Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N-:2]C.[NH2:4][C:5]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8].C(N)=O>O>[F:14][C:12]1[CH:13]=[C:5]2[C:6]([C:7](=[O:8])[NH:2][CH:1]=[N:4]2)=[CH:10][CH:11]=1
Reactant: C[N-]C
Reactant: Nc1cc(F)ccc1C(=O)O
Solvent: O
Solvent: NC=O
Product: O=c1[nH]cnc2cc(F)ccc12
Temperature: 180 °C
Yield: 78 %

Procedure:
A catalytic amount (1 ml) of N,N-dimethylamide was added to 2-amino-4-fluorobenzoic acid (50 g, 322 mmol) and formamide (77 ml, 1934 mmol), and the resulting solution was stirred. The solution was heated to 180° C. and stirred for 14 hours. The temperature of the solution was cooled to room temperature, and 300 ml of distilled water was added thereto. The resulting solid was stirred about 30 min, and filtered to obtain the title compound 41.3 g (yield: 78%).
Reaction SMILES: Cl[C:2]1[N:3]([CH3:10])[C:4](=[O:9])[S:5][C:6]=1[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[O:31][CH2:30][CH2:29][CH2:28]3)O1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)C.O.C(OCC)(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[O:31]1[C:32]2[CH:33]=[CH:34][C:25]([C:2]3[N:3]([CH3:10])[C:4](=[O:9])[S:5][C:6]=3[CH:7]=[O:8])=[CH:26][C:27]=2[CH:28]=[CH:29][CH2:30]1
Reactant: Cn1c(Cl)c(C=O)sc1=O
Reactant: CC1(C)OB(c2ccc3c(c2)CCCO3)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(-c2ccc3c(c2)C=CCO3)c(C=O)sc1=O
Temperature: 25 °C
Yield: 34.8 %

Procedure:
Under a nitrogen atmosphere, a solution of 4-chloro-3-methyl-2-oxo-2,3-dihydro-thiazole-5-carbaldehyde (33b) (500 mg, 2.82 mmol), potassium carbonate (390 mg, 2.82 mmol), palladium diacetate (100 mg, 0.48 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman (732 mg, 2.82 mmol) and tetrabutylammonium bromide (910 mg, 2.82 mmol) in ethanol (7 mL) and water (10 mL) was stirred at 70° C. for 3 hours. The mixture was then cooled at room temperature and diluted with ethyl acetate (30 mL) and water (30 mL). The organic layer was washed with water (30 mL), brine (30 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 80/20) to afford the desired product as a white solid (270 mg, 0.98 mmol, 35%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([Cl:10])[CH:5]=1)(=[O:3])[CH3:2].CCCCCC.C(O[CH:20](OCC)[N:21]([CH3:23])[CH3:22])C>>[CH3:20][N:21]([CH3:23])[CH:22]=[CH:2][C:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([Cl:10])[CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccnc(Cl)c1
Reactant: CCOC(OCC)N(C)C
Solvent: CCCCCC
Product: CN(C)C=CC(=O)c1ccnc(Cl)c1
Temperature: 25 °C

Procedure:
A mixture of 4-acetyl-2-chloro-pyridine (1.72 g, 11 mmol) in N,N-dimethyl formamide diethyl acetal (10 mL) is heated to reflux for 1 hour and cooled to room temperature before adding hexane (8 mL). The solid is collected by filtration, washed with hexane and dried to give 3-dimethylamino-1-(2-chloro-4-pyridyl)-2-propen-1-one (1.70 g); ESI-MS (m/z): 211.0 (M++H).
Reaction SMILES: [NH2:1][C@H:2]([CH3:30])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[N:25]=[CH:26][S:27][CH:28]=3)=[C:18]([Cl:29])[CH:17]=1)=[N:8][CH:9]=[N:10]2.[OH:31][C@H:32]1[CH2:37][CH2:36][O:35][C:33]1=[O:34]>>[Cl:29][C:18]1[CH:17]=[C:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[CH:14][C:5]=3[O:4][CH2:3][C@H:2]([NH:1][C:33](=[O:34])[C@@H:32]([OH:31])[CH2:37][CH2:36][OH:35])[CH3:30])[N:10]=[CH:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[N:25]=[CH:26][S:27][CH:28]=1
Reactant: C[C@@H](N)COc1cccc2ncnc(Nc3ccc(OCc4cscn4)c(Cl)c3)c12
Reactant: O=C1OCC[C@@H]1O
Product: C[C@H](COc1cccc2ncnc(Nc3ccc(OCc4cscn4)c(Cl)c3)c12)NC(=O)[C@@H](O)CCO
Yield: 58 %

Procedure:
The procedure described in Example 63 was repeated using 5-{[(2R)-2-aminopropyl]oxy}-N-[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 73, preparation of starting materials) and (S)-(−)-α-hydroxy-γ-butyrolactone to give the title compound in 58% yield; NMR spectrum (DMSO-d6) 1.23 (d, 3H), 1.27-1.40 (m, 1H), 1.60-1.62 (m, 1H), 3.33-3.46 (m, 2H), 3.87-3.97 (m, 1H), 4.19-4.41 (m, 3H), 4.42-4.58 (m, 1H), 5.35 (s, 2H), 5.40 (d, 1H), 7.14 (d, 1H), 7.25-7.38 (m, 2H), 7.53 (dd, 1H), 7.72 (t, 1H), 7.80 (d, 1H), 7.92-8.05 (m, 2H), 8.47 (s, 1H), 9.14 (d, 1H), 9.75 (s, 1H); Mass spectrum MH+ 543.9.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:42][C:43]1[N:44]=[CH:45][NH:46][CH:47]=1)[C:3]([NH:5][C@@H:6]([CH2:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[C@@H:7]([OH:34])[CH2:8][C@@H:9]([CH:31]([CH3:33])[CH3:32])[CH:10]([OH:30])[CH2:11][N:12]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:4].[NH:48](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:49]([C:57](O)=[O:58])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(N1CCOCC1)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C=O>[CH:36]1([CH2:35][C@H:6]([NH:5][C:3](=[O:4])[C@H:2]([CH2:42][C:43]2[N:44]=[CH:45][NH:46][CH:47]=2)[NH:1][C:57](=[O:58])[C@H:49]([CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[NH2:48])[C@@H:7]([OH:34])[CH2:8][C@@H:9]([CH:31]([CH3:33])[CH3:32])[CH:10]([OH:30])[CH2:11][N:12]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)[C@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(O)CN(Cc1ccccn1)C(=O)OCc1ccccc1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)[C@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](N)Cc1ccccc1)C(O)CN(Cc1ccccn1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
A mixture of 340 mg (0.52 mmol) of benzyl [(2RS,3S, 5S,6S)-6-[(S)-α-amino-4-imidazolepropionamido]-7-cyclohexyl-2,5-dihydroxy-3-isopropylheptyl]-(2-pyridylmethyl)carbamate, 225 mg (0.58 mmol) of Fmoc-Phe-OH, 0.132 ml (1.05 mmol) of 4-ethylmorpholine, 155 mg (1.15 mmol) of HOBT, 121 mg (0.63 mmol) of EDC and 10 ml of dimethylformamide is stirred at room temperature overnight. Thereafter, the reaction mixture is poured into 70 ml of ice-cold 2N sodium bicarbonate solution and extracted three times with 150 ml of ethyl acetate each time. The organic extracts are washed in succession with 70 ml of sodium bicarbonate solution and 70 ml of saturated sodium chloride solution, combined, dried and evaporated. The residue (640 mg) in 30 ml of methylene chloride and 1 ml of piperidine is stirred at room temperature for 2.5 hours. Then, the reaction mixture is evaporated and the residue (500 mg) is chromatographed on 50 mg of silica gel with a 14:1:0.1 mixture of methylene chloride, methanol and ammonia as the eluting agent. Recrystallization of the crude product obtained (320 mg) from methylene chloride/ether/hexane yields 280 mg of benzyl [(2RS,3S,5S,6S)-7-cyclohexyl-2,5-dihydroxy-3-isopropyl-6-[[N-(3-phenyl-L-alanyl)-L-histidyl]amino]heptyl]-(2-pyridylmethyl)carbamate as a white solid, melting point 94°.
Reaction SMILES: [K].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br.C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccc(O)cc2)cc1
Reactant: BrCCCCCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(-c2ccc(OCCCCCCBr)cc2)cc1

Procedure:
To 500 ml of toluene in a 100 ml round bottom flask, fitted with a condenser and magnetic stirrer, are added 7.6 g (0.03M) of the potassium salt of 4-hydroxy-4'-nitrobiphenyl, 36.6 g (0.15M) of 1,6-dibromohexane, and 0.5 g of 18-crown-6 ether. The mixture is refluxed for about 20 hours, and then filtered hot. The solvent is evaporated, and the residual crude product is recrystallized from hexane to provide purified product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=1.[F:27][C:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[C:30]([F:37])[N:29]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[F:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]3[S:16][C:15]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=4[C:13]=3[CH3:22])(=[O:10])=[O:11])=[C:4]([C:23]([F:25])([F:26])[F:24])[CH:3]=2)[CH:31]=[C:30]([F:37])[N:29]=1
Reactant: OB(O)c1cc(F)nc(F)c1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)sc2ccc(F)cc12
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: CCO
Solvent: COCCOC
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3cc(F)nc(F)c3)cc2C(F)(F)F)sc2ccc(F)cc12
Yield: 42.7 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-trifluoromethyl-phenyl)-amide (0.12 g) and 2,6-difluoropyridine-4-boronic acid (0.063 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0.32 ml) and 2 M aqueous sodium carbonate solution (1.0 ml) with tetrakis(triphenylphosphine)palladium (0.055 g) to obtain the title compound (0.055 g) as a brownish solid. MS (ISP): 520.2 (M+NH4)+
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1>C(Cl)Cl>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([N:1]2[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C1CNCCNC1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(N2CCCNCC2)cc1
Yield: 82.7 %

Procedure:
A solution of hexahydro-1H-1,4-diazepine (0.20 mol) and 1-fluoro-4-nitro-benzene (0.10 mol) in DCM (300 ml) was stirred at room temperature for 24 hours under nitrogen atmosphere. Yellow crystals precipitated. The precipitate was collected on filter, washed with ether and dried. The residue (21.1 g, 87%) was taken up in water and treated with a 3 N NaOH solution. This mixture was extracted with DCM (3×500 ml), dried (Na2SO4), filtered, and the solvent was removed under reduced pressure and dried under vacuum at room temperature for 16 hours, yielding 18.3 g of hexahydro-1-(4-nitrophenyl)-1H-1,4-diazepine (interm. 1), melting point 115-116° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([N:7]([CH2:9][CH2:10][CH2:11][CH3:12])[CH3:8])[C:3]=1[C:13]#[N:14].[CH3:15][N:16]=[C:17]=[O:18].C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC>O1CCCC1>[CH3:15][NH:16][C:17]([NH:1][C:2]1[S:6][N:5]=[C:4]([N:7]([CH2:9][CH2:10][CH2:11][CH3:12])[CH3:8])[C:3]=1[C:13]#[N:14])=[O:18]
Reactant: CCCCN(C)c1nsc(N)c1C#N
Reactant: CN=C=O
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: C1CCOC1
Product: CCCCN(C)c1nsc(NC(=O)NC)c1C#N
Yield: 46.1 %

Procedure:
In the manner of Example XI, part D, 7 g of 5-amino-3-(butylmethylamino)-4-cyanoisothiazole, 4.1 ml (4 g) of methyl isocyanate, and a catalytic amount of dibutyltin diacetate in 50 ml of tetrahydrofuran were allowed to react. The volatile materials were removed under reduced pressure and the residue was crystallized from 35 ml of 70:30 diethyl ether:hexane to yield solid material, mp 102° (decomposes). This material was recrystallized from 70 ml of 40:60 diethylether:hexane to yield 4.1 g of 1-methyl-3-(3-(butylmethylamino)-4-cyano-5-isothiazolyl)urea mp 169°-170°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][CH2:18][OH:19])=[CH:15][CH:14]=1.[O:22]1[CH:27]=[CH:26][CH2:25][CH2:24][CH2:23]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:19][CH2:18][CH2:17][C:16]1[CH:20]=[CH:21][C:13]([Br:12])=[CH:14][CH:15]=1
Reactant: C1=COCCC1
Reactant: OCCc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Brc1ccc(CCOC2CCCCO2)cc1

Procedure:
p-Toluenesulfonic acid (0.30 g) was added to a solution of 4-bromophenethyl alcohol (9.50 g, 47.24 mmol) in methylene chloride (50 ml), and the mixture was stirred under ice-cooling. To the mixture was added 3,4-dihydropyran (5.53 g, 65.74 mmol). After stirring under ice-cooling for 20 minutes, a saturated aqueous solution of sodium bicarbonate (40 ml) was added to the reaction mixture. The resulting mixture was extracted with methylene chloride and dried over magnesium sulfate. After evaporation of the solvent, the desired 4-(2-(tetrahydropyran-2-yloxy)ethyl)bromobenzene was obtained (13.40 g, 99%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=2[CH3:20])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([Mg]Cl)(C)C.[B:26](OC)([O:29]C)[O:27]C>O1CCCC1>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=2[CH3:20])=[CH:3][C:2]=1[B:26]([OH:29])[OH:27]
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(I)c2)c(C)c1
Reactant: COB(OC)OC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(OC)c(B(O)O)c2)c(C)c1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
Into a 10000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of methyl 4-(3-iodo-4-methoxyphenyl)-3-methylbenzoate (600 g, 1.57 mol, 1.00 equiv) in tetrahydrofuran (5000 mL). This was followed by the addition of isopropyl magnesium chloride (960 mL, 1.20 equiv) dropwise with stirring at <−25° C. over 60 min. The reaction was maintained for 1 h at −15° C., followed by addition of trimethyl borate (329.2 g, 3.17 mol, 2.00 equiv) dropwise with stirring at <−20° C. over 30 min. The resulting solution was stirred for 60 min at <0° C., then quenched by the addition of 5000 mL of H3PO4 (aq. 1M). The bulk of THF was removed under vacuum. The solid was collected by filtration and washed with 2×200 ml of toluene. This resulted in 300 g (crude) of [2-methoxy-5-[4-(methoxycarbonyl)-2-methylphenyl]phenyl]boronic acid as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH2:37]([O:36][C:34]([N:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1)=[O:35])[CH3:38]
Reactant: O=C(NCC1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CCC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (pyrrolidin-3-ylmethyl)-amide (example A146) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: C[C:2]1([C:10]2([C:23]3(C)[CH:28]=[CH:27][C:26](C)=[CH:25][CH:24]3N)[C:19]3[C:14](=[CH:15][C:16](N(C)C)=[CH:17][CH:18]=3)C(=O)O2)[CH:7]=[CH:6][C:5](C)=[CH:4][CH:3]1N.CC1(C2(C3(C)C=CC(C)=CC3N)C3C(=CC=CC=3)C(=O)O2)C=CC(C)=CC1N>>[C:2]1([CH:10]([C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1=CC(N)C(C)(C2(C3(C)C=CC(C)=CC3N)OC(=O)c3cc(N(C)C)ccc32)C=C1
Agent: CC1=CC(N)C(C)(C2(C3(C)C=CC(C)=CC3N)OC(=O)c3ccccc32)C=C1
Product: c1ccc(C(c2ccccc2)c2ccccc2)cc1

Procedure:
3,3-bis(p-dimethyl aminophenyl)-6-dimethylaminophthalide [alternate name: crystal violet lactone] and 3,3-bis(p-dimethyl aminophenyl)phthalide [alternate name: malachite green lactone]
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:6]=2[O:5][C:4](=O)[CH:3]=1.[CH3:14][NH2:15]>CO>[CH3:14][N:15]1[C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:12])[C:11]=2[C:2]([CH3:1])=[CH:3][C:4]1=[O:5]
Reactant: Cc1cc(=O)oc2c1C(=O)CCC2
Reactant: CN
Solvent: CO
Product: Cc1cc(=O)n(C)c2c1C(=O)CCC2
Temperature: -9 °C

Procedure:
4.46 g (0.025 mol) of 4-methyl-5,6,7,8-tetrahydro- cumarin-5-one are dissolved in a mixture of 41.9 g of liquid methylamine in 100 ml of methanol pre- cooled to -9° C., With cooling, and heated to 180° C. for 3 hours in an autoclave. After cooling the methanol and methylamine are distilled off using a rotary evaporator, the residue is chromatographed on a silica gel column using ethylene chloride/ethanol (95:5) and recrystallised from cyclohexane/ethyl acetate (1:1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1([CH2:16][C:17]([OH:19])=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[CH2:32]([N:34](CC)[CH2:35][CH3:36])[CH3:33].C(NCC)C.C(OC(N1C(=O)CC2(CCCCC2)C1)=O)(C)(C)C>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.C(Cl)(Cl)Cl.CCCCCC>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1([CH2:16][C:17](=[O:19])[N:34]([CH2:35][CH3:36])[CH2:32][CH3:33])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC1(CC(=O)O)CCCCC1
Reactant: CCN(CC)CC
Agent: CC(C)(C)OC(=O)N1CC2(CCCCC2)CC1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)CC1(CNC(=O)OC(C)(C)C)CCCCC1
Reaction time: 0.17 h
Yield: 76 %

Procedure:
[1-(Tert-butoxycarbonylamino-methyl)-cyclohexyl]-acetic acid (271 mg, 1 mmol) was dissolved in dry dichloromethane (5 ml) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC-HCl; 576 mg, 3 mmol, 3 molequivalents) and triethylamine (404 mg, 4 mmol, 4 molequivalents) were added thereto. After 10 minutes of stirring, diethylamine (146 mg, 2 mmol, 2 molequivalents) and 4-dimethylamino-pyridine (DMAP; 25 mg, 0.2 mmol, 0.2 molequivalents) were added to the reaction mixture, and the mixture was stirred at 25° C. for 20 hours, while monitoring the reaction by TLC using a 2:8 hexane:ethyl acetate mixture as eluent, and until the appearance of a spot of the amide in the middle of the TLC plate was observed. Chloroform was thereafter added and the mixture was washed with NaHCO3, twice with 1M HCl, dried over Na2SO4 and the solvents were evaporated under reduced pressure to give (1-diethylcarbamoylmethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (248 mg, 76% yield) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:34]([NH:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:35])[CH2:11][CH2:10]2)=[CH:6][CH:7]=1
Reactant: NCCCN1CCC(C(Nc2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: O=C=Nc1ccccc1
Product: O=C(NCCCN1CCC(C(Nc2ccc(F)cc2)c2ccc(F)cc2)CC1)Nc1ccccc1

Procedure:
The compound of Example 59 is reacted with phenyl isocyanate in an aprotic solvent to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:10]([CH3:15])[CH2:11][C:12]([OH:14])=O)=[O:9])=[CH:4][CH:3]=1.[NH2:16][CH:17]1[C:35](=[O:36])[N:19]2[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH2:24][S:25][C:26]3[S:30][C:29]([CH3:31])=[N:28][N:27]=3)[CH2:22][S:23][C@H:18]12>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:10]([CH3:15])[CH2:11][C:12]([NH:16][CH:17]2[C:35](=[O:36])[N:19]3[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH2:24][S:25][C:26]4[S:30][C:29]([CH3:31])=[N:28][N:27]=4)[CH2:22][S:23][C@H:18]23)=[O:14])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Reactant: CC(CC(=O)O)S(=O)c1ccc(O)cc1
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CC(C)S(=O)c4ccc(O)cc4)[C@H]3SC2)s1

Procedure:
456 mg. of 3-(p-hydroxyphenylsulfinyl)butyric acid and 7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 400 mg. of 7-[3-(p-hydroxyphenylsulfinyl)butyramido]-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([CH3:26])([C:22]([O:24]C)=[O:23])[CH3:21])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([C:22]([OH:24])=[O:23])([CH3:26])[CH3:21])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(C)(C)Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1)C(=O)O
Yield: 88.2 %

Procedure:
A mixture of 4-tert-butyl-2-[5-(2-methyl-2-methoxycarbonylpropyl)benzofuran-2-yl]thiazole (0.33 g) and 1N aqueous sodium hydroxide (2 ml) in methanol (5 ml) was stirred under reflux for 5 hours. After being cooled, the resulting mixture was concentrated under reduced pressure and adjusted to pH 6 with diluted aqueous hydrochloric acid. The resulting crystals were collected by filtration and washed with water to give 4-tert-butyl-2-[5-(2-carboxy-2-methylpropyl)benzofuran-2-yl]thiazole (0.28 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=3)=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[N:14]=2)=[CH:6][CH:5]=1)([O-])=O.CN(C)C=O.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>[Fe].O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:11][C:12]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=3)=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)[N:14]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc(-c3ccc([N+](=O)[O-])cc3)c(-c3ccc([N+](=O)[O-])cc3)s2)cc1
Agent: [Fe]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(-c2nc(-c3ccc(N)cc3)c(-c3ccc(N)cc3)s2)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
15 g (0.034 mol) of the thus obtained 2,4,5-tris(4'-nitrophenyl)thiazole was mixed with 500 ml of N,N-dimethylformamide and 20 g of iron powder. The mixture was admixed with 10 ml of concentrated sulfuric acid and 30 ml of water. The admixture was heated to a temperature of 100° C. with thorough stirring. After 1 hour passed, the solution was neutralized with a saturated aqueous solution of sodium hydrogencarbonate with the reaction temperature kept at 100° C. to adjust the pH value thereof to 8. The reaction solution was then hot-filtered. The filtrate was poured into 3 l of ice water to produce a light yellow precipitate of 2,4,5-tris(4'-aminophenyl)thiazole which was then filtered off and dried to obtain 11.3 g (yield: 94%) of the product.