Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[N:13]1[CH:18]=[CH:17][C:16]([NH:19][CH3:20])=[CH:15][CH:14]=1>>[CH3:12][C:4]1[N:3]=[C:2]([N:19]([C:16]2[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=2)[CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1nc(Cl)c2ccccc2n1
Reactant: CNc1ccncc1
Product: Cc1nc(N(C)c2ccncc2)c2ccccc2n1

Procedure:
The title compound was prepared from 4-chloro-2-methyl-quinazoline (0.178 g, 2.13 mmol) and (pyridin-4-yl)-methyl-amine (0.108 g, 1.84 mmol) by a procedure similar to examples 125c (0.224 g, 49%). 1H NMR (CDCl3): 8.39 (m, 2H), 7.91 (d, J=8.4, 1H), 7.73 (ddd, J=1.2, 6.6, 8.4, 1H), 7.41 (m, 1H), 7.23-7.29 (m, 1H), 6.79-6.82 (m, 2H), 3.70 (s, 3H), 2.83 (s, 3H).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]2[CH:7]=[C:6](/[C:16](=[CH:20]\[CH:21]3[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]3)/[C:17](O)=[O:18])[CH:5]=[CH:4][C:3]1=2.[CH3:29][N:30]1[CH:34]=[CH:33][C:32]([NH2:35])=[N:31]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1>CN(C)C=O.C(OCC)(=O)C>[O:28]=[S:2]1(=[O:1])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]2[CH:7]=[C:6](/[C:16](=[CH:20]\[CH:21]3[CH2:22][CH2:23][C:24](=[O:27])[CH2:25][CH2:26]3)/[C:17]([NH:35][C:32]3[CH:33]=[CH:34][N:30]([CH3:29])[N:31]=3)=[O:18])[CH:5]=[CH:4][C:3]1=2
Reactant: Cn1ccc(N)n1
Reactant: O=C1CCC(/C=C(/C(=O)O)c2ccc3c(c2)Nc2ccccc2S3(=O)=O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc(NC(=O)/C(=C/C2CCC(=O)CC2)c2ccc3c(c2)Nc2ccccc2S3(=O)=O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
276 mg of (E)-2-(5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-3-(4-oxocyclohexyl)acrylic acid, 101 mg of commercial 1-methyl-1H-pyrazol-3-ylamine and 0.61 ml of N,N-diisopropylethylamine are dissolved in 10 ml of dimethylformamide. 318 mg of HATU and 114 mg of HOAT are added, and the mixture stirred at room temperature for two hours. The reaction mixture is then diluted by addition of 100 ml of ethyl acetate and washed five times with in each case 30 ml of water. The organic phase is dried over MgSO4, and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane (100%)=>:ethyl acetate (100%). This gives 134 mg of (E)-2-(5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(4-oxocyclohexyl)acrylamide.
Reaction SMILES: C1(O[C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)C=CC=CC=1.[CH2:17]([CH2:19][NH2:20])[OH:18]>C(Cl)(Cl)Cl>[OH:18][CH2:17][CH2:19][NH:20][C:8](=[O:16])[C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1
Reactant: O=C(Oc1ccccc1)c1ccc(O)cc1
Reactant: NCCO
Solvent: ClC(Cl)Cl
Product: O=C(NCCO)c1ccc(O)cc1
Temperature: 150 °C
Yield: 95 %

Procedure:
A mixture of 128.40g (.60 moles) of phenyl-4-hydroxybenzoate and 36.97g 606 moles) of ethanolamine was heated to 150° C. while stirring under a nitrogen atmosphere. After 2 hours at 150° C. the amber melt was cooled to ~150° C. and then poured into 1000 ml of chloroform. Within a few minutes a solid yellow precipitate formed. The precipitate was isolated by vacuum filtration washed with fresh chloroform and then air dried. This material was identified by NMR and IR spectroscopy as N-(2-hydroxyethyl)-p-hydroxybenzamide. A 95% yield was obtained.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.C(N(CC)CC)C.[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27])#[N:19]>C(Cl)Cl>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:18]#[N:19])(=[O:28])=[O:27])[N:3]=1
Reactant: Brc1n[nH]c2ccccc12
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccccc1S(=O)(=O)n1nc(Br)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To a solution of 3-bromo-1H-indazole (200 mg, 1.02 mmol) in 2 ml CH2Cl2 was added triethylamine (308 mg, 3.05 mmol) and 2-cyanobenzene-1-sulfonyl chloride (205 mg, 1.02 mmol). The reaction mixture was stirred overnight at room temperature. After completion the reaction mixture was concentrated under reduced pressure and the product was purified on SiO2 using 0% to 50% ethyl acetate in heptane as the eluent to give 3-bromo-1-(2-cyanophenylsulfonyl)-1H-indazole (360 mg) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[NH:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=1.[C:16](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:16][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[NH:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1cccc2ccc(O)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc2cccc(NC(C)=O)c2c1
Temperature: 25 °C
Yield: 86.1 %

Procedure:
To a mixture of N-(7-hydroxynaphthyl)acetamide (175.4 g, 0.872 mol), potassium carbonate (301 g, 2.18 mol), and acetone (1 l) was added iodomethane (270 mL, 4.36 mol). The reaction mixture was refluxed for 6 hr, cooled to room temperature, and the solvent removed. The residue was filtered through silica with ethyl acetate and triturated with ethyl acetate to yield 161.6 g (86%) of a gray solid. An analytical sample was further purified by preparative reverse phase HPLC to yield the title compound as a white solid: mp 154-155° C.; 1H NMR (DMSO-d6): δ 2.19 (3H, s), 3.90 (3H, s), 7.19 (1H, dd, J=2.39 Hz, J=8.94 Hz), 7.29-7.34 (2H, m), 7.39 (1H; d, J=1.86 Hz), 7.75-7.68 (2H, m), 7.87 (1H, d, J=8.96 Hz), 9.82 (1H, s); MS (ESI) m/z 216 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:30](COCC[Si](C)(C)C)[C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:22][CH:23]=3)[C:15]=2[CH:14]=1.C(N)CN.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[NH:30][C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:21]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[N:22][CH:23]=3)[C:15]=2[CH:14]=1
Reactant: COc1ccc2c(c1)c(-c1cc3c(ncc4cnc(-c5ccccc5)n43)n1COCC[Si](C)(C)C)cn2C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: NCCN
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4cnc(-c5ccccc5)n43)[nH]1)cn2C
Temperature: 90 °C
Yield: 9.9 %

Procedure:
7-(5-Methoxy-1-methyl-1H-indol-3-yl)-1-phenyl-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.054 g, 0.103 mmol) in DMF (3 mL) was treated with ethylenediamine (0.207 ml, 3.09 mmol) and TBAF (1 M in THF, 0.412 mL, 0.412 mmol). The solution was heated to about 90° C. for about 70 min. The mixture was cooled to ambient temperature and the mixture was diluted with EtOAc (10 mL), washed with water (6 mL), dried over anhydrous MgSO4, filtered, and concentrated to give a yellow residue. The residue was purified by silica gel chromatography eluting with 1-6% MeOH/DCM to provide a yellow solid. The solid was triturated with heptane (2 mL) to provide 7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-phenyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.004 g, 10%): LC/MS (Table 2, Method a) Rt=2.26 min; MS m/z: 394 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1/[CH:4]=[N:5]/[NH:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([CH3:14])[N:8]=1.O.O.O.NCl.O>CCO>[Cl:13][C:11]1[CH:10]=[C:9]([CH3:14])[N:8]2[C:4]([C:3]3[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=3[Cl:1])=[N:5][N:6]=[C:7]2[CH:12]=1
Reactant: Cc1cc(Cl)cc(N/N=C/c2ccccc2Cl)n1
Agent: NCl
Solvent: CCO
Solvent: O
Product: Cc1cc(Cl)cc2nnc(-c3ccccc3Cl)n12
Temperature: 80 °C

Procedure:
A mixture of (E)-1-(2-chlorobenzylidene)-2-(4-chloro-6-methylpyridin-2-yl)hydrazine (0.247 g, 0.882 mmol) and chloramine trihydrate (0.273 g, 0.970 mmol) in 7 mL of EtOH was heated at 80° C. for 2 h. After cooling to RT, water was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 1.05 g of crude material. The crude material was purified by silica gel chromatography (50-75% EtOAc in hexanes) to afford 7-chloro-3-(2-chlorophenyl)-5-methyl-[1,2,4]triazolo[4,3-a]pyridine as an off white solid. MS (ESI, pos. ion) m/z: 278.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:6](=[O:17])[NH:5][C:4](=[O:18])[C:3]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:27](Cl)(=O)[C:28]([CH3:31])([CH3:30])[CH3:29]>N1C=CC=CC=1>[CH2:20]([N:19]1[C:3]2[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=3)[C:2]=2[N:1]=[C:27]1[C:28]([CH3:31])([CH3:30])[CH3:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccc(Cn2c(N)c(NCc3ccccc3)c(=O)[nH]c2=O)cc1
Solvent: c1ccncc1
Product: COc1ccc(Cn2c(=O)[nH]c(=O)c3c2nc(C(C)(C)C)n3Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.5 %

Procedure:
Compound C4 (10.2 g, 29.0 mmol) was dissolved in pyridine (10 mL), to the solution was added pivaloyl chloride (3.50 mL, 30.5 mmol, 1.1 equivalents), and then the mixture was stirred at room temperature for 24 hours. After the reaction solution was concentrated, ethyl acetate was added to the resulting residue, and the deposited solid (7.51 g, 59%) was collected by filtration. The resulting solid was dissolved in 2 mol/L aqueous sodium hydroxide (50 mL), the mixture was refluxed with heating for 1 hour, and the reaction mixture was adjusted to pH 6 with 4 mol/L hydrochloric acid under ice cooling. The deposited solid was collected by filtration and dried under reduced pressure to obtain the title compound (6.61 g, 92%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.F[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(-n2cncn2)cc1
Temperature: 90 °C
Yield: 73.2 %

Procedure:
1,2,4-Triazole (0.82 g, 0.01 mol), ethyl 4-fluorobenzoate (2 g, 0.01 mol) and anhydrous potassium carbonate (1.43 g, 0.01 mol) was dissolved in DMSO (30 ml) and heated to 90° C. for 18 h. The solution was poured into water (50 ml), extracted with ethyl acetate (50 ml), dried (sodium sulphate), filtered and evaporated to dryness under reduced pressure. The white solid was purified by flash column chromatography (silica, diethyl ether) to afford a white solid (1.59 g, 73%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].CS(O[CH:13]1[CH2:30][CH2:29][C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:15][CH2:14]1)(=O)=O>CN(C=O)C.O>[N:1]1([CH:13]2[CH2:30][CH2:29][C:16]3([CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:20][CH2:21]3)[CH2:15][CH2:14]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(OS(C)(=O)=O)CC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CCC(n3ccnc3)CC2)CC1
Reaction time: 0.33 h
Yield: 59 %

Procedure:
Imidazole (1.17 g, 17.3 mmol, 3.0 eq.) was added to a stirred suspension of NaH (20.16 mmol, 3.5 eq.) in DMF (10 ml) at 0° C. and the reaction mixture was allowed to stir at the same temperature for 20 min. A solution of tert-butyl 9-(methylsulfonyloxy)-3-azaspiro[5.5]undecane-3-carboxylate (2.0 g, 5.76 mmol, 1.0 eq.) in DMF (5 ml) was added to the reaction mixture at 0° C. and it was stirred at RT for 16 h. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (60 ml) and dried over sodium sulfate. The solvent was evaporated under reduced pressure to obtain the crude product which was purified by column chromatography (silica gel; 3% MeOH/MC) to yield the desired product as a colorless oil. Yield: 59% (1.10 g, 3.45 mmol).
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:8]=[CH:7][S:6][CH:5]=1.C([Li])CCC.[CH3:15][CH:16]([CH3:25])[C:17]([C:19]1[CH:20]=[N:21][CH:22]=[N:23][CH:24]=1)=[O:18]>O1CCCC1>[OH:18][C:17]([C:19]1[CH:24]=[N:23][CH:22]=[N:21][CH:20]=1)([CH:16]([CH3:25])[CH3:15])[C:2]#[C:3][C:4]1[CH:8]=[CH:7][S:6][CH:5]=1
Reactant: CC(C)C(=O)c1cncnc1
Reactant: BrC(Br)=Cc1ccsc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)C(O)(C#Cc1ccsc1)c1cncnc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the product of Stage (1) (0.22 g, 0.82 mmol) in dry tetrahydrofuran (15 ml) at --78° C. under nitrogen was slowly added n-butyl lithium (2.5 M in hexane; 0.8 ml, 2 mmol). After stirring for one hour at --78° C., the reaction mixture was allowed to warm to room temperature before 2-methyl-1-pyrimidin-5-ylpropan-1-one (0.2 g, 1.3 mmol) was added. After 20 minutes, the reaction was quenched by addition of water, and the product was extracted with ether (2×20ml). The combined organic extracts were washed with water, dried over sodium sulphate, filtered, and concentrated under reduced pressure to give an oil which was chromatographed on silica. Elution with ethyl acetate - hexane (1:1) gave the desired product as a yellow oil which solidified slowly on standing to give a solid of melting point 102-105° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[CH2:13]([O:15][C:16]([Sn](CCCC)(CCCC)CCCC)=[CH2:17])[CH3:14]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:16]([O:15][C:13]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1)=[CH2:14])[CH3:17]
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: C=C(OCC)c1nc(OC)ccc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 4 h

Procedure:
To a suspension of 2-chloro-6-methoxy-3-nitropyridine (600 g) and PdCl2(PPh3)2 (33.5 g) in acetonitrile (4200 ml) at 65° C. under N2 was added dropwise over 2 h (1-ethoxyvinyl)-tributyl-stannane (1182 ml). The resulting suspension was stirred at 65° C. for 4 h then left to cool to room temperature overnight. The reaction mixture was quenched with 10% KF aqueous solution (3600 ml) with vigorous stirring and stirred for 1 h. The resulting solid was removed by vacuum filtration and washed with acetonitrile (7×1000 ml). The layers were separated and the organic layer was evaporated to 3000 ml. This was filtered through Whatman, GF/B glass microfibre filter paper and the small amount of brown solid removed was washed with MeCN (1800 ml). EtOAc (3600 ml) was added and the volume reduced to 1800 ml. Cyclohexane (3600 ml) was added and the volume reduced to 3000 ml. Cyclohexane (2400 ml) and silica gel (600 g, 1 wt) were added and allowed to stir at room temperature for 1.5 h. The solid was removed by vacuum filtration and washed with EtOAc/cyclohexane, 1:8 (4200 ml). The filtrate was reduced to 1800 ml. Cyclohexane (2400 ml) was added and the volume reduced to 1800 ml. Cyclohexane (3600 ml) and EtOAc (600 ml) and silica gel (600 g, 1 wt) were added and stirred for 1.5 h. The solid was removed by vacuum filtration and washed with EtOAc/cyclohexane 1:8 (4200 ml). The solvents were evaporated to dryness. MeCN (2000 ml) was added and evaporated to give an orange coloured oil.
Reaction SMILES: [CH2:1]1[S:5][C@@H:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]N2C(=O)C(S([O-])(=O)=O)CC2=O)=[O:11])[C@H:3]2[NH:24][C:25]([NH:27][C@@H:2]12)=[O:26].[Na+].[NH2:29][C:30]1[CH:31]=[C:32]([B:36]([OH:38])[OH:37])[CH:33]=[CH:34][CH:35]=1>>[OH:12][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][C@H:4]1[C@@H:3]2[C@@H:2]([NH:27][C:25]([NH:24]2)=[O:26])[CH2:1][S:5]1)=[O:11].[NH2:29][C:30]1[CH:31]=[C:32]([B:36]([OH:38])[OH:37])[CH:33]=[CH:34][CH:35]=1
Reactant: O=C1N[C@H]2[C@H](CS[C@H]2CCCCC(=O)ON2C(=O)CC(S(=O)(=O)[O-])C2=O)N1
Agent: Nc1cccc(B(O)O)c1
Agent: [Na+]
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21

Procedure:
The reaction scheme is illustrated in FIG. 6. FIG. 7 shows IR spectra of the reactants sulfo-NHS-biotin (top) and m-aminophenylboronic acid (middle), and the non-purified reaction mixture after stirring (bottom), comprising the reaction product (i.e. the compound with formula (II)). The bottom spectrum shows an additional vibration at about 1685 cm-1 (indicated with an arrow in FIG. 7) which can be attributed to the amide bond formed between biotin and m-aminophenylboronic acid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[S:68][C:67]([C:69]#[N:70])=[CH:66][CH:65]=1>>[C:69]([C:67]1[S:68][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][CH:66]=1)#[N:70]
Reactant: N#Cc1ccc(N)s1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)s2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Yield: 40.4 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.3 g, 0.52 mmol), was reacted with diisopropylethylamine (0.34 g, 2.6 mmol), diphenylphosphinic chloride (0.37 g, 1.6 mmol), then reacted with 5-amino-thiophene-2-carbonitrile prepared in Example 186 (0.11 g, 0.85 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (5-cyano-thiophen-2-yl)-amide as a white solid (Yield 0.12 g, 37%).
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[N:10]=[CH:11][N:12]4[C:18]=3[CH2:17][NH:16][C:15](=O)[C:14]3[CH:20]=[C:21]([Br:24])[CH:22]=[CH:23][C:13]4=3)[O:6][N:5]=2)[CH2:3][CH2:2]1.CN(C)C1C=CC(C)=CC=1.P(Cl)(Cl)([Cl:37])=O>ClC1C=CC=CC=1>[Cl:37][C:15]1[C:14]2[CH:20]=[C:21]([Br:24])[CH:22]=[CH:23][C:13]=2[N:12]2[C:18]([CH2:17][N:16]=1)=[C:9]([C:7]1[O:6][N:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[N:8]=1)[N:10]=[CH:11]2
Reactant: O=C1NCc2c(-c3nc(C4CC4)no3)ncn2-c2ccc(Br)cc21
Reactant: O=P(Cl)(Cl)Cl
Solvent: Clc1ccccc1
Solvent: Cc1ccc(N(C)C)cc1
Product: ClC1=NCc2c(-c3nc(C4CC4)no3)ncn2-c2ccc(Br)cc21

Procedure:
3(-3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-8-bromo-4,5-dihydro-2,5,10b-triaza-benzo[e]azulene-6-one (1.1 g, 20.3 mmol) and N,N-dimethyl-p-toluidine (881 μL, 6.1 mmol) were mixed in chlorobenzene (8 mL) under Argon. Phosphorus oxychloride (279 μL, 3.1 mmol) was then added at room temperature and the resulting mixture heated under reflux for 2.5 h. After cooling, the mixture was evaporated and then extracted with CH2Cl2 (50 mL) and water (25 mL). The organic layer was separated, dried (Na2SO4) and evaporated. Chromatography on silica gel eluting with CH2Cl2: Acetone (30:1). Yield: 550 mg (67%). m/z 403/405 (M—H−).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=2)O1.Br[C:24]1[CH:36]=[CH:35][C:27]2[S:28][C:29]([C:31]([O:33][CH3:34])=[O:32])=[CH:30][C:26]=2[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+]>COCCOC.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>[CH3:34][O:33][C:31]([C:29]1[S:28][C:27]2[CH:35]=[CH:36][C:24]([C:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH:14]=3)=[CH:25][C:26]=2[CH:30]=1)=[O:32]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COC(=O)c1cc2cc(Br)ccc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Product: COC(=O)c1cc2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)ccc2s1
Yield: 165.9 %

Procedure:
1.1 g of tert-butyl 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (purity 70%), 0.7 g of methyl 5-bromobenzo[b]thiophene-2-carboxylate, 0.15 g of PalladiumTetrakis (PdP(Ph3)4), 5.5 ml of 2M sodium carbonate solution and 0.42 g of lithium chloride are placed in 30 ml of DME in a round-bottomed flask under a stream of nitrogen. The mixture is heated at the reflux temperature for 3 hours. The solvent is evaporated off and the residue is dissolved in 35 ml of ethyl acetate. This solution is washed with 2M sodium carbonate solution. The organic phase is dried over Na2SO4, filtered and evaporated under vacuum. 1.6 g of an oily material are isolated, and this material is purified by flash chromatography on a Biotage® column, using 98/2 cyclohexane/ethyl acetate as eluent. 0.45 g of a yellowish solid is isolated.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[OH-].[CH2:13]([N+:17]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>O>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([O-:1])=[CH:3][CH:4]=1)=[O:7].[CH2:26]([N+:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:27][CH2:28][CH3:29]
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O
Product: COC(=O)c1ccc([O-])cc1
Temperature: 60 °C

Procedure:
A glass flask with reflux condenser, heatable oil bath, mechanical stirrer and internal thermometer was charged at room temperature with 38.00 g of methyl 4-hydroxybenzoate and 277.92 g of water and these components were stirred together thoroughly. Subsequently 162.00 g of tetrabutylammonium hydroxide (40% strength in water) were added and the reaction mixture was heated to 60° C. It was stirred at 60° C. for one hour (the contents of the flask become clear). Then the reaction mixture was cooled and the water was distilled off under reduced pressure, 20 mbar, at 30-45° C. The product was then washed with butyl acetate and dried at 80° C. and 10 mbar in a vacuum drying cabinet. This gave a white solid.