate in vacuo to obtain a residue which was dried at 0.05 Torr overnight to give the title compound. This material was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6][CH:5]=1.[CH3:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].O>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[CH3:12])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccc(NC(=O)c2ccccc2C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
To a solution of 6-aminonicotinic acid methyl ester (4 g) in pyridine (40 ml) is added with stirring 2-methylbenzoyl chloride (6.73 g) under ice-cooling, and the mixture is stirred at room temperature overnight. To the reaction solution is added water, and the precipitated crystals are collected by filtration, and dried to give 6-(2-methylbenzoylamino)nicotinic acid methyl ester (5.7 g) as white powder.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([F:11])[CH:4]=1.[CH3:12][S:13]([C:16]1[CH:42]=[CH:41][C:19]([CH2:20][NH:21][C:22]([C:24]2[C:29](=[O:30])[C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]([F:39])[F:38])[CH:32]=3)=[C:27]([CH3:40])[NH:26][CH:25]=2)=[O:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>>[CH3:12][S:13]([C:16]1[CH:17]=[CH:18][C:19]([CH2:20][NH:21][C:22]([C:24]2[C:29](=[O:30])[C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]([F:38])[F:39])[CH:32]=3)=[C:27]([CH3:40])[N:26]([CH2:2][C:3]3[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([F:11])[CH:4]=3)[CH:25]=2)=[O:23])=[CH:41][CH:42]=1)(=[O:15])=[O:14]
Reactant: Cc1[nH]cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)c1-c1cccc(C(F)F)c1
Reactant: N#Cc1ccc(CBr)cc1F
Product: Cc1c(-c2cccc(C(F)F)c2)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cn1Cc1ccc(C#N)c(F)c1

Procedure:
Example 39 is prepared as described for example 2.1, substituting benzyl bromide with 4-bromomethyl-2-fluoro-benzonitrile and substituting preparation 5 with preparation 39a. ESI mass spectrum: [M+H]+=580; Retention time HPLC: 1.03 min (Z018_S04).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[C:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)=[O:15].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:9]=[C:8]2[C:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)=[O:15]
Reactant: COc1ccc2[nH]cc(C(=O)c3cccc4ccccc34)c2c1
Reactant: CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCn1cc(C(=O)c2cccc3ccccc23)c2cc(OC)ccc21
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (1.54 g, 45 7 mmol, 60% in mineral oil) in DMF (100 ml) under nitrogen was added dropwise a solution of 5-methoxy-3-(1-naphthoyl)-1H-indole 4 (9.83 g, 32.6 mmol) in DMF (50 ml) and the mixture was stirred at 40° C. for 1 h. The solution was then cooled to room temperature and to this mixture was added a solution of 1-bromopentane (8.2 g, 54.3 mmol) in DMF (25 ml). The mixture was stirred at 60° C. for 1 h. The solvent was removed under high vacuum and the crude product was suspended in water (200 ml) and extracted by ethyl acetate (2×200 ml). The combined ethyl acetate phases were washed by water (1×100 ml), brine (1×100 ml), dried over sodium sulphate, filtered and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane/ethyl acetate (7/3) to give the title compound 5 as an oil which solidified upon cooling (7.1 g, 59%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]1.[Cl:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([Cl:42])[C:28]=1[OH:43].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:26].[Cl:26][C:27]1[CH:32]=[C:31]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:17][CH2:18][C@H:19]([CH2:22][N:23]([CH3:24])[CH3:25])[CH2:20][CH2:21]2)[CH:30]=[C:29]([Cl:42])[C:28]=1[OH:43]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure II, 1-(6-chloro-4-{trans-4-[(dimethylamino)methyl]cyclohexylamino}-1,5-naphthyridin-3-yl)ethanone (153 mg, 0.42 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (180 mg, 0.63 mmol) followed by formation of the dihydrochloride salt to afford the desired product (164 mg, 69%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 9.15 (s, 1H), 8.46 (d, J=9.0 Hz, 1H), 8.33 (d, J=9.0 Hz, 1H), 8.12 (s, 2H), 5.76-5.71 (m, 1H), 3.09 (d, J=6.6 Hz, 2H), 2.76 (s, 3H), 2.50-2.40 (m, 2H), 2.08-1.98 (m, 3H), 1.74-1.64 (m, 2H), 1.47-1.37 (m, 2H); ESI MS m/z 493 [M+H]+; HPLC>99% (AUC), tR=9.83 min.
Reaction SMILES: [N+](=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[NH:5][C:4]1=[O:13])=[N-].[I:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH:23]([CH3:25])[CH3:24])=[CH2:22])=[CH:17][CH:16]=1>C1C=CC=CC=1.C1COCC1>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4](=[O:13])[C@:3]12[CH2:22][C@:21]1([C:18]1[CH:17]=[CH:16][C:15]([I:14])=[CH:20][CH:19]=1)[CH:23]([CH3:25])[CH3:24]
Reactant: [N-]=[N+]=C1C(=O)Nc2ccc(F)cc21
Reactant: C=C(c1ccc(I)cc1)C(C)C
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CC(C)[C@@]1(c2ccc(I)cc2)C[C@@]12C(=O)Nc1ccc(F)cc12
Temperature: 80 °C
Yield: 105.9 %

Procedure:
The 3-diazo-5-fluoroindolin-2-one (0.177 g, 1 mmol) and Rh(OAc)2 dimer (2.2 mg) were placed into a Schlenk tube under Argon atmosphere, then dissolved in dry benzene (3 mL). The mixture was heated to 80° C. for 10 minutes. The 1-iodo-4-(3-methylbut-1-en-2-yl)benzene (0.544 g) was dissolved in dry THF (2 mL) and added into the mixture in one portion. The mixture was concentrated in vacuo, the residue was purified by flash column chromatography (Petroleum ether: AcOEt=5:1) to give the title compound as white powder (0.446 g, 53%). LC/MS m/e calcd. for C19H17FINO: 421, observed (M+H)+: 422.1.
Reaction SMILES: C([O:4][C:5]1[CH2:9][C@H:8]([C@@:10]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14](=[O:15])[O:13][C@H:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[O:11]2)[CH2:7][CH:6]=1)(=O)C.C[N+]1([O-])CC[O:30]CC1.S([O-])([O-])=O.[Na+].[Na+]>C(#N)C.O.C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[C:16]([C@H:12]1[O:13][C:14](=[O:15])[C@@:10]([C@H:8]2[CH2:7][C:6](=[O:30])[C@H:5]([OH:4])[CH2:9]2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[O:11]1)([CH3:17])([CH3:18])[CH3:19]
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(=O)OC1=CC[C@@H]([C@]2(c3ccccc3)O[C@@H](C(C)(C)C)OC2=O)C1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[C@H]1OC(=O)[C@](c2ccccc2)([C@H]2CC(=O)[C@H](O)C2)O1
Reaction time: 3 h
Yield: 20.5 %

Procedure:
To a solution of 169 mg of (4R)-4-((2R,4R)-2-(t-butyl)-5-oxo-4-phenyl-1,3-dioxolan-4-yl)-1-cyclopentenyl acetate in 7.5 ml of acetonitrile and water (2:1), 80 mg of N-methyl morpholine-oxide and 0.2 ml of 2% aqueous osmium tetraoxide solution were successively added at 0° C. by the order stated, followed by 3 hours' stirring at the same temperature. Sodium sulfite was added to the reaction liquid and stirred for further 30 minutes. The reaction liquid was then diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the residue obtained was purified on silica gel column chromatography (eluent: hexane−hexane/ethyl acetate=2/1) to provide 32 mg of the title compound as a colorless solid.
Reaction SMILES: [Br:1][C@H:2]1[C@H:7]([OH:8])[C:6]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:5]=2[O:4][C:3]1([CH3:16])[CH3:15].C(Cl)CCl.[N+:21]([C:24]1[CH:25]=[C:26]([CH:36]=[C:37]([N+:39]([O-:41])=[O:40])[CH:38]=1)[C:27]([S:29][CH2:30][C@H:31]([CH3:35])[C:32](Cl)=[O:33])=[O:28])([O-:23])=[O:22]>N1C=CC=CC=1>[Br:1][C@H:2]1[C@H:7]([O:8][C:32](=[O:33])[C@H:31]([CH3:35])[CH2:30][S:29][C:27](=[O:28])[C:26]2[CH:36]=[C:37]([N+:39]([O-:41])=[O:40])[CH:38]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=2)[C:6]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:5]=2[O:4][C:3]1([CH3:16])[CH3:15]
Reactant: C[C@@H](CSC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)C(=O)Cl
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](O)[C@@H]1Br
Solvent: ClCCCl
Solvent: c1ccncc1
Product: C[C@H](CSC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)C(=O)O[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.1 %

Procedure:
To a mixture of 14.5 g of (±)-trans-3-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-4-hydroxy-2H-1-benzopyran, 60 ml of ethylene chloride and 1.6 ml of pyridine was added 5.5 g of (S)-(-)-3-(3,5-dinitrobenzoylthio)-2-methylpropionyl chloride under ice-cooling and was stirred for 1.5 hours under room temperature. The reaction mixture was washed with diluted hydrochloric acid once and 10% aqueous sodium chloride solution twice. The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure to give 8.9 g of (±)-trans-3-bromo-6-cyano 3,4-dihydro-2,2-dimethyl-4-[(S)-(-)-3-(3,5-dinitrobenzoylthio)-2-methylpropionyloxy]-2H-1benzopyran as light yellow semicrystals.