Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][C:12]=3[CH:25]=2)=[CH:4][C:3]=1[N+:26]([O-])=O>[Pd].CO>[NH2:26][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:13][C:12]=3[CH:25]=2)[CH:6]=[N:7][C:2]=1[NH2:1]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3cnc(N)c([N+](=O)[O-])c3)cc2C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3cnc(N)c(N)c3)cc2C1
Reaction time: 18 h
Yield: 95.4 %

Procedure:
A mixture of 1,1-dimethylethyl 7-(6-amino-5-nitropyridin-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (0.58 g, 1.5 mmol), palladium (10% on charcoal, 0.50 g) and methanol (30 mL) was hydrogenated in a Parr apparatus at 45 psi for 18 hours. The mixture was filtered then concentrated and dried to give 1,1-dimethylethyl 7-(5,6-diaminopyridin-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (0.51 g, 96% yield), MS (EI) for C19H24N4O3: 357 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Br:18])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2scnc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc2scnc12
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
A solution of 4-Methyl benzothiazole (16.0 g, 107 mmol) in 535 mL of CCl4 was treated with NBS (19.0 g, 107 mmol) and AIBN (2.28 g, 13.9 mmol) at 20° C. and stirred at 70° C. for 2.5 h. The resulting mixture was filtered through Celite washing with Et2O (150 mL) and concentrated in vacuo. The residue was submitted to a silica gel column chromatography with toluene:Et2O=50:3 to 50:5 as eluate to afford 4-bromomethyl benzothiazole as a yellowish solid. (20.4 g, 89.9 mmol, 84%) Rf=0.61 (toluene-Et2O 10:1); 1H NMR (400 MHz, CDCl3) δ 9.07 (1H, s), 7.90 (1H, d, J=7.5 Hz), 7.55 (1H, d, J=7.5 Hz), 7.41 (1H, t, J=7.5 Hz), 5.08 (2H, s); 13C NMR (99.5 MHz, CDCl3) δ 154.1, 151.4, 134.3, 132.6, 127.0, 125.6, 122.3, 29.5.
Reaction SMILES: C([C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([I:13])[C:6]=2[CH:5]=1)(O)=O>N1C2C(=CC=CC=2)C=CC=1.C(OCC)(=O)C.CCOCC.[Cu]>[I:13][C:12]1[C:6]2[CH:5]=[CH:4][S:8][C:7]=2[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)c1cc2c(I)cccc2s1
Agent: [Cu]
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Solvent: CCOCC
Product: Ic1cccc2sccc12
Temperature: 200 °C
Yield: 90.6 %

Procedure:
A mixture of 2-carboxy-4-iodobenzo[b]thiophene (2 g) and copper powder (0.05 g) in quinoline (10 ml) was heated at 200° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (50 ml) and ether (50 ml). The mixture was washed with 5% hydrochloric acid solution (3 times) and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with toluene to afford 4-iodobenzo[b]thiophene (1.55 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[N+:21]([O-])([OH:23])=[O:22].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[C:8]([OH:10])=[O:9])(=[O:3])=[O:4]
Reactant: O=[N+]([O-])O
Reactant: CS(=O)(=O)c1cc(C(=O)O)ccc1Oc1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CS(=O)(=O)c1cc(C(=O)O)ccc1Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
3-Methylsulfonyl-4-(4-nitrophenoxy)benzoic acid was prepared by reacting 0.02 mol of 3-methylsulfonyl-4-phenoxybenzoic acid with 0.96 ml of 100% nitric acid at -10° C. in a mixture composed of 8 ml of acetic anhydride and 4 ml of glacial acetic acid. After the mixture had been stirred at this temperature for 1.5 hours, it was then stirred at room temperature for 24 hours and at 40° C. for a further 6 hours. It was then poured into ice water and the amorphous, oily product was crystallized with water by stirring. Yellow crystalline substance,
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][C:12]([N+:18]([O-])=O)=[C:13]([CH:17]=1)[C:14]([NH2:16])=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S1C=CC=C1>CO.[Pd]>[NH2:18][C:12]1[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:17][C:13]=1[C:14]([NH2:16])=[O:15]
Reactant: NC(=O)c1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: c1ccsc1
Product: NC(=O)c1cc(C(=O)c2ccccc2)ccc1N
Yield: 41 %

Procedure:
A mixture of 7.76 parts of intermediate 14, namely 5-benzoyl-2-nitrobenzamide, 2 parts of a solution of thiophene in methanol 4% and 198 parts of methanol was hydrogenated overnight at normal pressure and at 50° C. with 2 parts of palladium-on-charcoal catalyst 10%. The catalyst was filtered off and washed with tetrahydrofuran. The combined filtrates were evaporated and the residue was co-evaporated with methylbenzene. The residue was purified by column chromatography (silica gel; CHCl3 /CH3OH/CH3OH(NH3) 90:5:5). The eluent of the desired fraction was evaporated and the residue was taken up in methanol. This solution was concentrated and the product was filtered off, washed with methanol and 2,2'-oxybispropane and dried in vacuo at 60° C., yielding 2.84 parts (41.0%) of 2-amino-5-benzoylbenzamide; mp. 225.2° C. (interm. 15).
Reaction SMILES: [ClH:1].C1(C[N:9]2[CH2:14][CH2:13][C:12]([NH:16][C:17](=[O:19])[CH3:18])([CH3:15])[CH2:11][CH2:10]2)C=CC=CC=1.[H][H]>CO.[Pd]>[ClH:1].[CH3:15][C:12]1([NH:16][C:17](=[O:19])[CH3:18])[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1
Reactant: CC(=O)NC1(C)CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(=O)NC1(C)CCNCC1
Yield: 91.2 %

Procedure:
A solution of 19 g of N-[1-(phenylmethyl)-4-methyl-4-piperidinyl]acetamide hydrochloride in 400 ml of methanol was hydrogenated at normal pressure and at room temperature with 5 g of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 11.8 g of N-[4-methyl-4-piperidinyl]acetamide hydrochloride; mp. 230°-233° C. (interm. 3).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[NH2:20][NH2:21]>CCO>[NH:20]([C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1)[NH2:21]
Reactant: NN
Reactant: CN(c1ccccn1)S(=O)(=O)c1ccc(Cl)nc1
Solvent: O
Solvent: CCO
Product: CN(c1ccccn1)S(=O)(=O)c1ccc(NN)nc1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
A solution of 1.4 g (4.9 mmol) of 6-chloro-N-methyl-N-pyridin-2-ylpyridine-3-sulfonamide and 0.96 mL (19.7 mmol) of hydrazine monohydrate in 8 mL of EtOH is heated for 12 hours at 80° C. The precipitate obtained, after cooling to room temperature, is filtered off, washed with 10 mL of EtOH and then dried under vacuum. 0.85 g of 6-hydrazino-N-methyl-N-pyridin-2-ylpyridine-3-sulfonamide is obtained in the form of pale yellow crystals.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br.Br[C:9]1[S:13][C:12]([NH2:14])=[N:11][CH:10]=1.[SH:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]>CN(C=O)C.O>[NH2:14][C:12]1[S:13][C:9]([S:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:10][N:11]=1
Reactant: Nc1ncc(Br)s1
Reactant: COC(=O)CCS
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCSc1cnc(N)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
K2CO3 (14.0 g, 100 mmol) was added to a solution of 5-bromothiazol-2-amine hydrobromide (13.0 g, 50 mmol) in 90 ml of dry DMF at 0° C. under nitrogen. After 0.5 h, methyl 3-sulfanylpropanoate (6.0 g, 50 mmol) was added dropwise to the mixture over the course of 30 min and stirred at ambient temperature for 48 h. Then the mixture was diluted with 500 ml of water and extracted with TBME. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography on silica gel to give the title compound (7.6 g, 70% yield) 1H NMR (400 Mz, CDCl3) δ2.53 (t, 2H), 2.75 (t, 2H), 3.58 (s, 3H), 7.25 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:9][CH:10]([CH2:19][CH3:20])[CH:11]([C:15]([O:17][CH3:18])=[O:16])[C:12](=[O:14])[N:13]=2)[CH:5]=[C:4]([Cl:21])[N:3]=1.[CH3:22][C:23](C)([O-])C.[K+].ICC>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:9][CH:10]([CH2:19][CH3:20])[C:11]([CH2:22][CH3:23])([C:15]([O:17][CH3:18])=[O:16])[C:12](=[O:14])[N:13]=2)[CH:5]=[C:4]([Cl:21])[N:3]=1
Reactant: CCC1NC(c2cc(Cl)nc(Cl)c2)=NC(=O)C1C(=O)OC
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCI
Product: CCC1NC(c2cc(Cl)nc(Cl)c2)=NC(=O)C1(CC)C(=O)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
To 27.0 g (81.8 mmol) of 2-(2,6-dichloro-4-pyridyl)-6-ethyl-5-methoxycarbonyl5,6-dihydropyrimidin-4-one in 500 mL of dimethylformamide was added at 0° C. over 30 min via a solid addition funnel 19.3 g (172 mmol) of potassium-t-butoxide followed by the dropwise addition over 15 min of 13.3 g (85.2 mmol) of iodoethane. The reaction was stirred at 0° C. for one hour before quenching onto 700 mL of ice water. The aqueous was acidified to pH=1 (conc. HCl) and extracted with EtOAc (3×400 mL). The organics were combined before washing with water (2×500 mL), and saturated NaCl (1×300 mL) drying over MgSO4, filtering and evaporating to dryness in vacuo to give 27.32 g (76.3 mmol, 93%) of the desired product as a pale yellow solid with mp=202°-203° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2[CH2:16][CH2:17][CH2:18][CH2:19][C:11]1=2.O.C(OCC)(=O)C.C(OCC)(=O)C>C(O)(=O)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:10](=[O:15])[C:11]3[CH2:19][CH2:18][CH2:17][CH2:16][C:12]=3[C:13]2=[O:14])=[C:4]([F:9])[CH:3]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1ccc(Cl)cc1F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
A mixture of 4-chloro-2-fluoroaniline (19.0 g, 130.6 mmol), and 3,4,5,6-tetrahydrophthalic anhydride (19.85 g, 130.6 mmol) in acetic acid (150 mL) is refluxed for 2 hours, treated with additional 4-chloro-2-fluoroaniline (3.0 g), refluxed for 90 minutes, stirred at room temperature overnight and poured into a water/ethyl acetate mixture. The organic phase is washed sequentially with water, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a purple oil. Flash column chromatography of the oil using silica gel and 15% to 20% ethyl acetate in hexanes solutions gives the title product as an off-white solid (25.3 g, mp 81°-82° C.).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH3:20][NH2:21]>C1COCC1.CCN(C(C)C)C(C)C>[CH3:20][NH:21][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: CN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2N methylamine in THF and DIEA to give 2-methylamino-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 270 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([NH:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:16]1)=[O:13].I[CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:39][CH:38]=2)=[CH:31][CH:30]=1>>[C:40]1([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:39]=[CH:38][C:37]([CH2:36][CH2:35][C:32]2[CH:33]=[CH:34][C:29]([CH2:28][CH2:27][CH2:26][O:1][C:2]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=3[C:12]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:16]3)=[O:13])=[CH:30][CH:31]=2)=[CH:42][CH:41]=1
Reactant: ICCCc1ccc(CCc2ccc(-c3ccccc3)cc2)cc1
Reactant: COC(=O)c1ccc(O)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Product: COC(=O)c1ccc(OCCCc2ccc(CCc3ccc(-c4ccccc4)cc3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1

Procedure:
Preparation takes place in analogy to Example 22 from the (+)-B-enantiomer of methyl 4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate (see Example IX, method 2) and 4-{2-[4-(3-iodopropyl)phenyl]ethyl}biphenyl.
Reaction SMILES: [C:1]1(OB(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[F:24][C:25]([F:54])([F:53])[C:26]1[CH:27]=[C:28]([CH:46]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:48]=1)[CH2:29][N:30]1[CH2:37][CH2:36][CH2:35][NH:34][C:33]2[N:38]=[C:39]([S:43][CH3:44])[N:40]=[C:41](Cl)[C:32]=2[C:31]1=[O:45]>C(OCC)(=O)C.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.O1CCOCC1>[F:24][C:25]([F:54])([F:53])[C:26]1[CH:27]=[C:28]([CH:46]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:48]=1)[CH2:29][N:30]1[CH2:37][CH2:36][CH2:35][NH:34][C:33]2[N:38]=[C:39]([S:43][CH3:44])[N:40]=[C:41]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:32]=2[C:31]1=[O:45]
Reactant: CSc1nc(Cl)c2c(n1)NCCCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C2=O
Reactant: OB(O)Oc1ccccc1
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: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CSc1nc2c(c(-c3ccccc3)n1)C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Yield: 99.7 %

Procedure:
Phenylboric acid (732 mg), tetrakis(triphenylphosphine)palladium (289 mg), toluene (15 ml), 1,4-dioxane (8 ml) and a 2 mol/L aqueous solution of sodium carbonate (15 ml) were added to 6-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-5,6,7,8,9,10-hexahydro-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 7; 2.43 g). While heated, the mixture was refluxed for 5 hours under a stream of argon gas. Subsequently, the reaction mixture was diluted with ethyl acetate, was washed with a 2 mol/L aqueous solution of sodium carbonate, and was then dried over anhydrous sodium sulfate. The solvent was removed and the resulting residue was purified on a silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-2-(methylthio)-5-oxo-4-phenylpyrimido[4,5-b][1,5]diazocine (2.63 g, 100%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1)=[O:39].[C:47]1([N:53]=[C:54]=[O:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][CH2:43][N:42]([C:54]([NH:53][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:55])[CH2:41]1)=[O:39]
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCCNC1
Reactant: O=C=Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCCN(C(=O)Nc2ccccc2)C1
Yield: 42 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-3-carboxamide bis(trifluoroacetate) and phenyl isocyanate as starting materials in 42% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.43 (s, 1H), 9.40 (s, 1H), 9.38 (s, 1H), 8.59 (s, 1H), 8.14 (s, 1H), 8.00 (s, 1H), 7.72 (s, 1H), 7.44 (d, 2H), 7.21 (m, 3H), 7.04 (m, 2H), 6.90 (m, 2H), 4.22 (d, 1H), 4.10 (d, 1H), 2.90 (m, 6H), 2.63 (m, 1H), 2.03 (m, 1H), 1.72 (m, 2H), 1.47 (m, 1H). LCMS for C31H31ClN7O2 (M+H)+: m/z=568.2.
Reaction SMILES: C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[NH2:14][C:15]1[N:23]=[C:22]2[C:18]([NH:19][CH:20]=[N:21]2)=[C:17]([N:24]([CH3:26])[CH3:25])[N:16]=1.[N:27]([C@@H:30]1[C@@H:34]([CH2:35][OH:36])[O:33][C@@H:32](N2C=C(C)C(=O)NC2=O)[CH2:31]1)=[N+:28]=[N-:29]>>[NH2:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[C@@H:32]2[O:33][C@H:34]([CH2:35][OH:36])[C@@H:30]([N:27]=[N+:28]=[N-:29])[CH2:31]2)=[C:17]([N:24]([CH3:26])[CH3:25])[N:16]=1
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CN(C)c1nc(N)nc2nc[nH]c12
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: CN(C)c1nc(N)nc2c1ncn2[C@H]1C[C@H](N=[N+]=[N-])[C@@H](CO)O1
Temperature: 50 °C
Yield: 41 %

Procedure:
To 500 mL of an aqueous pH 6.0, 50 mM citrate buffer, prepared as described in Example 2c, was added 2-amino-6-dimethylaminopurine (0.0891 g, 0.5 mmol) and 3'-azido-3'-deoxythymidine (0.668 g, 2.5 mmol). Solution was achieved by heating the mixture at 50° C. with sonication. A sample was removed as a control. A 24 mL solution of trans-N-deoxyribosylase (Example 2b) at an activity of 1400 units/mL was added. The reaction was heated at 50° C. Seven days later 0.0891 g, 0.5 mmol, of 2-amino-6-dimethylamino purine was added to the reaction. The reaction was terminated after fourteen days. The reaction was heated to 80° C. to precipitate the enzyme and then filtered. The aqueous solution was extracted with ethyl acetate to remove the product. The combined ethyl acetate fractions were dried with magnesium sulfate, filtered, and the solvent was removed in vacuo to give a foam. The foam was chromatographed on 90 g of silica gel eluted with chloroform/methanol (97:3, v/v). Chromatography a second time on silica gel (230-400 mesh) eluted with chloroform/methanol (98:2, v/v) gave pure product. The product containing fractions were combined and the solvents removed in vacuo to give the product as a solid (41% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][N:4]=[CH:3]1.[OH-].[Na+].Cl>C(O)C>[CH3:1][N:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=[CH:3]1
Reactant: CCOC(=O)c1cncn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1cncc1C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.7 %

Procedure:
A mixture of 1.5 g of ethyl 1-methyl-5-imidazolecarboxylate, 5 mL of ethanol and 5 mL of 10% NaOH was stirred at room temperature for 12 h. The mixture was acidified to pH 2 with conc. HCl, diluted with 10 mL of ice water. The precipitated product was collected by filtration in 2 crops. Drying under vacuum gave 843 mg of 1-methyl-5-imidazolecarboxylic acid as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1(C)C=CC=CC=1>[C:1]1([C@@H:7]2[CH2:16][NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cnc3ccccc3n2)cc1
Solvent: Cc1ccccc1
Product: c1ccc([C@@H]2CNc3ccccc3N2)cc1
Temperature: 40 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
To an argon-purged pressure-resistant glass vessel (100 mL) equipped with a magnetic stir bar, RuCl[(R)-daipena][(R)-segphos] (2.0 mg, 1.9 μmol) and KO(t-Bu) (10.3 mg, 0.0918 mmol) were added, and the vessel was purged with argon again. To this vessel, a toluene (0.38 mL) solution containing 2-phenylquinoxaline (39.0 mg, 0.189 mmol) and being degassed by the freeze-pump-thaw technique in advance was added by pressure transfer using a cannula. An operation in which hydrogen was introduced into the pressure-resistant vessel up to 0.8 MPa and then released was repeated 10 times to completely substitute the inside with hydrogen. Then, hydrogen was introduced up to 2.0 MPa, and the vessel was stirred in a water bath at 40° C. for 16 hours. After hydrogen was released, the solution was concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (hexane:ethyl acetate=4:1 to 2:1) to obtain (R)-1,2,3,4-tetrahydro-2-phenylquinoxaline (39.3 mg, 99%). A result of an analysis was conducted by high performance liquid chromatography (column: CHIRALCEL OD-H, mobile phase: hexane:IPA=90:10, 1 mL/min) showed that the optical purity of this product was 96% ee.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:19])[CH:10]([OH:20])[N:9]=1.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:19])[CH:10]([O:20][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([Cl:21])=[CH:23][CH:24]=2)[N:9]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: O=C1Nc2ccccc2C(c2ccccc2F)=NC1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(OC1N=C(c2ccccc2F)c2ccccc2NC1=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 1,3-dihydro-5-(2-fluorophenyl)-3-hydroxy-2H-1,4-benzodiazepin-2-one (610 mg, 2.25 mmole) in 25 ml of methylene chloride was treated with 4-chlorobenzoyl chloride (0.314 ml, 2.48 mmole) at room temperature. 4-Dimethylaminopyridine (303 mg, 2.48 mmole) was added and within minutes the reaction mixture became homogeneous. The reaction mixture was protected from moisture and stirred at room temperature overnight. An additional equivalent each of 4-chlorobenzoyl chloride and 4-dimethylaminopyridine were added and stirring was continued for 8 hours at 40°-45° C. The reaction mixture was diluted to 150 ml with methylene chloride and washed in succession with 10% citric acid solution (3×50 ml), saturated sodium bicarbonate solution (3×50 ml) and brine (50 ml). Rotoevaporation of the dried (MgSO4) organic phase gave a foam which on trituration with ether afforded a beige solid. The mother liquors were concentrated and the residue chromatographed on silica gel (hexane-ethyl acetate, 1:1 v/v) to give the title compound.
Reaction SMILES: [C:1]1([C:7](=O)[C:8]([C:13]#N)=[CH:9][N:10](C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+]([O-])([O-])=O.[OH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH2:32])=[NH2+:31])=[CH:25][CH:24]=1.[OH-].[Na+]>>[C:9]([C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:31][C:30]([NH:29][C:26]2[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][OH:20])=[CH:28][CH:27]=2)=[N:32][CH:13]=1)#[N:10]
Reactant: CN(C)C=C(C#N)C(=O)c1ccccc1
Reactant: NC(=[NH2+])Nc1ccc(CCO)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1cnc(Nc2ccc(CCO)cc2)nc1-c1ccccc1

Procedure:
5-Cyano-4-phenyl-N-[4-(2-hydroxyethyl)phenyl]pyrimidine-2-amine was prepared from 1-phenyl-2-cyano-3-dimethylaminopropen-1-one (4.0 g, 20 mmol), 4-(2-hydroxyethyl)phenyl-guanidinium nitrate (4.24 g,20 mmol) and sodium hydroxide (800 mg, 20.0 mmol) as a yellow solid (3.50 g), m.p. 142-143°. δH (CDCl3) 8.68 (1H, s), 8.03 (2H, dd, J 6.0, 2.0 Hz), 7.66 (1H, bs), 7.59-7.51 (5H, m), 7.23 (2H, m), 3.88 (2H, t, J 6.5 Hz), 2.87 (2H, t, J 6.5 Hz) and 1.62 (2H, bs).