Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10](=[N:12][OH:13])[CH3:11].[H-].[Na+].[C:16]([NH:23][CH2:24][CH2:25][CH2:26]Cl)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CN(C)C=O>[C:11]1([C:10](=[N:12][O:13][CH2:26][CH2:25][CH2:24][NH:23][C:16](=[O:17])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:2]2[NH:1][C:5]3=[CH:6][N:7]=[CH:8][CH:9]=[C:4]3[CH:3]=2)[CH:11]=[CH:10][CH:2]=[CH:3][CH:4]=1
Reactant: CC(=NO)c1cc2ccncc2[nH]1
Reactant: CC(C)(C)OC(=O)NCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCON=C(c1ccccc1)c1cc2ccncc2[nH]1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
A mixture of 1-(1H-pyrrolo[2,3-c]pyridin-2-yl)ethanone oxime (Example 72) (100 mg, 0.42 mmol) and sodium hydride (18 mg of a 60% in mineral oil, 0.45 mmol) in N,N-dimethylformamide (4 mL) was stirred for 0.5 h. N-Boc chloropropylamine (86 mg, 0.44 mmol) was added dropwise and the reaction mixture was heated at 60° C. for 3 h. After stirring at room temperature for 12 h, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate, and concentrated to an oil. Purification by Biotage chromatography (30 to 100% ethyl acetate in hexanes) produced tert-butyl 3-[[[phenyl (1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]propylcarbamate (76 mg, 46%) as a white solid: mp 52-58° C.; ESI MS m/z 395 [C22H26N4O3+H]+; HPLC (Method A) 98.6% (AUC), tR=19.2 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[NH:10][C:5]2=[CH:4][CH:3]=1.[C:14]([O-:17])([O-])=O.[Cs+].[Cs+].[C:20]([Si:24]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45]Cl)[CH:40]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[Si:24]([O:17][CH2:14][C:43]1[CH:44]=[C:39]([CH:40]=[CH:41][CH:42]=1)[CH2:38][N:10]1[C:5]2[C:6](=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:8]=[C:9]1[C:11]([O:13][CH2:45][C:41]1[CH:42]=[CH:43][CH:44]=[C:39]([CH2:38][O:37][Si:24]([C:20]([CH3:23])([CH3:21])[CH3:22])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:40]=1)=[O:12])([C:20]([CH3:23])([CH3:21])[CH3:22])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)[Si](OCc1cccc(CCl)c1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cc2nc(Cl)ccc2[nH]1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCc1cccc(COC(=O)c2cc3nc(Cl)ccc3n2Cc2cccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)c1)(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
5-Chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (0.803 g, 4.08 mmol, from Example 99, Step 1) in DMF (20 mL) was treated with Cs2CO3 (4.0 g, 12 mmol), followed by the addition of tert-butyl{[3-(chloromethyl)benzyl]oxy}diphenylsilane (3.9 g, 9.9 mmol, from Step 2). After stirring overnight, the crude reaction mixture was partitioned between water and ethyl acetate and the aqueous layer was extracted with an additional two portions of ethyl acetate. The combined organic extracts were washed sequentially with water and brine, dried over sodium sulfate, filtered and concentrated. The product was purified by flash chromatography, eluting with a slow gradient from 0-20% EtOAc/hexanes. Yield: (2.18 g, 58%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:18]([O:21][C:22]1N=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:20])[CH3:19].N1C=CC=C[CH:33]=1>ClCCl>[Cl:8][C:6]1[CH:7]=[C:2]([NH:1][S:28]([C:25]2[CH:26]=[CH:33][C:22]([O:21][CH:18]([CH3:20])[CH3:19])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[C:3]([C:9](=[O:10])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[N:4][CH:5]=1
Reactant: Nc1cc(Cl)cnc1C(=O)c1cccc(F)c1
Reactant: c1ccncc1
Reactant: CC(C)Oc1ccc(S(=O)(=O)Cl)cn1
Solvent: ClCCl
Product: CC(C)Oc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2cccc(F)c2)cc1
Reaction time: 15 h
Yield: 26 %

Procedure:
A 25 mL round-bottom flask was charged with (3-amino-5-chloropyridin-2-yl)(3-fluorophenyl)methanone (130 mg, 0.52 mmol), 6-isopropoxypyridine-3-sulfonyl chloride (130 mg, 0.55 mmol), pyridine (2 mL) and dichloromethane (2 mL). The resultant solution was heated to 70° C. and stirred for 15 h. The pyridine was removed in vacuo and THF (5 mL) and 4.0 N NaOH (2 mL) were added. The mixture was stirred at 60° C. for 24 h. The solvent was subsequently removed in vacuo and the residue was diluted with water (5 mL) and the pH was adjusted to 6-7 with 10% HCl. The resultant aqueous solution was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified through automated normal-phase chromatography to afford N-(5-chloro-2-(3-fluorobenzoyl)pyridin-3-yl)-4-isopropoxybenzenesulfonamide (60 mg, 26%): 1H NMR (400 MHz, CDCl3) δ 10.62 (s, 1H), 8.58 (d, 1H), 8.32 (d, 1H), 8.18 (d, 1H), 7.86 (dd, 1H), 7.60 (dd, 1H), 7.52 (dt, 1H), 7.40 (m, 1H), 7.30 (dd, 1H), 6.60 (d, 1H), 5.30 (sep, 1H), 1.30 (d, 1H); MS (ES) (M++2H) expect 250.0. found 250.1.
Reaction SMILES: Cl[CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([NH:22][C:23]([NH2:25])=[S:24])[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]1>C(O)C.O1CCOCC1>[S:24]1[C:3]2[CH2:4][CH2:5][CH2:6][C:2]=2[N:25]=[C:23]1[NH:22][C:12]1[CH:13]=[CH:14][C:15]([N:16]2[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]2)=[C:10]([O:9][CH3:8])[CH:11]=1
Reactant: O=C1CCCC1Cl
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Solvent: CCO
Solvent: C1COCCO1
Product: COc1cc(Nc2nc3c(s2)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 1 step e) from 40 mg (0.33 mmol) 2-chlorocyclopentanone and 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea in ethanol (1.5 ml) and dioxane (1.5 ml). The crude product was purified on silica gel with methylene chloride/methanol 19/1 yielding 41 mg (42%) (5,6-dihydro-4H-cyclopentathiazol-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a light yellow solid. MS ISP (m/e): 327.3 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.25 (s, 1H), 7.64 (s, 1H), 7.44 (s, 1H), 7.32 (d, 1H), 7.23 (d, 1H), 7.01 (s, 1H), 3.78 (s, 3H), 2.78 (br t, 2H), 2.67 (br t, 2H), 2.35 (m, 2H), 2.14 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[O:14])[NH:12][N:11]3[C:15](=[O:26])[N:16]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:17]=[C:10]3[C:9]=2[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[CH:4][CH:3]=1.[F:34][C:35]([F:45])([F:44])[C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:34][C:35]([F:44])([F:45])[C:36]1[CH:43]=[CH:42][C:39]([CH2:40][N:12]2[C:13](=[O:14])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[C:9]([C:27]3[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=3)[C:10]3=[N:17][N:16]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:15](=[O:26])[N:11]23)=[CH:38][CH:37]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: C[Si](C)(C)CCOCn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c(=O)[nH]n2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c(=O)n(Cc3ccc(C(F)(F)F)cc3)n2c1=O
Temperature: 80 °C
Yield: 109.9 %

Procedure:
The solution of 7,8-bis(4-chlorophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazine-3,6(2H,5H)-dione, (112 mg, 0.22 mmol), prepared as described in example 6B, 4-(trifluoromethyl)benzyl bromide (58 mg, 0.24 mmol), K2CO3 (91 mg, 0.66 mmol) in DMF (2 ml), was heated at 80° C. for 0.75 hour. After this time, the solution was cooled to RT and diluted with ethyl acetate. The resulting solution was washed with water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound, 5-(4-(trifluoromethyl)benzyl)-7,8-bis(4-chlorophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazine-3,6(2H,5H)-dione, (160 mg).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[H-].[Na+].[NH2:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12](F)[C:9]=1[C:10]#[N:11].[O:17]1CCOCC1>>[NH2:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([O:2][CH2:1][CH2:3][NH2:4])[C:9]=1[C:10]([NH2:11])=[O:17]
Reactant: N#Cc1c(N)cccc1F
Reactant: NCCO
Reactant: C1COCCO1
Agent: [H-]
Agent: [Na+]
Product: NCCOc1cccc(N)c1C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
444 μl (7.4 mmol) ethanolamine are dissolved in 4 ml 1,4-dioxane, combined with 312 mg (7.8 mmol) sodium hydride and stirred for 30 min at ambient temperature. 1 g (7.4 mmol) 2-amino-6-fluorobenzonitrile are metered into this reaction mixture and it is stirred for 6 days at ambient temperature. Then the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier material used is silica gel and the eluant used is dichloromethane to which 10% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:21]2[CH2:22][CH2:23][N:18]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:19][CH2:20]2)=[O:8])=[CH:9][CH:10]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Nc1ccc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1ccc(C(=O)N2CCN(Cc3ccccc3)CC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
To a stirred solution of 6-aminonicotinic acid (1 g, 7.24 mmol) in dimethylformamide (50 mL) was added 1-benzylpiperazine (1.258 mL, 1.276 g, 7.24 mmol), triethylamine (2.018 mL, 1.465 g, 14.48 mmol), 1-hydroxybenzotriazole hydrate (1.109 g, 7.24 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.388 g, 7.24 mmol). After being stirred overnight at room temperature the reaction mixture was concentrated under vacuum. Purification by silica chromatography (eluting with 5% methanol/dichloromethane) gave the title compound (1.8 g).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:4].[C:12]1([C@@H:18]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:19]([O:21][C@@H:22]2[CH:27]3[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]3)[CH2:23]2)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCOC(C)=O>[Cl-:1].[O:4]=[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH2:2][N+:24]12[CH2:25][CH2:26][CH:27]([CH2:28][CH2:29]1)[C@@H:22]([O:21][C:19](=[O:20])[C@@H:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:23]2
Reactant: O=C(CCl)Nc1ccccn1
Reactant: O=C(O[C@H]1CN2CCC1CC2)[C@H](Nc1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)[C@H](Nc1ccccc1)c1ccccc1)C2)Nc1ccccn1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
2-Chloro-N-(pyridin-2-yl)acetamide (30.4 mg, 0.18 mmol) was added to a solution of (R)—((R)-quinuclidin-3-yl) 2-phenyl-2-(phenylamino)acetate (diastereomer 1 of I2) (60 mg, 0.18 mmol) in EtOAc (2 ml). The reaction mixture was stirred at room temperature overnight (UPLC-MS: complete conversion). The solvent was evaporated, and the crude rodcut was triturated with Et2O (2 ml). The product was further purified by preparative HPLC to obtain (R)-1-(2-oxo-2-(pyridin-2-ylamino)ethyl)-3-((R)-2-phenyl-2-(phenylamino)acetoxy)-1-azoniabicyclo[2.2.2]octane chloride (34.5 mg, 38.2% yield).
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([C:31]([F:34])([F:33])[F:32])[C:24]([N:26]([CH:28]([CH3:30])[CH3:29])[CH3:27])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].[NH2:40][CH2:41][CH:42]1[CH2:44][CH2:43]1>ClCCl.CN(C=O)C>[CH:42]1([CH2:41][NH:40][CH2:2][C:3]2[N:7]([C:8]3[CH:9]=[C:10]([C:14]4[CH2:20][C:19](=[O:21])[NH:18][C:17]5[CH:22]=[C:23]([C:31]([F:32])([F:33])[F:34])[C:24]([N:26]([CH:28]([CH3:29])[CH3:30])[CH3:27])=[CH:25][C:16]=5[N:15]=4)[CH:11]=[CH:12][CH:13]=3)[N:6]=[N:5][CH:4]=2)[CH2:44][CH2:43]1
Reactant: CC(C)N(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Reactant: NCC1CC1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)N(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CNCC3CC3)c1)=N2

Procedure:
The title compound was prepared from 4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isopropyl-methyl-amino)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 119) (210 mg, 0.44 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with aminomethyl-cyclopropane in DMF according to the method described in Example 45. Obtained as a light brown solid (110 mg, 47%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][CH:15]([C:17]([OH:19])=O)[N:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]2=[O:26])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH3:27][C:28]1[C:29]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[N:30][CH:31]=[CH:32][CH:33]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][CH:15]([C:17]([N:37]3[CH2:38][CH2:39][N:34]([C:29]4[C:28]([CH3:27])=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:35][CH2:36]3)=[O:19])[N:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]2=[O:26])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(S(=O)(=O)N2CC(C(=O)O)N(c3ccccc3)C2=O)c1
Reactant: Cc1cccnc1N1CCNCC1
Product: COc1cccc(S(=O)(=O)N2CC(C(=O)N3CCN(c4ncccc4C)CC3)N(c3ccccc3)C2=O)c1

Procedure:
In analogy to example 1, (RS)-1-(3-methoxy-benzenesulfonyl)-2-oxo-3-phenyl-imidazolidine-4-carboxylic acid (step 4 of example 1) was reacted with 1-(3-methyl-pyridin-2-yl)piperazine to give the title compound as a colorless solid. MS: 536.2 ([M+H]+)
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[S:9]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10]1.N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[C:1]([Si:5]([CH3:7])([CH3:6])[O:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][S:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OCCc1ccsc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCc1ccsc1
Reaction time: 16 h

Procedure:
tert-Butylchlorodimethylsilane (3.88 g) was added to a stirred solution of 2-(thiophen-3-yl)ethanol (3.00 g) and 1H-imidazole (4.78 g) in DMF (30 mL) cooled in ice bath. After 16 h, the reaction mixture was diluted with ethyl acetate (300 mL), washed with water (3×150 mL) and evaporated in vacuo. Purification was by silica gel chromatography eluting with isohexane and then 1:5 ethyl acetate:isohexane, to collect the subtitled compound as an oil. Yield 5.2 g.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O>[OH:12][C:6]1[CH:11]=[CH:10][C:9]([CH:2]([OH:3])[C:1]([OH:5])=[O:4])=[CH:8][CH:7]=1
Reactant: Oc1ccccc1
Reactant: O=CC(=O)O
Solvent: O
Product: O=C(O)C(O)c1ccc(O)cc1

Procedure:
condensing glyoxylic acid with phenol at a temperature of 15°-80° C. in the absence of a strong mineral base and in the presence of a tertiary amine, said tertiary amine being insoluble or slightly soluble in water and being liquid at ambient temperature, and said glyoxylic acid being in aqueous solution at a concentration greater than 50% by weight, to produce parahydroxymandelic acid, and
Reaction SMILES: Cl[C:2]([C:4]1[C:5](Cl)=[C:6]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:7]([O:9][CH3:10])=[O:8])=[O:3].[ClH:16].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([CH2:22][O:23][NH2:24])=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([CH2:22][O:23][NH:24][C:12]2[CH:13]([Cl:14])[C:4](=[C:2]=[O:3])[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:11]=2[Cl:16])=[CH:20][CH:19]=1
Reactant: NOCc1ccc(Cl)cc1
Reactant: Cl
Reactant: COC(=O)c1ccc(Cl)c(C(=O)Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1=CC(=C=O)C(Cl)C(NOCc2ccc(Cl)cc2)=C1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 122.2 %

Procedure:
10.70 g (0.04 mol) of methyl 3-chlorocarbonyl-2,4-dichloro-benzoate in 50 ml of methylene chloride were slowly added dropwise at approximately 30° C. to a solution of 7.76 g (0.04 mol) of 4-chlorobenzyloxyamine hydrochloride and 4.05 g (0.04 mol) of triethylamine in 200 ml of methylene chloride. After the reaction mixture had been stirred for 12 hours at room temperature, it was washed with dilute phosphoric acid, dried and concentrated. After the residue had been extracted by stirring with diethyl ether, 19.00 g of methyl 3-(4-chlorobenzyloxy)amino-carbonyl-2,4-dichlorobenzoate were obtained.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[CH3:8][N:9]([CH3:30])[CH:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:29]=2[C:28]2[CH2:27][NH:26][CH2:25][CH2:24][C:23]=2[S:22]3)[CH2:12][CH2:11]1.C(Cl)(=O)C>ClCCl>[CH3:8][N:9]([CH3:30])[CH:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:29]=2[C:28]2[CH2:27][N:26]([C:3](=[O:5])[CH3:2])[CH2:25][CH2:24][C:23]=2[S:22]3)[CH2:12][CH2:11]1
Reactant: O=C(O)C(F)(F)F
Reactant: CN(C)C1CCC(Oc2cccc3sc4c(c23)CNCC4)CC1
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CC(=O)N1CCc2sc3cccc(OC4CCC(N(C)C)CC4)c3c2C1
Reaction time: 2 h

Procedure:
To a solution of N,N-dimethyl-4-[8-thia-4-azatricyclo[7,4,0,0-[2,7]]trideca-1(13),2(7),9,11-tetraen-13-yloxy]cyclohexan-1-amine trifluoroacetate (43 mg) and TEA (50 mg, 0.49 mmol, 3.80 equiv) in 10 mL of dichloromethane at 0° C. was added acetyl chloride (20 mg, 0.25 mmol, 1.96 equiv) at 0° C. The resulting solution was stirred for 2 hours at this temperature under nitrogen. The reaction was then quenched with CH3OH and concentrated under vacuum. The crude product was purified by preparative HPLC under the following conditions (Waters): Column: Xbridge Prep C18, 5 μm, 19*50 mm; mobile phase: water with 0.05% NH4HCO3 and CH3CN (10% CH3CN up to 35% in 11 min, up to 95% in 1.5 min, down to 10% in 1.5 min); flow rate: 20 mL/min; UV detection at 254/220 nm. This resulted in 12.6 mg (26%) of 1-(13-[[4-(dimethylamino)cyclohexyl]oxy]-8-thia-4-azatricyclo[7.4.0.0-[2,7]]trideca-1(13),2(7),9,11-tetraen-4-yl)ethan-1-one as a white solid. MS (ES): m/z 375 (M+H)+. 1H NMR (400 MHz, CD3OD): δ 1.30-1.65 (m, 4H), 1.94 (d, 2H), 2.13 (s, 3H), 2.20-2.32 (m, 9H), 2.81, 2.91 (t, t, 2H, J=5.7 Hz), 3.77, 3.84 (t, t, 2H, J=5.7 Hz), 5.02-5.18 (m, 1H), 8.38, 8.39 (s, s, 1H).
Reaction SMILES: [S:1]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C@@H:22]([C:24]([OH:26])=[O:25])[NH2:23])([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2].C(N1[CH2:34][CH2:33][O:32]CC1)C.C[O:36][CH:37](OC)[C:38]1[CH:43]=C[C:41](C(O)=O)=[CH:40][CH:39]=1.S(N[C@H](C(O)=O)CCCCN)(C1C2C=CC=C(N(C)C)C=2C=CC=1)(=O)=O>CN(C)C=O.C(O)(=O)C>[S:1]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C@@H:22]([C:24]([OH:26])=[O:25])[NH:23][C:33](=[O:32])[C:34]1[CH:41]=[CH:40][CH:39]=[C:38]([CH:37]=[O:36])[CH:43]=1)([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:2])=[O:3]
Reactant: CN(C)c1cccc2c(S(=O)(=O)NCCCC[C@H](N)C(=O)O)cccc12
Reactant: COC(OC)c1ccc(C(=O)O)cc1
Reactant: CCN1CCOCC1
Agent: CN(C)c1cccc2c(S(=O)(=O)N[C@@H](CCCCN)C(=O)O)cccc12
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CN(C)c1cccc2c(S(=O)(=O)NCCCC[C@H](NC(=O)c3cccc(C=O)c3)C(=O)O)cccc12
Reaction time: 4 h

Procedure:
Nε-dansyl-L-lysine (Sigma, 9.5 mg) was dissolved in 100 μl dimethylformamide under gentle warming. N-ethyl-morpholine (3 μl) was added, so that the apparent pH, as judged by spotting onto moist pH paper, was between 8 and 8.5. This solution was mixed with a solution of 7.3 mg of the hydroxysuccinimido ester of 4-carboxybenzaldehyde dimethylacetal in 50 μl dimethylformamide. The apparent pH was checked in the same way as before, and adjusted with N-ethylmorpholine (1 μl at a time) if necessary. After 4 hours and 30 minutes (the apparent pH having been checked from time to time and adjusted if necessary), a similar solution of 7.3 mg of the active ester was added and the reaction allowed to continue for a further 4 hours. The reaction, as judged by t.l.c., was then essentially complete. The t.l.c. system was that described in Example 1(c) and the Rf values were approx. 0.3 and 0.6 for dansyl-lysine and the product, respectively. The mixture was then diluted to 1 ml with acetic acid (1%. v/v), centrifuged, and the supernatant subjected to HPLC (system of Example 4(c)). The major fluorescent peak eluting on the gradient (around 40% acetonitrile) was pooled, and the acetonitrile was driven off in a current of air. The product was characterized by measurement of its electrophoretic mobility at pH 6.5 (predicted and observed, 0.5 [mAsp=1.0]). To this stock solution (600 μl) were added 6 μl M HCl, and the solution was diluted ten-fold with 10−3M HCl. This brought the concentration to 0.7 mM, as judged by direct comparison of the u.v. absorption spectrum with that of a solution of dansyl-lysine of known concentration. It was assumed that the optical density of the dansyl chromophore would be approximately the same in the two substances.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][N:15]=2)[C:8](=[O:24])[CH:7]=1.[Br:30]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>ClCCl>[Br:30][C:7]1[C:8](=[O:24])[N:9]([CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][N:15]=2)[C:10]([CH3:12])=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(Cn2c(C)cc(OCc3ccc(F)cc3F)cc2=O)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl 6-{[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}nicotinate (350 mg, 0.87 mmol) (1.0 g, 2.5 mmol) was added into 150 ml of dichloromethane followed by addition of N-bromo succinimide (500 mg, 2.8 mmol). The solution was stirred at room temperature for 3 hours. Saturated sodium bicarbonate solution (300 ml) was added into the reaction mixture and it was transferred to a separatory funnel. The product was extracted with ethyl acetate (500 ml X2). The combined ethyl acetate solution was dried over anhydrous magnesium sulfate and evaporated to dryness. 1H NMR (400 MHz, CDCl3) δ 9.08 (app d, J=2.15 Hz, 1H), 8.21 (dd, J=6.04, 2.15 Hz, 1H), 7.55 (app qt, J=6.31 Hz, 1H), 7.41 (d, J=6.31 Hz, 1H), 6.91 (m, 1H), 6.84 (m, 1H), 6.02 (s, 1H), 5.42 (s, 2H), 5.19 (s, 2H), 3.91 (s, 3H), 2.45 (s, 3H); LC/MS, tr=2.85 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 479 (M+H). ES-HRMS m/z 479.0415 (M+H calcd for C21H18BrF2N2O4 requires 479.0413).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:16][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccccc1Br
Solvent: ClC(Cl)Cl
Product: CC(C)(C)NS(=O)(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.9 %

Procedure:
To a stirred solution of 2-bromobenzenesulfonyl chloride (Lancaster Synthesis) (2.21 g, 8.65 mmol) in chloroform (40 ml) under nitrogen at room temperature was added tert-butylamine (Aldrich) (2.30 ml, 21.9 mmol). The orange solution was stirred at room temperature for 12 hours, then the mixture evaporated to dryness. Flash chromatography (silica gel, 15% ethyl acetate-hexane) afforded the title compound, (2.12 g, 84%) as a white solid; 1H NMR (300 MHz, CDCl3) δ8.18 (d, J=8.5 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.50-7.35 (m, 2H), 5.11 (s, 1H), 1.20 (s, 9H).