Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6]C)=[CH:4][CH:3]=1.[CH2:10]([N:12](CC)CC)C.[CH3:17][O:18][C:19](=[O:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27]>ClCCl>[NH3:6].[CH3:17][O:18][C:19](=[O:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](=[O:28])(=[O:27])[NH:12][CH2:10][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:9][CH:8]=1
Reactant: CNc1ccc(F)cc1
Reactant: CCN(CC)CC
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NCc1ccc(F)cc1
Product: N
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.6 %

Procedure:
A solution of 4-fluoro-N-methylaniline (0.53 g), triethylamine (0.65 g) and dichloromethane (2.0 mL) was treated with 2-chlorosulfonylbenzoic acid methyl ester (1.0 g), and the resulting mixture was stirred at room temperature for 24 hours. The mixture was partitioned between water and dichloromethane, and the organic phase was washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on SCX-2, eluting with methanol and then 2.0 M ammonia in methanol to afford the title compound as a pale yellow solid (1.2 g).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([O:22]C)=[O:21])=[N:18][CH:19]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=2)[CH2:6][C@@H:5]1[CH3:33])(=[O:3])[CH3:2].O.[OH-].[Li+].C(O)(=O)C>O1CCOCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([OH:22])=[O:21])=[N:18][CH:19]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=2)[CH2:6][C@@H:5]1[CH3:33])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2ccc(C#N)cn2)C[C@H](C)N3C(C)=O)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)O)nc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
Methyl 5-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)picolinate (for a preparation see Intermediate 33)(2.94 g, 6.66 mmol) was dissolved in anhydrous 1,4-dioxane (20 ml). Water (20.0 ml) was added followed by lithium hydroxide (0.319 g, 13.32 mmol) and reaction mixture stirred at r.t. After 1 h, the 1,4-dioxane was removed in vacuo and aqueous residue was treated with acetic acid (1.144 ml, 19.98 mmol). The resulting orange precipitate was stirred for 20 min, isolated by filtration, washed with water and dried under vacuum overnight to give 5-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)picolinic acid (2.16 g, 4.55 mmol, 68.3% yield) as a brown solid. LCMS (Formate, 2 min), Rt=0.68 min, MH+=428.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.[Cu]>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([O:17][C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)=[CH:3][CH:4]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: COc1ccc(Br)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 210 °C
Reaction time: 2 h

Procedure:
A mixture of 4-bromoanisole (35 ml, 0.28 mol), 4-chlorophenol (43 g, 0.33 mol), anhydrous K2CO3 (13 g, 0.09 mol) and copper bronze (0.38 g, 5.98 mmol) were stirred under a nitrogen atmosphere at 210° C. for 2 hours. After cooling to room temperature, the mixture was dissolved in methylene chloride, extracted two times with 1N NaOH, dried (MgSO4) and the solvent removed under reduced pressure to give a brown liquid. Excess 4-bromoanisole was removed by distillation under reduced pressure (60°-73° C., 1 mm) and the residual crystalline solid was purified by HPLC (hexane-methylene chloride). 4-Methoxy-4'-chlorodiphenyl ether was isolated as a white crystalline solid (28.84 g, 44%), mp 49°-51° C.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[CH:7]([C:11]([O:13]CC3C=CC([N+]([O-])=O)=CC=3)=[O:12])[C:8](=O)[CH2:9][C@H:5]12)[CH3:3].[CH3:26][N:27]([CH3:39])[C:28]([C@@H:30]1[CH2:34][C@H:33]([SH:35])[CH2:32][N+:31]1([CH2:37][CH3:38])[CH3:36])=[O:29]>>[CH2:37]([N+:31]1([CH3:36])[CH2:32][C@@H:33]([S:35][C:8]2[CH2:9][C@@H:5]3[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:24](=[O:25])[N:6]3[C:7]=2[C:11]([O-:13])=[O:12])[CH2:34][C@H:30]1[C:28](=[O:29])[N:27]([CH3:26])[CH3:39])[CH3:38]
Reactant: CC[N+]1(C)C[C@@H](S)C[C@H]1C(=O)N(C)C
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Product: CC[N+]1(C)C[C@@H](SC2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)C[C@H]1C(=O)N(C)C
Yield: 10.1 %

Procedure:
Following a procedure similar to that described in Example 6, but using 459 mg of 4-nitrobenzyl (5R, 6S)-6-[(1R)-1-hydroxyethyl]-2-oxo-1-carbapenam-3-carboxylate and 580 mg of the crude (2S, 4S)-2-(N,N-dimethylcarbamoyl)-1-ethyl-1-methyl-4-mercaptopyrrolidinium salt [prepared as described in Example 9-(2)], 55 mg of the title compound were obtained.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH3:7])=[C:2]=[S:3].[CH:8]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(N(CC)CC)C>ClCCl>[CH2:4]([NH:1][C:2]([NH:15][CH:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:3])[CH2:5][CH2:6][CH3:7]
Reactant: NC1CCCCCC1
Reactant: CCCCN=C=S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCNC(=S)NC1CCCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
A solution prepared by dissolving 1-isothiocyanatobutane (3.0 ml, 26.0 mmol) in dichloromethane (5 ml) was slowly added to a solution prepared by dissolving 1-cycloheptylamine (3.3 ml, 26.0 mmol) in dichloromethane (20 ml) at 0° C. for 15 minutes. Triethylamine (7.3 ml, 52.1 mmol) was added to the mixed reaction solution and stirred at room temperature for 2 hours. After confirming completion of the reaction, distilled water (10 ml) was added to the reaction solution, and 1N of an HCl aqueous solution was added to neutralize. After separating an organic layer, a aqueous layer was extracted over dichloromethane (3×20 ml), and the organic layer was dried on sodium sulfate anhydrous, filtered and concentrated. The concentrated organic layer was purified by flash column chromatography (hexane:ethylacetate=3:1), thereby obtaining a target compound as a yellow liquid (4.1 g, 68%). The compound was used in the subsequent reaction.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=1.[C:17]([OH:21])(C)(C)[CH3:18].C(OC(C)C)(C)C>[Zn]>[C:17]([O:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:14][CH:13]=1)(=[O:21])[CH3:18]
Reactant: CC(C)(C)O
Reactant: OCc1ccc(COC2CCCCO2)cc1
Agent: [Zn]
Solvent: CC(C)OC(C)C
Product: CC(=O)OCc1ccc(COC2CCCCO2)cc1
Yield: 92.9 %

Procedure:
Under a nitrogen atmosphere, a mixture of (4-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)methanol (3.0 mmol), t-butanol (3.6 mmol), the zinc cluster obtained in the above-described Example 5 (0.0375 mmol), and diisopropyl ether (5.0 ml) was refluxed for 18 hours. As a result, 4-((tetrahydro-2H-pyran-2-yloxy)methyl)benzyl acetate was obtained in a yield of 92.9%.
Reaction SMILES: [CH3:1][C@:2]12[C:11](=O)[O:10][C:8](=[O:9])[C@@:7]1([CH3:13])[C@H:6]1[O:14][C@@H:3]2[CH2:4][CH2:5]1.[NH2:15]C1SC2C=C(C(O)=O)C=CC=2N=1.C1(C)C=CC=CC=1>C(N(CC)CC)C>[CH3:1][C@:2]12[C:11](=[O:10])[NH:15][C:8](=[O:9])[C@@:7]1([CH3:13])[C@H:6]1[O:14][C@@H:3]2[CH2:4][CH2:5]1
Reactant: C[C@@]12C(=O)OC(=O)[C@]1(C)[C@H]1CC[C@@H]2O1
Reactant: Nc1nc2ccc(C(=O)O)cc2s1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[C@@]12C(=O)NC(=O)[C@]1(C)[C@H]1CC[C@@H]2O1
Temperature: 180 °C

Procedure:
A mixture of cantharidin (50 mg, 0.26 mmol), 2-amino-6-carboxybenzothiazole (294 mg, 1.27 mmol), and a mixture of dried toluene and dried triethylamine (4 mL; 2:1, v/v) may be sealed in a tube and heated for 3 hours at 180° C. The reaction mixture may be concentrated, followed by flash chromatography (dichloromethane:methanol, 10:1) that may give the product CAN039 (51.9 mg, 55%) of formula (3) as a white solid with the following characterization: mp=180-181° C.; Rf=0.27 (hexane:acetone, 2:1); 1H NMR (CD3OD, 500 MHz): δ 1.34 (6H, s), 1.72-1.74 (2H, m), 1.97-2.00 (2H, m), 4.69-4.70 (2H, m), 8.08 (1H, d, J=8.5 Hz), 8.18 (1H, dd, J=8.5 Hz and 1.5 Hz), 8.70-8.71 (1H, m); 13C NMR (CDCl3): δ 12.1, 23.7, 54.6, 85.0, 85.1, 122.5, 123.9, 127.9, 128.3, 132.7, 151.9, 155.3, 168.0, 178.7; MS (EI) m/z (%): 372 (M+); HRMS calcd. for C18H16N2O5S [M]+ found 358.0776.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH2:10]([NH2:13])[CH2:11][CH3:12]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:13][CH2:10][CH2:11][CH3:12])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: CCCN
Solvent: CCO
Product: CCCNc1cc(C)nc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.3 %

Procedure:
Under a nitrogen atmosphere, a solution of 17.0 grams (0.12 mole) of 2-amino-4-chloro-6-methylpyrimidine (commercially available) and 20 mL (0.24 mole) of n-propylamine was stirred, and 25 mL of ethanol was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for one hour. After, this time, the reaction mixture was heated to reflux where it stirred for 2.5 hours. An additional five mL of n-propylamine was added to the reaction mixture, then it was allowed to stir at ambient temperature for about 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 250 mL of 10% methanol in methylene chloride. The cloudy solution was filtered through 300 grams of basic alumina (deactivated with 18 mL of water) using 10% methanol in methylene chloride as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding about 21 grams of 2-amino-4-propylamino-6-methylpyrimidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][CH2:8][C:9]([NH2:12])([CH3:11])[CH3:10])[CH:6]=1.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([OH:33])[CH:28](OCC)O)=[CH:23][C:22]=1[NH:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:37])=[O:36])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BH4-].[Na+].C(O)(=O)C>C(O)C>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([OH:33])[CH2:28][NH:12][C:9]([CH3:10])([CH3:11])[CH2:8][CH2:7][N:5]2[CH:6]=[C:2]([I:1])[N:3]=[CH:4]2)=[CH:23][C:22]=1[NH:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:36])=[O:37])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(N)CCn1cnc(I)c1
Reactant: CCOC(O)C(O)c1ccc(OCc2ccccc2)c(NS(=O)(=O)c2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(CCn1cnc(I)c1)NCC(O)c1ccc(OCc2ccccc2)c(NS(=O)(=O)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
2.1 g (7.7 mmol) of 3-(4-iodimidazol-1-yl)-1,1-dimethyl-propylamine and 3.4 g (7.7 mmol) of N-[2-benzyloxy-5-(2-ethoxy-1,2-dihydroxy-ethyl)-phenyl]-phenylsulphonamide in 25 mL ethanol were refluxed for 18 h. The reaction mixture was cooled to 0° C. and then combined with 0.3 g (7.7 mmol) sodium borohydride. The mixture was stirred for a further 3 h at ambient temperature and then combined with glacial acetic acid. The solvent was removed using the rotary evaporator and the residue was dissolved in 300 mL ethyl acetate/water (1:2). The aqueous phase was made alkaline with conc. ammonia and separated from the organic phase. The organic phase was washed twice with 100 mL water and once with 100 mL of saturated aqueous sodium chloride solution, dried over sodium sulphate and freed from solvent using the rotary evaporator. The residue was purified by flash column chromatography [methylene chloride/methanol/ammonia (90:10:1)]. 3.5 g (5.0 mmol, 69%) N-(2-benzyloxy-5-{1-hydroxy-2-[3-(4-iodo-imidazol-1-yl)-1,1-dimethyl-propylamino]-ethyl}-phenyl)-phenylsulphonamide were obtained as a yellowish solid.
Reaction SMILES: CS(C)=O.C(N(CC)CC)C.Cl.Cl.[NH2:14][CH2:15][CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1.F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1>O>[N+:29]([C:26]1[CH:27]=[CH:28][C:23]([NH:14][CH2:15][CH2:16][C:17]2[NH:21][CH:20]=[N:19][CH:18]=2)=[CH:24][CH:25]=1)([O-:31])=[O:30]
Reactant: NCCc1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=[N+]([O-])c1ccc(NCCc2cnc[nH]2)cc1
Temperature: 80 °C
Reaction time: 10 h
Yield: 89.6 %

Procedure:
100 ml of DMSO were introduced into a 500 ml three-necked flask and treated with 30.9 g of triethylamine, 18.4 g of histamine dihydrochloride and 14.4 g of 1-fluoro-4-nitrobenzene. The mixture was stirred at 80° C. for 10 h, treated with 20 ml of water and stirred at 80° C. for a further 3 h. Following this, the mixture was allowed to cool to room temperature and poured onto 1 l of ice. The resulting precipitate was filtered off with suction and dried in vacuo at 50° C., 20.8 g of crude product being obtained.
Reaction SMILES: C1(N)CCCCC1.[CH:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9].[Na]>CO>[CH:11]1([NH:10][CH:8]=[O:9])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=CNc1ccccc1
Agent: [Na]
Solvent: NC1CCCCC1
Solvent: CO
Product: O=CNC1CCCCC1
Temperature: 100 °C
Yield: 79 %

Procedure:
To the reactor described in Example 1, there is placed 99 grams cyclohexylamine, 14 grams (0.1 mole) of sodium formanilide and 150 grams of methanol. The autoclave is closed and purged with carbon monoxide, the temperature raised to 100° C. with atmospheric steam and carbon monoxide introduced at 28 kg/cm2 for about an hour. The reaction mixture is then cooled and vented, 10 milliliters of concentrated hydrochloric acid is added and the solvent is removed by distillation. Benzene is then added and the benzene solution filtered through a bed of filter acid. Distillation gives N-cyclohexyl formamide, boiling point 118°-130° C. at 3 milliliters. The expected yield is about 79%.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH2:31]([NH2:35])[CH:32]([CH3:34])[CH3:33]>>[ClH:1].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[C@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([NH:35][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:27])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@@H]4CN5CCC4CC5)oc23)c1
Reactant: CC(C)CN
Agent: Cl
Product: CC(C)CNC(=O)c1cccc(-c2cccc3cc(C(=O)N[C@@H]4CN5CCC4CC5)oc23)c1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 153) and 17.1 mg (0.23 mmol) of iso-butylamine are reacted together by general method E. 40.3 mg (71.4% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][P:26]([O:31][CH2:32][CH3:33])(=[O:30])[O:27][CH2:28][CH3:29]>>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[N:12]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][P:26](=[O:30])([O:31][CH2:32][CH3:33])[O:27][CH2:28][CH3:29])[CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c2[nH]cnc2n(CCCC)c1=O
Reactant: CCOP(=O)(CCCCCBr)OCC
Product: CCCCn1c(=O)c2c(ncn2CCCCCP(=O)(OCC)OCC)n(CCCC)c1=O

Procedure:
The title substance was prepared from 1,3-dibutylxanthine and diethyl 5-bromopentanephosphonate analogously to Example 9.
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@@H:26]5[CH2:30][CH2:29][CH2:28][O:27]5)[CH:20]=4)[C:15]3=[O:31])=[CH:10][C:9]=2[O:32][CH3:33])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:34][C:35]1([CH3:38])[CH2:37][O:36]1>>[OH:36][C:35]([CH3:38])([CH3:37])[CH2:34][N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@@H:26]5[CH2:30][CH2:29][CH2:28][O:27]5)[CH:20]=4)[C:15]3=[O:31])=[CH:10][C:9]=2[O:32][CH3:33])[CH2:2][CH2:3]1
Reactant: CC1(C)CO1
Reactant: COc1cc(-n2ccc3cc(OC[C@@H]4CCCO4)ccc3c2=O)ccc1N1CCCNCC1
Product: COc1cc(-n2ccc3cc(OC[C@@H]4CCCO4)ccc3c2=O)ccc1N1CCCN(CC(C)(C)O)CC1

Procedure:
Reaction of 2-(4-[1,4]Diazepan-1-yl-3-methoxy-phenyl)-6-[(S)-1-(tetrahydro-furan-2-yl)methoxy]-2H-isoquinolin-1-one and 2,2-Dimethyl-oxirane by method U resulted in the desired product with the molecular weight 521.66 (C30H39N3O5); MS (ESI): 522 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([C:10]3[C:14]([CH3:15])=[N:13][NH:12][C:11]=3[NH2:16])[S:9][C:5]=2[CH:4]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH3:15][C:14]1[C:10]([C:8]2[S:9][C:5]3[CH:4]=[C:3]([CH2:2][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH:18]=[CH:17][C:6]=3[N:7]=2)=[C:11]([NH2:16])[NH:12][N:13]=1
Reactant: C1COCCN1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(CBr)cc2s1
Product: Cc1n[nH]c(N)c1-c1nc2ccc(CN3CCOCC3)cc2s1

Procedure:
The title compound (27 mg) was prepared starting from 40 mg of 4-(6-bromomethylbenzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine and excess morpholine. MS (m/z, ES+): 330.1 (M+1, 30%), 243 (M-O(CH2)4N, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:17]([OH:19])=O)[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:32][C:33]1[NH:37][N:36]=[N:35][N:34]=1>>[NH:34]1[C:33]([NH:32][C:17]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([C:8]3[CH:9]=[CH:10][C:11]([N:14]([CH3:15])[CH3:16])=[CH:12][CH:13]=3)[N:5]=2)=[O:19])=[N:37][N:36]=[N:35]1
Reactant: Nc1nnn[nH]1
Reactant: Cc1cc(C(=O)O)nc(-c2ccc(N(C)C)cc2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1cc(C(=O)Nc2nnn[nH]2)nc(-c2ccc(N(C)C)cc2)c1
Yield: 19 %

Procedure:
In the same manner as described in Example 1-(1), 4-methyl-6-(4-dimethylaminophenyl)-2-pyridinecarboxylic acid (1.25 g), carbonyldiimidazole (1.38 g) and 5-aminotetrazole (0.47 g) are reacted to give N-(5-tetrazolyl)-4-methyl-6-(4-dimethylaminophenyl)-2-pyridinecarboxamide (0.3 g). M.P. 265°-269° C. (decomp.) (wetted from 255° C.) (recrystallized from dimethylformamide-ethanol)
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C([N:14](CC)CC)C>C1(C)C=CC=CC=1>[C:4]1(=[O:5])[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1](=[O:6])[NH:14]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1NC(=O)c2ccccc21
Temperature: 20 °C

Procedure:
0.8 g of phthalic anhydride and 2 ml of triethylamine were added to a solution of 3 g of the product of Stage B in 30 ml of toluene and then the mixture was heated for 16 hours at reflux. The reaction medium was cooled to 20° C. and washed with 20 ml of N hydrochloric acid. After decanting, washing with water and drying, the solvent was evaporated off to obtain 4.42 g of the expected product which was used as is for the following stage.
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[O:18][CH3:19])([OH:6])[CH2:3]1>CO.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:4]2([OH:6])[CH2:5][C:2]([F:20])([F:1])[CH2:3]2)=[C:10]([O:18][CH3:19])[CH:11]=1
Reactant: COc1cc([N+](=O)[O-])ccc1OCC1(O)CC(F)(F)C1
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)ccc1OCC1(O)CC(F)(F)C1
Reaction time: 1.5 h
Yield: 100 %

Procedure:
A mixture of 3,3-difluoro-1-((2-methoxy-4-nitrophenoxy)methyl)cyclobutanol (32.0 g, 111 mmol) prepared in Part F and 10% Pd/C (2.0 g, 1.879 mmol) in 700 mL MeOH was stirred under H2 at 50 psi for 1.5 h. After filtration, the filtrate was concentrated to give 1-((4-amino-2-methoxyphenoxy)methyl)-3,3-difluorocyclobutanol (28.9 g, 111 mmol, quantitative yield) as a light purple solid. 1H NMR (400 MHz, CD3OD) δ 6.68 (1H, d, J=8.56 Hz), 6.35 (1H, d, J=2.52 Hz), 6.16 (1H, dd, J=8.31, 2.52 Hz), 4.77 (3H, br. s.), 3.78 (2H, s), 3.68 (3H, s), 2.68-2.82 (2H, m), 2.38-2.56 (2H, m).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[C:6](=[C:14]([O:26][CH3:27])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH3:22])=[C:17]([N+:23]([O-])=O)[CH:16]=2)[C:5]1=[O:28])(=[O:3])[CH3:2].[H][H].[CH:31](O)=O>[Ni]>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[C:6](=[C:14]([O:26][CH3:27])[C:15]2[CH:20]=[CH:19][C:18]3[N:21]([CH3:31])[CH:22]=[N:23][C:17]=3[CH:16]=2)[C:5]1=[O:28])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CNc1ccc(C(OC)=C2C(=O)N(C(C)=O)c3cc(F)ccc32)cc1[N+](=O)[O-]
Reactant: O=CO
Agent: [Ni]
Product: COC(=C1C(=O)N(C(C)=O)c2cc(F)ccc21)c1ccc2c(c1)ncn2C

Procedure:
0.40 g of 1-acetyl-6-fluoro-3-[1-methoxy-1-(4-methylamino-3-nitrophenyl)methylene]-2-indolinone are hydrogenated in 5.0 ml formic acid with the addition of 0.20 g of Raney nickel for 3 hours under 50 psi of hydrogen atmosphere. The catalyst is eliminated by suction filtering and the filtrate is evaporated down. The residue is stirred with diethyl ether, then after crystallisation suction filtered and dried.
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5](=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[CH2:22]([O:24][C:25](=[O:30])[CH2:26][C:27](=[NH:29])[NH2:28])[CH3:23]>C(O)C>[CH2:22]([O:24][C:25]([C:26]1[CH:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:4]([OH:3])=[O:21])=[C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:28][C:27]=1[NH2:29])=[O:30])[CH3:23]
Reactant: CCOC(=O)CC(=N)N
Reactant: CCOC(=O)C(=Cc1ccccc1)C(=O)c1ccccc1
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(c2ccccc2)=C(C(=O)O)C1c1ccccc1
Yield: 48 %

Procedure:
Upon boiling a solution of 14.0 g of benzylidenebenzoylacetic acid ethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 150 ml of ethanol for 2 hours, 2-amino-4,6-diphenyl-1,4-dihydropyridine-3,5-dicarboxylic acid ethyl ester of melting point 183°C (ethanol) is obtained.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].Cl[CH2:9][C:10]1[O:14][C:13]([C:15]2[N:16]=[CH:17][N:18]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[C:22](=[O:29])[N:21]4[CH2:30][CH2:31][C@H:20]4[C:19]=23)=[N:12][N:11]=1>CN(C)C=O>[CH2:1]([N:4]([CH2:9][C:10]1[O:14][C:13]([C:15]2[N:16]=[CH:17][N:18]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[C:22](=[O:29])[N:21]4[CH2:30][CH2:31][C@H:20]4[C:19]=23)=[N:12][N:11]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: O=C1c2ccccc2-n2cnc(-c3nnc(CCl)o3)c2[C@@H]2CCN12
Reactant: CCCNCCC
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1nnc(-c2ncn3c2[C@@H]2CCN2C(=O)c2ccccc2-3)o1
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.7 %

Procedure:
0.94 ml (73 mmol) of dipropylamine was added to a solution of 1.17 g (3.42 mmol) of (S)-1-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one in 10 ml of dimethylformamide, whereupon the mixture was stirred at room temperature for 12 hours. The dimethylformamide was evaporated and the residue was partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase was washed twice with methylene chloride and the organic phases were dried with sodium sulfate, filtered and evaporated. Chromatography (silica gel, methylene chloride/methanol 95:5) yielded 0.900 g (65%) of (S)-1-(5-dipropylaminomethyl-1,3,4-oxadiazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a]-[1,4]benzodiazepin-9-one as a colourless foam, Rf=0.46 (silica gel, methylene chloride/methanol 95:5).