Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14]>CO>[C:1]1([C:7]2[N:11]([CH2:14][CH2:13][C:12]([O:16][CH3:17])=[O:15])[CH:10]=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CC(=O)OC
Reactant: c1ccc(-c2ncc[nH]2)cc1
Solvent: CO
Product: COC(=O)CCn1ccnc1-c1ccccc1
Temperature: 60 °C
Reaction time: 20 h
Yield: 83.9 %

Procedure:
A mixture of 144 g of 2-phenylimidazole, 103 g of methyl acrylate and 500 g of methanol was heated and stirred at 60° C. for 20 hours. The solvent was distilled off in vacuo. Purification by column chromatography gave 193 g of methyl 3-(2-phenyl-1H-imidazol-1-yl)propionate (yield 84%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[NH:20][C:19](=[O:24])[N:18]([CH2:25][CH2:26][CH3:27])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:28]([O:30][CH2:31]Cl)[CH3:29]>CN(C)C=O.O.CO>[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[N:20]([CH2:31][O:30][CH2:28][CH3:29])[C:19](=[O:24])[N:18]([CH2:25][CH2:26][CH3:27])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOCCl
Reactant: CCCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(=O)n(COCC)c(=O)c2c1ncn2Cc1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
1.71 g (12.0 mmol) of potassium carbonate were added to a hot solution of 2.2 g (7.7 mmol) of 7-benzyl-3-propylxanthine from stage a) in 60 ml of dimethylformamide at 60° C. and the mixture was stirred at 60° C. for 1 hour. 0.93 ml (10.0 mmol) of ethoxymethyl chloride was then added dropwise and the mixture was stirred at 80° C. for 4.5 hours. A further 0.5 ml (5.3 mmol) of ethoxymethyl chloride was then added and the mixture was again stirred for 6 hours. 12 ml of water and 5 ml of methanol were then added, the mixture was allowed to stand overnight, 60 ml of water were added again and the mixture was extracted three times using methyl tert-butyl ether. The combined organic phases were washed twice with water, dried using magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column, dichloromethane/methanol (19.8/0.2).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:27]=[C:26]4[C:22]([CH2:23][CH2:24][NH:25]4)=[CH:21][C:20]=3[O:28][CH3:29])[NH:15][C:14]3=[N:30][CH:31]=[CH:32][C:13]=23)[C:3]=1[C:4]([NH2:6])=[O:5].Br[CH2:34][C:35](Cl)=[O:36].[NH:38]1[CH:42]=[CH:41][N:40]=[CH:39]1.CCN(C(C)C)C(C)C>C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:27]=[C:26]4[C:22]([CH2:23][CH2:24][N:25]4[C:35](=[O:36])[CH2:34][N:38]4[CH:42]=[CH:41][N:40]=[CH:39]4)=[CH:21][C:20]=3[O:28][CH3:29])[NH:15][C:14]3=[N:30][CH:31]=[CH:32][C:13]=23)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: O=C(Cl)CBr
Reactant: c1c[nH]cn1
Reactant: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccnc-3[nH]1)NCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccnc-3[nH]1)N(C(=O)Cn1ccnc1)CC2
Yield: 83 %

Procedure:
A −40° C. solution of 2-fluoro-6-[(2-{[5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide (70 mg, 0.16 mmol) in THF (10 mL) was treated with a solution of bromoacetyl chloride (31 mg, 0.19 mmol) in THF (1 mL), followed by imidazole (10 mL) and DIPEA (1 mL). After 3 days the resulting mixture was concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2. The crude product was dissolved in THF (150 mL), diluted with EtOAc (50 mL), washed with a saturated NaHCO3 solution (100 mL), a saturated NaCl solution (100 mL) and a mixture of water (50 mL) and a saturated Na2CO3 solution (50 mL). The organic layer was dried (Na2SO4) and concentrated, and the residue was triturated with CH2Cl2 to obtain 2-fluoro-6-[(2-{[1-(1H-imidazol-1-ylacetyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide as a white solid (72 mg, 83%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.18 (t, J=8.15 Hz, 2H), 3.77 (s, 3H), 4.18 (t, J=8.06 Hz, 2H), 6.19 (s, 1H), 6.78-6.94 (m, 3H), 6.97 (s, 1H), 7.07 (s, 1H), 7.29 (q, J=7.69 Hz, 1H), 7.54 (s, 1H), 7.55 (s, 1H), 7.99 (s, 1H), 8.07 (s, 1H), 8.46 (d, J=8.42 Hz, 1H), 8.58 (s, 1H), 10.52 (s, 1H), 11.27 (s, 1H), a CH2 signal with 2 protons is missing, may overlap with water peak in sample; ESIMS (M+H)+=542.11.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C@@H:10]1([C:16]([OH:18])=O)[CH2:12][C@@H:11]1[C:13]([OH:15])=[O:14].[CH3:19][NH:20][CH2:21][CH2:22][CH3:23].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.ClCCl>[CH3:19][N:20]([CH2:21][CH2:22][CH3:23])[C:16]([C@H:10]1[CH2:12][C@H:11]1[C:13]([OH:15])=[O:14])=[O:18]
Reactant: O=C(O)[C@H]1C[C@H]1C(=O)O
Reactant: CCCNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCN(C)C(=O)[C@H]1C[C@H]1C(=O)O
Reaction time: 60 h
Yield: 34.7 %

Procedure:
Add diisopropylethylamine (2.68 mL, 15.4 mmol) and cis-cyclopropane-1,2-dicarboxylic acid (0.50 g, 3.84 mmol) to a slurry of 2-chlorotrityl chloro resin (3.00 g, Nova Bio) in 7:1 dichloromethane:dimethylfomamide (10.0 mL). Stir over night and then filter the slurry. Wash the resin with 17:2:1 dichloromethane:methanol:dimethylformamide (3×20 mL) followed by dichloromethane (3×20 mL). Add the filtered resin to a solution of diisopropylethylamine (1.34 mL, 7.69 mmol), methylpropylamine (0.788 mL, 7.69 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (2.915 g, 7.69 mmol), and HOBT (1.177 g, 7.69 mmol) in dimethylformamide (10 mL) and shake for 2.5 days. Filter and wash the resin with dimethylformamide (3×20 mL) and dichloromethane (5×20 mL). Add trifluoroacetic acid (1 mL) to a slurry of the washed resin in dichloromethane (20 mL). Shake for 45 minutes and filter. Wash the resin with dichloromethane (2×20 mL) and concentrate this filtrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with dichloromethane containing 10-40% of 5% (2:1 methanol:acetic acid) in dichloromethane to provide the title compound (0.247 g, 34.7%).
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[C:17]([CH2:19][CH3:20])[C:16]([NH2:21])=[C:15]([CH2:22][CH3:23])[CH:14]=1)[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]([NH2:10])=[C:4]([CH2:11][CH3:12])[CH:3]=1.[CH2:24]([C:26]([CH3:28])=O)[CH3:25]>[Pt].O1CCCC1>[CH:24]([NH:21][C:16]1[C:17]([CH2:19][CH3:20])=[CH:18][C:13]([CH2:1][C:2]2[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]([NH:10][CH:1]([CH2:2][CH3:3])[CH3:13])=[C:4]([CH2:11][CH3:12])[CH:3]=2)=[CH:14][C:15]=1[CH2:22][CH3:23])([CH2:26][CH3:28])[CH3:25]
Reactant: CCC(C)=O
Reactant: CCc1cc(Cc2cc(CC)c(N)c(CC)c2)cc(CC)c1N
Agent: [Pt]
Solvent: C1CCOC1
Product: CCc1cc(Cc2cc(CC)c(NC(C)CC)c(CC)c2)cc(CC)c1NC(C)CC
Temperature: 110 °C
Yield: 86 %

Procedure:
4,4′-Methylenebis(2,6-diethylbenzeneamine) (3 g), Pt(S)/C (0.3 g), Amberlyst-15 (0.3 g), methyl ethyl ketone (25 g), and tetrahydrofuran (THF; 25 g) were charged into a 100 mL metal autoclave at 22° C. The closed autoclave was purged 3 times with 90 psig (7.22×105 Pa) of H2 at 22° C. The reaction mixture was then heated at 100-120° C. under 125 psig (9.63×105 Pa) of H2 for 5 hrs (until no further H2 uptake was observed). The product mixture was cooled to 22° C. and degassed. A diluted product sample was analyzed by GC (180° C. for 5 minutes at 10° C. per minute rate; final temperature, 270° C.). The GC data (normalization method) showed 100% conversion of 4,4′-methylenebis(2,6-diethylbenzeneamine), and an 86% yield of N,N′-di-sec-butyl-4,4′-methylenebis(2,6-diethylbenzeneamine).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[NH:15][NH2:16].[C:17]([C:19](=[C:25]([O:29]CC)[O:26][CH2:27][CH3:28])[C:20]([O:22][CH2:23][CH3:24])=O)#[N:18]>C(O)C>[CH2:27]([O:26][C:25]([C:19]1[C:20]([O:22][CH2:23][CH3:24])=[N:16][N:15]([C:3]2[CH:4]=[C:5]([S:9][CH2:10][C:11]([F:13])([F:14])[F:12])[C:6]([CH3:8])=[CH:7][C:2]=2[F:1])[C:17]=1[NH2:18])=[O:29])[CH3:28]
Reactant: Cc1cc(F)c(NN)cc1SCC(F)(F)F
Reactant: CCOC(=O)C(C#N)=C(OCC)OCC
Solvent: CCO
Product: CCOC(=O)c1c(OCC)nn(-c2cc(SCC(F)(F)F)c(C)cc2F)c1N
Yield: 17.9 %

Procedure:
5.0 g of 2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenylhydrazine was dissolved in 50 mL of ethanol, and 5.0 g of ethyl 2-cyano-3,3-diethoxyacrylate was added, followed by stirring under reflux with heating for 6 hours. Then, the solvent was distilled off under reduced pressure, and extraction with ethyl acetate was carried out. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:3) to obtain 1.48g of ethyl-5-amino-3-ethoxy-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}pyrazole-4-carboxylate.
Reaction SMILES: [CH2:1]([C:6]1[CH:31]=[CH:30][C:9]([CH:10]=[CH:11][C:12]([NH:14][C:15]2[C:20]3[O:21][CH:22]([C:25]4[NH:29][N:28]=[N:27][N:26]=4)[CH2:23][O:24][C:19]=3[CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(O)C.[H][H]>[C].[Pd].C(OCC)(=O)C>[CH2:1]([C:6]1[CH:31]=[CH:30][C:9]([CH2:10][CH2:11][C:12]([NH:14][C:15]2[C:20]3[O:21][CH:22]([C:25]4[NH:29][N:28]=[N:27][N:26]=4)[CH2:23][O:24][C:19]=3[CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [H][H]
Reactant: CCCCCc1ccc(C=CC(=O)Nc2cccc3c2OC(c2nnn[nH]2)CO3)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCc1ccc(CCC(=O)Nc2cccc3c2OC(c2nnn[nH]2)CO3)cc1
Yield: 93.1 %

Procedure:
8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane (216 mg; synthesized in example 2(1)) and palladium-carbon (50 mg; content 5) were suspended in a mixed solvent (6 ml) of ethanol, ethanol and ethyl acetate (1:1:1). In an atmosphere of hydrogen, the suspension was stirred for 90 min at room temperature. After stirring, the suspension was filtered through celite. The filtrate was condenced under reduced pressure. Thre residue was purified by column chromatography on silica gel (methylene chloride:methanol=19:1) to give the title compound (202 mg) having the following physical data:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[C:10](=[O:19])[O:9][N:8]=2)=[N:4][O:5][N:6]=1.[C:20]([O:24][C:25]([NH:27][CH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Cl:18][C:14]1[CH:13]=[C:12]([N:11]2[C:10](=[O:19])[O:9][N:8]=[C:7]2[C:3]2[C:2]([NH:1][C:33]([C:32]3[CH:31]=[CH:30][C:29]([CH2:28][NH:27][C:25](=[O:26])[O:24][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:37][CH:36]=3)=[O:34])=[N:6][O:5][N:4]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1nonc1-c1noc(=O)n1-c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2nonc2-c2noc(=O)n2-c2cccc(Cl)c2)cc1
Reaction time: 16 h
Yield: 23.8 %

Procedure:
A solution of 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-chlorophenyl)-1,2,4-oxadiazol-5(4H)-one (50 mg, 0.18 mmol) and 4-{[(tert-butoxycarbonyl)amino]methyl}benzoic acid (49 mg, 0.2 mmol) in dichloromethane (3.5 mL) was treated with 4-dimethylaminopyridine (13 mg, 0.1 mmol) and N,N-diisopropylethylamine (93 μL, 0.54 mmol). After the reaction mixture turned clear, it was treated with bromotris(pyrrolydino)phosphonium hexafluorophosphate (50 mg, 0.11 mmol) and additional N,N-diisopropylethylamine (93 μL, 0.54 mmol). The reaction mixture was stirred for 16 h, treated with additional bromotris(pyrrolydino)phosphonium hexafluorophosphate (50 mg, 0.11 mmol), and stirred for another 6 h. The reaction mixture was diluted with ethyl acetate (60 mL) and washed with 0.1 M HCl (2×25 mL) and brine (25 mL), dried with sodium sulfate, filtered, and concentrated. Purification of the crude reaction mixture by preparative LCMS gave the desired product (22 mg, 24%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:14]=1[NH2:15]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:15][C:14]1[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:13]=1[Cl:12])=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Product: O=C(Nc1cc(C(F)(F)F)ccc1Cl)c1cc(Br)ccc1O
Yield: 34.2 %

Procedure:
Using 5-bromosalicylic acid and 2-chloro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][CH:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([OH:11])=O)=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2].ON1C2C=CC=CC=2N=N1.C1C=CC2N(O)N=NC=2C=1.CN(C)CCCN=C=NCC.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1.Cl.[CH3:73][O:74][C:75]1[CH:86]=[C:85]2[C:78]([NH:79][CH:80]=[C:81]2[CH2:82][CH2:83][NH2:84])=[CH:77][CH:76]=1>CN(C=O)C>[CH3:73][O:74][C:75]1[CH:86]=[C:85]2[C:78](=[CH:77][CH:76]=1)[NH:79][CH:80]=[C:81]2[CH2:82][CH2:83][NH:84][C:9](=[O:11])[CH:8]([O:7][C:6]1[CH:16]=[CH:17][C:3]([C:1]#[N:2])=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:5]=1)[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CC(Oc1ccc(C#N)c(C(F)(F)F)c1)C(=O)O
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1ccc2[nH]cc(CCNC(=O)C(CC(C)C)Oc3ccc(C#N)c(C(F)(F)F)c3)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The compound was prepared in the following manner. To 0.25 gm (0.83 mmol) of 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid in dimethylformamdie “DMF” (15 mL) were added 0.14 gm (1.04 mmol) of 1-Hydroxy-benzotriazole HOBT, 0.2 gm (1.04 mmol) of (3-(dimethylamino)propyl)ethylcarbodiimide EDCl, 0.23 gm (2.28 mmol) N-methyl morpholine, and approximately 234 mg of 5-methoxytryptamine hydrochloride (1.04 mmol). The resultant mixtures were stirred at room temperature for approximately 18 hours. The reactions were quenched with sodium bicarbonate (20 mL) and extracted with ethyl acetate (3 times 20 mL). The solvent was removed in vacuo to obtain oils that were then purified by HPLC.
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])([O:5]CC)OCC.C(OC(=O)C)(=O)C.C([O:20][C:21](=O)[CH:22]([CH3:31])[C:23](=[O:30])[CH2:24][C:25](OCC)=O)C.[CH3:33][NH2:34]>C(OCC)C.O>[CH2:9]([O:8][C:1]([C:24]1[C:23]([OH:30])=[C:22]([CH3:31])[C:21](=[O:20])[N:34]([CH3:33])[CH:25]=1)=[O:5])[CH3:10]
Reactant: CCOC(=O)CC(=O)C(C)C(=O)OCC
Reactant: CCOC(OCC)OCC
Reactant: CN
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1cn(C)c(=O)c(C)c1O
Temperature: 135 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Triethyl orthoformate (3.85 mL, 23.12 mmol) and acetic anhydride (4.37 mL, 46.25 mmol) were added to 2-methyl-3-oxo-pentanedioic acid diethyl ester (Caliskan et al Aust. J. Chem. 1999, 52 (11), 1013-1020) (5.0 g, 23.1 mmol) and the reaction mixture heated to 135° C. After 1 hour, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was cooled to 0° C. and methylamine (40% in water, 5.0 mL, 57.81 mmol) was added with stirring. Water (20 mL) was added and the reaction mixture stirred for 16 hours. The reaction mixture was extracted with ethyl acetate and the aqueous layer acidified to pH 2 with 10% aqueous HCl. The acidified aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated to give a solid. Trituration with diethyl ether yielded 4.88 g (55%) clean desired product. 4-Hydroxy-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester was carried forward as described in Example 1, Steps B-D. MS APCI (−) m/z 353, 355 (M−, Br pattern) detected; 1H NMR (400 MHz, CD3OD) δ 8.49 (s, 1H), 7.36 (dd, 1H), 7.24 (dd, 1H), 6.71 (m, 1H), 3.60 (s, 3H), 1.68 (s, 3H).
Reaction SMILES: [CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)[C:2]#[CH:3].[CH2:20]=O.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[N:22]1([CH2:20][C:3]#[C:2][CH2:1][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: C#CCN1c2ccccc2C(=O)Nc2cccnc21
Reactant: C1COCCN1
Reactant: C=O
Product: O=C1Nc2cccnc2N(CC#CCN2CCOCC2)c2ccccc21
Yield: 19 %

Procedure:
Prepared analogously to Example lb) from 5,11-dihydro-11-(prop-2-ynyl)-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, paraformaldehyde and morpholine in a yield of 19% of theory. Colourless crystals, m.p. 168° C.
Reaction SMILES: C(OC([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][S:23]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:14]([CH:43]=O)[CH:13]=3)[CH2:9]1)=O)(C)(C)C>C(O)=O>[NH3:8].[CH3:21][C@@H:19]1[CH2:20][NH:8][CH2:9][C@@H:10]2[N:18]1[C:17]1[C:12]([CH2:11]2)=[CH:13][C:14]2=[CH:43][S:23][CH:22]=[C:15]2[N:16]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(C=O)c(CSC(c4ccccc4)(c4ccccc4)c4ccccc4)nc3N21
Solvent: O=CO
Product: C[C@@H]1CNC[C@H]2Cc3cc4cscc4nc3N21
Product: N
Yield: 168.3 %

Procedure:
A solution of 0.270 g (4R,9aR)-7-formyl-4-methyl-6-tritylsulfanylmethyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 5 ml 90% aqueous formic acid was kept at room temperature for 6 h. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and the aqueous phase was mixed with dichloromethane. The pH of the mixture was adjusted to 12.00 by addition of 2N aqueous sodium hydroxide and the phases were separated. The organic phase was evaporated and the residue was purified by chromatography on silica gel with dichloromethane:methanol:ammonia=90:10:1 to yield 0.092 g of the title compound as brownish solid (MS: 246.3 (M+H+)).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl>>[O:24]1[CH2:23][CH:22]1[CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(-c2ccc(OCC3CO3)cc2)cc1

Procedure:
A suspension of 10 g of 4-hydroxybiphenyl and 10 g of pulverised potassium carbonate in 75 ml of epichlorohydrin is stirred under reflux from 4 hours. The reaction mixture is concentrated by evaporation, water is added to the residue and the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulphate and concentrated by evaporation. The residue is recrystallised from isopropanol, yielding 4-(2,3-epoxypropoxy)-biphenyl having a melting point of 86°-88°.
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:15]2[C@:6]3([CH2:18][CH2:17][N:16]([CH3:19])[C@@H:14]2[CH2:13][C:12]2[CH:11]=[CH:10][C:9]([O:20][CH3:21])=[CH:8][C:7]3=2)[CH2:5][C:4](=[O:22])[CH2:3]1.C([O-])([O-])=O.[K+].[K+].[N:29]#CBr>C(Cl)(Cl)Cl>[C:19]([N:16]1[CH2:17][CH2:18][C@@:6]23[C:7]4[CH:8]=[C:9]([O:20][CH3:21])[CH:10]=[CH:11][C:12]=4[CH2:13][C@@H:14]1[C@@H:15]2[C@@H:2]([CH3:1])[CH2:3][C:4](=[O:22])[CH2:5]3)#[N:29]
Reactant: COc1ccc2c(c1)[C@]13CCN(C)[C@H](C2)[C@@H]1[C@@H](C)CC(=O)C3
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)[C@]13CCN(C#N)[C@H](C2)[C@@H]1[C@@H](C)CC(=O)C3
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A rapidly stirred mixture of 8β,17-dimethyl-3-methoxymorphinan-6-one (free base; prepared in Part A) in chloroform (1.0 g/10 ml) containing 1.5 g finely powdered dry K2CO3 was treated dropwise with a solution of cyanogen bromide in chloroform (1.2 equivalents; 1.0 g/20 ml). The mixture was stirred rapidly for 30 minutes and then heated at reflux for an additional two hours. The solution was cooled, filtered, evaporated to dryness and azeotroped with alcohol. The crystalline, mp. 202°-205° C., product was obtained in 81% yield and was used without further pruification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[N:12]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:13]=1[CH3:14].[I:23]I>ClC1C=CC=CC=1>[I-:23].[F:1][C:2]1[CH:11]=[CH:10][C:9]2[N+:8]3[CH:14]=[C:13]4[CH:15]=[CH:16][C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=5[N:12]4[C:7]=3[CH:6]=[CH:5][C:4]=2[CH:3]=1
Reactant: Cc1ccc2ccccc2n1
Reactant: Fc1ccc2ncccc2c1
Reactant: II
Solvent: Clc1ccccc1
Product: Fc1ccc2c(ccc3n4c(ccc5ccccc54)c[n+]23)c1
Product: [I-]
Temperature: 100 °C

Procedure:
A mixture of 294 g. of 6-fluoroquinoline, 74.6 g. of quinaldine, 1.7 l. of chlorobenzene and 254 g. of iodine is stirred for 2 hours at 20°-25° C., then stirred and heated at 100° C. for 4 days. About 1 l. of solvent is removed by evaporation at reduced pressure and the residue is cooled to 0°-5° C. The precipitate is collected, washed with cold chlorobenzene, dried and pulverized. The finely divided solid is suspended with stirring and cooling in 500 ml. of methanol and 55 ml. of hydrazine is added to destroy excess iodine. The resulting solid 3-fluoroimidazo[1,2-a:3,4-a']diquinolin-15-ium iodide is collected by filtration, washed with cold methanol and dried; m.p. 310°-316° C.
Reaction SMILES: [CH:1]([O-:3])=[O:2].[K+:4].[C:5](=[O:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[C:14]1([CH:21]=[CH:20][C:18]([OH:19])=[CH:17][CH:16]=1)[OH:15]>O>[OH:15][C:14]1[CH:21]=[C:20]([C:5]([O-:7])=[O:6])[C:18]([OH:19])=[CH:17][C:16]=1[C:1]([O-:3])=[O:2].[K+:4].[K+:4]
Reactant: Oc1ccc(O)cc1
Reactant: O=C=O
Reactant: O=C[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C([O-])c1cc(O)c(C(=O)[O-])cc1O
Yield: 87 %

Procedure:
In a glass reactor having a bottom outlet and equipped with a spiral-shaped stirrer and a thermocouple potassium formate (329 g) was melted under vacuum. When the temperature of the melt reached 190° C., the reactor was aerated with CO2 and potassium carbonate (125.04 g, 0.906 mole) and hydroquinone (80.06 g, 0.728 mole) were added to the melt. The reaction mixture was stirred at 200° C. under 1.5 bar CO2 for four and one-half hours. Then 250 ml of water were added to the reaction mixture, and the slurry was removed from the reactor and crystallized from 3.5 l of boiling water. After cooling, the product was filtered off and washed with ice water. Drying under vacuum at 100° C. produced 87% of pale yellow dipotassium 2,5-dihydroxyterephthalate (K2 -2,5-DHTA, 173.77 g, 0.634 mole). The filtrate was boiled down and the residue was reused in a carboxylating reaction using potassium carbonate (95.90 g, 0.695 mole) and hydroquinone (75.06 g, 0.682 mole). According to the above specification, 98% pale yellow K2 -2,5-DHTA (184.31 g, 0.673 mole) was obtained. Repetition of this recycle process using potassium carbonate (94.14 g, 0.682 mole) and hydroquinone (75.16 g, 0.683 mole) according to the above specification produced 95% pale yellow K2 -2,5-DHTA (178.65 g, 0.652 mole).