Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[SH:2][C:3]1[NH:7][N:6]=[N:5][CH:4]=1.[OH-].[Na+].[NH2:10][C@@H:11]1[C:39](=[O:40])[N:13]2[C:14]([C:36]([OH:38])=[O:37])=[C:15]([CH2:18]OC(=O)C3C=CC=CC=3C(=O)NC(OCC)=O)[CH2:16][S:17][C@H:12]12.Cl>O.CO>[NH2:10][C@@H:11]1[C:39](=[O:40])[N:13]2[C:14]([C:36]([OH:38])=[O:37])=[C:15]([CH2:18][S:2][C:3]3[NH:7][N:6]=[N:5][CH:4]=3)[CH2:16][S:17][C@H:12]12
Reactant: Sc1cnn[nH]1
Reactant: CCOC(=O)NC(=O)c1ccccc1C(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: O
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3cnn[nH]3)CS[C@H]12
Temperature: 25 °C
Yield: 61.5 %

Procedure:
in water (2 ml) containing sodium salt of 5-mercapto-1H-1,2,3-triazole (120 mg) and sodium hydroxide (40 mg) is dissolved under ice cooling 7β-amino-3-[2-(N-carboethoxycarbamoyl)benzoyloxy]methyl-3-cephem-4-carboxylic acid (450 mg) and to the mixture is added diluted hydrochloric acid to adjust its pH to 5.5 under stirring, followed by further stirring for one hour at 60° C. To the solution, is added methanol (5 ml) and the mixture is allowed to cool to the room temperature. The cooled mixture is adjusted its pH to 3.9 by adding diluted hydrochloric acid under stirring and the resultant mixture is further stirred for one hour under ice-cooling. The precipitate is collected by filtration and washed with water and methanol in this order and then dried over phosphorus pentoxide. The procedure provides 7β-amino-3-(1H-1,2,3-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (193 mg).
Reaction SMILES: NS(C1C=CC(NC2SC(C#N)=C(N)N=2)=CC=1)(=O)=O.S.[NH2:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]2[S:33][C:34]([C:38](=[S:40])[NH2:39])=[C:35]([NH2:37])[N:36]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23].Br[CH2:42][C:43]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=O>C(N(CC)CC)C.N1C=CC=CC=1.CO>[NH2:37][C:35]1[N:36]=[C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([S:22]([NH2:21])(=[O:24])=[O:23])=[CH:26][CH:27]=2)[S:33][C:34]=1[C:38]1[S:40][CH:42]=[C:43]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[N:39]=1
Reactant: NC(=S)c1sc(Nc2ccc(S(N)(=O)=O)cc2)nc1N
Reactant: O=C(CBr)c1ccccc1
Agent: N#Cc1sc(Nc2ccc(S(N)(=O)=O)cc2)nc1N
Agent: S
Solvent: CO
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Nc1nc(Nc2ccc(S(N)(=O)=O)cc2)sc1-c1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-aminosulfonylphenyl)amino-4-amino-thiazole-5-carbonitrile (0.59 g, 2 mmol) in 20% triethylamine/pyridine (50 ml) was bubbled H2S gas at ice-water temperature for 30 minutes. Then the reaction solution was sealed and stirred at room temperature overnight. Argon gas was bubbled through the reaction solution for 60 minutes to replace the H2S, and then the solvents were removed at reduced pressure. The residue was dissolved in EtOAc, and the EtOAc solution was then washed with 5% citric acid (50 ml×3) followed by brine. The solvent was removed in vacuo and the residue was triturated in Et2O. The product 2-(4-aminosulfonylphenyl)amino-4-amino-thiazole-5-carbothioamide was collected by filtration (0.56 g, 95%). To prepare the title compound, a solution of 2-(4-aminosulfonylphenyl)amino-4-amino-thiazole-5-carbothioamide (164 mg, 0.5 mmol) and α-bromoacetophenone (110 mg, 0.55 mmol) in MeOH (20 ml) was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in EtOAc (50 ml). The EtOAc solution was washed with saturated NaHCO3 (10 ml), followed by brine. Purification of the residue by silica gel chromatography provided 4-(4′-amino-4-phenyl-[2,5′]bithiazolyl-2′-ylamino)-benzenesulfonamide. Mp 233-235° C. (decomp.). 1H NMR (CD3OD): δ7.96 (s, 1H), 7.82 (s, 4H), 7.44-7.25 (m, 4H). ESIMS (MH+): 430; (M−H−): 428.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[CH:10][CH:11]=1.[Li+].[CH3:24][CH:25]([N-]C(C)C)C.CCI>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]([CH2:24][CH3:25])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)Cc1cccc(OCc2c(C)cccc2C)c1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCI
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(CC)c1cccc(OCc2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred solution of Ethyl 3-(2,6-dimethylbenzyloxy)phenylacetate (Step B, 4.84 g, 16.2 mmol) in dry THF (60 ml) and HMPA (15 ml) at −78° C. under a dry argon atmosphere was added LDA drop wise (2 M solution in THF, 25 ml, 48.72 mmol), and the resulting orange solution was stirred at low temperature for 30 minutes before CH3CH2I (10.13 g, 64.96 mmol) was added. The reaction mixture was slowly warmed to room temperature and stirred for 15 hours. The reaction was quenched with aqueous citric acid, and the product was extracted with EtOAc (2×), the organic phase washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hex:ethyl acetate 4:1) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[F:20][C:21]([F:33])([F:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[N:14]1[CH2:19][CH2:18][N:17]([S:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]([F:20])([F:32])[F:33])(=[O:30])=[O:29])[CH2:16][CH2:15]1
Reactant: O=C1C(Cl)=C(N2CCNCC2)C(=O)c2ccccc21
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Product: O=C1C(Cl)=C(N2CCN(S(=O)(=O)c3ccccc3C(F)(F)F)CC2)C(=O)c2ccccc21

Procedure:
A 1.5 g portion of 3-chloro-2-piperazinyl-1,4-naphthoquinone and 1.26 g of 2-trifluoromethylbenzenesulfonyl chloride were reacted as described in Example 56, giving 1.53 g of the desired product, mp 122-124°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:28](Cl)(=[O:32])[CH2:29][CH2:30][CH3:31]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCCC(=O)Cl
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Product: CCCC(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 18 mg, 50 μmol) and butanoyl chloride (16 mg, 150 μmol). Yield 18 mg (82%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:14]=[C:13]([F:15])[C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9]C)=[O:8].[Li+].[OH-].Cl>C1COCC1.O>[Cl:1][C:2]1[C:3]2[CH:14]=[C:13]([F:15])[C:12]([C:16]([F:17])([F:19])[F:18])=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1sc2cc(C(F)(F)F)c(F)cc2c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1sc2cc(C(F)(F)F)c(F)cc2c1Cl
Yield: 86.6 %

Procedure:
Methyl 3-chloro-5-fluoro-6-trifluoromethyl-benzo[b]thiophene-2-carboxylate 10d (180 mg, 0.58 mmol) was stirred with LiOH (55 mg, 2.3 mmol) in THF (5 mL) and H2O (2.5 mL) for 4 h. Aqueous 1N HCl solution was added to the mixture to adjust pH to 3˜4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na2SO4 and concentrated to give 10f (150 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[S-:15][C:16]#[N:17].[NH4+].BrBr.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.O.C(OCC)(=O)C>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][C:5]1[CH:13]=[CH:14][C:2]2[N:1]=[C:16]([NH2:17])[S:15][C:3]=2[CH:4]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(Cc2ccccn2)cc1
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(Cc3ccccn3)cc2s1
Yield: 14.1 %

Procedure:
A solution of 2-(4-aminobenzyl)pyridine (4.5 g) and ammonium thiocyanate (3.7 g) in acetic acid (50 ml) was stirred at ambient temperature for 1 hour. A solution of bromine (1.3 ml) in acetic acid (5 ml) was dropwise added thereto at 10° to 15° C. under stirring and the resulting mixture was stirred at 10° to 20° C. for 1 hour. A mixture of ethyl acetate and water was added to the reaction mixture and the mixture was adjusted to pH 7.5 with potassium carbonate. An insoluble material was filtered off and the filtrate was separated. The resulting organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated and triturated with ethyl acetate. The precipitate was collected by filtration and dried to give 6-[(2-pyridyl)methyl]-2-aminobenzothiazole (0.83 g).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][C:17]([C:21]#[N:22])=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([C:23]#[N:24])[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:27][C:28]([F:37])([F:36])[C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32].O>CS(C)=O>[C:23]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:20]1[CH:19]=[CH:18][C:17]([C:21](=[NH:22])[NH:32][C:31]3[CH:33]=[CH:34][CH:35]=[C:29]([C:28]([F:36])([F:37])[F:27])[CH:30]=3)=[CH:16][C:15]2=1)#[N:24]
Reactant: N#Cc1ccc2c(c1)c1cc(C#N)ccc1n2Cc1ccccc1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc2c(c1)c1cc(C(=N)Nc3cccc(C(F)(F)F)c3)ccc1n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 25.9 %

Procedure:
A slurry of 9-benzyl-3,6-dicyanocarbazole (3.8 g, see Example 3C) and sodium hydride (50% in oil, 1.21 g) in 20 ml of dimethylsulfoxide is treated dropwise with m-trifluoromethylaniline (4.04 g). The reaction mixture is stirred at room temperature for four days and then poured into 500 ml of water and stirred vigorously for two hours. The resultant precipitate is collected by filtration and purified by column chromatography using one liter of silica gel. Elution with dichloromethane and 1% ethyl acetate/dichloromethane yields 1.5 g of 6-cyano-9-(phenylmethyl)-N-[3-(trifluoromethyl)phenyl]- 3-carbazolecarboximidamide. Elution with 20% ethyl acetate/dichloromethane/methanol (2:7:1) yields 2g of the desired diamidine, which is recrystallized from two liters of water containing 10 ml of concentrated hydrochloric acid to yield 1.6 g of the title compound, melting point 210°-220° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Si:14]([O:13][C@H:10]1[CH2:11][CH2:12][C@H:7]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)[CH2:8][CH2:9]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cn1ccnc1[C@H]1CC[C@H](O)CC1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cn1ccnc1[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of trans-4-(1-Methyl-1H-imidazol-2-yl)cyclohexanol (0.106 g, 0.588 mmol), tert-Butyldimethylsilyl chloride (0.177 g, 1.18 mmol), 4-Dimethylaminopyridine (10 mg, 0.1 mmol), 1H-Imidazole (120 mg, 1.76 mmol) and DCM (3.0 mL, 47 mmol) was stirred at ambient temperature for 1.5 h. The reaction mixture was diluted with DCM to ≈60 mL, washed with sat. NaHCO3 solution, water, and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel [Isco Combiflash, 2.5 g loading column/12 g column, eluting with DCM→4.9% MeOH in DCM]. Fractions containing the title compound were combined and dried in vacuo overnight, giving the title compound as yellow oil. 1H NMR (CDCl3, 400 MHz): δ=6.97 (brs, 1H), 6.78 (s, 1H), 3.69 (tt, J=10.6, 4.0 Hz, 1H), 3.61 (s, 3H), 2.60 (tt, J=11.8, 3.2 Hz, 1H), 2.04-1.96 (m, 2H), 1.95-1.87 (m, 2H), 1.87-1.72 (brm, 2H), 1.47-1.36 (m, 2H), 0.89 (s, 9H), 0.07 (s, 6H). MS (ES+): m/z=295.24 (100) [MH+]. HPLC: tR=3.20 min (verypolar—5 min, ZQ3). UV: λmax=216 nm.
Reaction SMILES: Cl[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:26]([NH:27][C:28](=[O:71])[C:29](=[N:55][O:56][CH2:57][C:58]3[CH:63]=[CH:62][C:61]([O:64]COCCOC)=[CH:60][CH:59]=3)[C:30]3[N:31]=[C:32]([NH:35]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:33][CH:34]=3)[C:25](=[O:72])[N:7]2[C:8]=1[C:9]([O:11]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:10].[SH:73][C:74]1[O:75][C:76]([C:79]2[CH:84]=[CH:83][C:82]([O:85]COCCOC)=[C:81]([O:92]COCCOC)[CH:80]=2)=[N:77][N:78]=1>>[NH2:35][C:32]1[S:33][CH:34]=[C:30]([C:29](=[N:55][O:56][CH2:57][C:58]2[CH:63]=[CH:62][C:61]([OH:64])=[CH:60][CH:59]=2)[C:28]([NH:27][C@@H:26]2[C:25](=[O:72])[N:7]3[C:8]([C:9]([OH:11])=[O:10])=[C:3]([CH2:2][S:73][C:74]4[O:75][C:76]([C:79]5[CH:84]=[CH:83][C:82]([OH:85])=[C:81]([OH:92])[CH:80]=5)=[N:77][N:78]=4)[CH2:4][S:5][C@H:6]23)=[O:71])[N:31]=1
Reactant: COCCOCOc1ccc(CON=C(C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Reactant: COCCOCOc1ccc(-c2nnc(S)o2)cc1OCOCCOC
Product: Nc1nc(C(=NOCc2ccc(O)cc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4nnc(-c5ccc(O)c(O)c5)o4)CS[C@H]23)cs1
Yield: 38 %

Procedure:
The same operation as in EXAMPLE 1 was conducted by using 2.04 g (2 mmol) of benzhydryl 3-chloromethyl-7β-{2-[4-(2-methoxyethoxymethoxy)benzyloxyimino]-2-(2-tritylaminothiazol-4-yl) acetamido}-3-cephem-4-carboxylate (syn-isomer) and 773 mg (2 mmol) of 2-mercapto-5-[3,4-di(2-methoxyethoxymethoxy) phenyl]-1,3,4-oxadiazole, whereby 530 g (yield: 38.0%) of the above identified compound was obtained.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[Na+].[Na+].B(O)(O)[C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1>C(COC)OC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)#[N:5]
Reactant: N#Cc1ccccc1Br
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
Nitrogen was bubbled through a solution of 2-bromobenzonitrile (309.4 g, 1.70 mol) in dimethoxyethane (4.2 L) for 30 minutes then the following reagents added in succession: tetrakis(triphenylphosphine)palladium(O), (95 g, 0.082 mol); 2M aqueous sodium carbonate solution (1785 mL, 3.57 mol); and p-tolylboronic acid (239.1 g, 1.76 mol). The reaction mixture was heated under an atmosphere of nitrogen at 70° to 78° C. for 19 hours. The two-phase mixture was cooled to room temperature and the layers separated. The organic layer was evaporated to dryness under reduced pressure. The aqueous layer was extracted with ether (3×1.2 L) and the extracts added to the organic residue. The insoluble material was filtered off and washed with ether. The filtrate was dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The oily residue was filtered to remove the solids and the filtrate distilled under high vacuum (0.1-0.2 torr) collecting the fraction boiling between 135° to 140° C. to afford 325 g of 2-cyano-4'-methylbiphenyl. MS (DEI) 193 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:16][CH2:17][CH2:18][CH:19]([NH2:23])[CH2:20][CH2:21][CH3:22]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([NH:23][CH:19]([CH2:20][CH2:21][CH3:22])[CH2:18][CH2:17][CH3:16])=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCCC(N)CCC
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Product: CCCC(CCC)NC(=O)C=Cc1ccc(OC)c(OC)c1

Procedure:
Prepared in a similar manner as described in example 4 from 3-(3,4-dimethoxy-phenyl)-acrylic acid and 4-heptylamine. MS (M+H, 306.2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=1.S(Cl)([Cl:19])=O>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][C:12]([C:14]([Cl:19])=[O:16])=[CH:11][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2Cl)o1
Product: O=C(Cl)c1ccc(-c2ccc(Cl)cc2Cl)o1

Procedure:
A solution of 28.28 g (0.11 moles) of 5-(2,4-dichlorophenyl)-2-furancarboxylic acid in 43 ml of thionyl chloride is heated at reflux of 3 hours. The solvent is removed and the residue is treated with 100 ml of toluene. the solvent is removed and the residue is carried on directly to the next step of the reaction.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][CH:8]=[CH:9][CH3:10])=[O:4].B#B.[O:13]1CCCC1>C(OCC)C>[CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][CH:8]([OH:13])[CH2:9][CH3:10])=[O:4]
Reactant: CC=CCCCC(=O)OC
Reactant: C1CCOC1
Agent: B#B
Solvent: CCOCC
Product: CCC(O)CCCC(=O)OC

Procedure:
Compound XL is prepared by reacting endo-bicycle[3.1.0]hex-2-ene-6-carboxylic acid methyl ester with diborane in a mixture of tetrahydrofuran and diethyl ether, a reaction generally known in the art, to give endo-bicyclo[3.100]63 hexan-3-ol-6-carboxylic acid methyl ester which is then reacted with dihydropyran in the presence of a catalytic amount of POCl3 to give the desired compound. This is then used as described in said Belgian patent to produce the endo form of bicyclo-ketone XVI.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]#[CH:10])[C:6](=[O:11])[CH:5]=[N:4][NH:3]1.[CH2:12]=[O:13].[OH-].[K+].O>C(O)(=O)C>[OH:13][CH2:12][N:3]1[C:2](=[O:1])[N:7]([CH2:8][C:9]#[CH:10])[C:6](=[O:11])[CH:5]=[N:4]1
Reactant: C#CCn1c(=O)cn[nH]c1=O
Reactant: C=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: C#CCn1c(=O)cnn(CO)c1=O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of 2.08 g 3,5-dioxo-4-propargyl-2,3,4,5-tetrahydro-1,2,4-triazine, 4.1 ml 35% aqueous formalin, 0.78 g potassium hydroxide and 7 ml water was stirred at 50° C. for 4 hours. After cooling to room temperature, the reaction solution was neutralized to a pH of 7 with acetic acid and extracted with three 30-ml portions of chloroform. The chloroform layers were combined, washed with 10 ml sodium chloride-saturated water and dried over magnesium sulfate. Chloroform was concentrated under reduced pressure to obtain a pale yellow semi-solid.
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:8]=[C:7]([N+]([O-])=O)[C:6]([CH3:12])=[CH:5][N+:4]=1[O-:13].Cl.[CH2:15]([OH:17])[CH3:16]>C(OCC)(=O)C>[CH2:15]([O:17][C:7]1[C:6]([CH3:12])=[CH:5][N+:4]([O-:13])=[C:3]([CH3:2])[CH:8]=1)[CH3:16]
Reactant: Cc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Reactant: CCO
Agent: Cl
Agent: [Na]
Solvent: CCOC(C)=O
Product: CCOc1cc(C)[n+]([O-])cc1C

Procedure:
13.5 g of sodium were dissolved in 2300 ml of ethanol under argon. 60 g of 2,5-dimethyl-4-nitropyridine 1-oxide were then added portionwise thereto and the solution was left to boil under reflux overnight. The pH was adjusted to 7 with 5N hydrogen chloride in ethyl acetate while cooling, whereupon the mixture was evaporated in vacuo. The residue was taken.up in 1 1 of methylene chloride, the solution was filtered through silica gel, which was rinsed with 500 ml of methylene chloride, and the combined filtrates were evaporated in vacuo. The product was chromatographed on 300 g of silica gel with methylene chloride/methanol (95:5). After crystallization from ether/petroleum ether there was obtained 4-ethoxy-2,5-dimethylpyridine 1-oxide of melting point 65-67° .
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](N)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13].II.N(OCCC(C)C)=O.C(I)[I:26]>C1COCC1.[Cu]I>[Cl:1][C:2]1[N:10]=[C:9]([I:26])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)n1cnc2c(Cl)nc(N)nc21
Reactant: ICI
Agent: [Cu]I
Agent: CC(C)CCON=O
Agent: II
Solvent: C1CCOC1
Product: CC(C)n1cnc2c(Cl)nc(I)nc21
Temperature: 25 °C
Yield: 324.6 %

Procedure:
6-Chloro-9-isopropyl-9H-purin-2-ylamine (2.7 g, 12.8 mmol), CuI (1.2 g, 13.4 mmol), I2 (3.3 g, 12.8 mmol), isoamyl nitrite (10.6 mL), and CH2I2 (5.3 g, 39.3 mmol) in THF (60 mL) were heated at reflux for 75 min. The mixture was cooled to rt, filtered through Celite, and adsorbed onto silica gel. Purification by chromatography (60% EtOAc/hexane) yielded an off-white solid (13.4 g, 54%): MS [M+H]+ 323; m.p.104° C.
Reaction SMILES: ClC1C(OC)=CC(OC)=C(Cl)C=1N1CC2C(=NC(NC)=NC=2)N(C2CCNCC2)C1=O.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].C(OC([N:46]1[CH2:51][CH2:50][CH:49]([N:52]2[C:57]3=[N:58][C:59]([NH:62][CH3:63])=[N:60][CH:61]=[C:56]3[CH2:55][N:54]([C:64]3[C:69]([F:70])=[C:68]([O:71][CH3:72])[CH:67]=[C:66]([O:73][CH3:74])[C:65]=3[F:75])[C:53]2=[O:76])[CH2:48][CH2:47]1)=O)(C)(C)C>>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[F:70][C:69]1[C:68]([O:71][CH3:72])=[CH:67][C:66]([O:73][CH3:74])=[C:65]([F:75])[C:64]=1[N:54]1[CH2:55][C:56]2[C:57](=[N:58][C:59]([NH:62][CH3:63])=[N:60][CH:61]=2)[N:52]([CH:49]2[CH2:50][CH2:51][NH:46][CH2:47][CH2:48]2)[C:53]1=[O:76]
Reactant: CNc1ncc2c(n1)N(C1CCN(C(=O)OC(C)(C)C)CC1)C(=O)N(c1c(F)c(OC)cc(OC)c1F)C2
Agent: CNc1ncc2c(n1)N(C1CCNCC1)C(=O)N(c1c(Cl)c(OC)cc(OC)c1Cl)C2
Solvent: O=C(O)C(F)(F)F
Product: CNc1ncc2c(n1)N(C1CCNCC1)C(=O)N(c1c(F)c(OC)cc(OC)c1F)C2

Procedure:
3-(2,6-Difluoro-3,5-dimethoxy-phenyl)-7-methylamino-1-piperidin-4-yl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one; compound with trifluoroacetic acid was synthesized in the same manner as 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-7-methylamino-1-piperidin-4-yl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, compound with trifluoroacetic acid; however, 4-[3-(2,6-difluoro-3,5-dimethoxy-phenyl)-7-methylamino-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (411 mg, 0.187 mmol) and trifluoroacetic acid (878 μL) were used to deliver the title compound (482 mg) as a white solid: HPLC=88% pure; mp 135° C.–140° C.; MS (APCI) 435.1, 436.1.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:4]=1[C:5](N(C)C)=[O:6].C(O)(=[O:19])C>O.[O-2].[O-2].[O-2].[Cr+6]>[C:5]([C:4]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:3]=1[CH:2]=[O:1])([OH:19])=[O:6]
Reactant: CN(C)C(=O)c1cc([N+](=O)[O-])ccc1CO
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Product: O=Cc1ccc([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-hydroxymethyl-5-nitro-N,N-dimethylbenzamide (17 g.) in glacial acetic acid (340 ml.) was added chromium trioxide (17 g.) in water (17 ml.) and glacial acetic acid (340-1). The reaction mixture was stirred at room temperature for 5 minutes, and then poured into ice-water (2 liters). The aqueous was extracted with chloroform (3 × 500 ml.). The chloroform extracts were combined and neutralised by washing with 10% sodium bicarbonate solution. The chloroform extracts were then washed thoroughly with water and dried over magnesium sulphate. The solution was then filtered and the solvent evaporated off to yield a gum.