Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:11]2[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=2[O:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[CH:6]=1)=[O:4].C(N=C(N(C)C)N(C)C)(C)(C)C.[N+:33]([CH3:36])([O-:35])=[O:34]>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]2[O:9][C:8]3[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=3[CH:6]([CH2:36][N+:33]([O-:35])=[O:34])[CH:5]([C:3]([O:2][CH3:1])=[O:4])[C:11]=2[CH:12]=1
Reactant: COC(=O)C1=Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: C[N+](=O)[O-]
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Product: COC(=O)C1c2cc(Cl)ccc2Oc2ccccc2C1C[N+](=O)[O-]

Procedure:
Example 8 of the European Patent EP 1710241 B1 also describes an alternative process for the synthesis of the lactam (VI), see Scheme 4. In this example, (5-chloro-2-phenoxyphenyl)acetic acid methyl ester (compound VIIIa) is reacted with methyl formate in the presence of potassium tert-butoxide to give 2-(5-chloro-2-phenoxyphenyl)-3-hydroxyacrylic acid methyl ester (compound IXa, E/Z mixture 9:1), which is directly cyclized with pyrophosphoric acid to obtain methyl 2-chlorodibenzo[b,f]oxepin-11-carboxylate (compound Xa), referred to us 8-chlorodibenzo[b,f]oxepin-10-carboxylic acid methyl ester in EP 1710241 B1, with 85% yield. This compound is then reacted with nitromethane in the presence of tert-butyl-tetramethylguanidine to give methyl 2-chloro-10-nitromethyl-10,11-dihydrodibenzo[b,f]oxepine-11-carboxylate (compound XIa), referred to us 8-chloro-1′-nitromethyl-10,11-dihydrodibenzo[b,f]oxepine-10-carboxylic acid methyl ester in EP 1710241 B1, with a trans to cis ratio of 8:1, which is directly hydrogenated in the presence of a sponge nickel catalyst to give methyl 10-aminomethyl-2-chloro-10,11-dihydrodibenzo[b,f]oxepine-11-carboxylate (compound XIIa), referred to us 11-aminomethyl-8-chloro-10,11-dihydrodibenzo[b,f]oxepine-10-carboxylic acid methyl ester in EP 1710241 B1, which after treatment with potassium tert-butoxide and dimethyl sulphate, is converted into the lactam (VIa) with an overall yield of 81% from compound (Xa), but predominantly corresponding to the undesired cis-isomer (approximately 85:15 ratio with respect to the trans-isomer), being therefore necessary to carry out one of the above described low-yield processes for the conversion of undesired cis-(VI) to trans-(VI).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:29][C:30]([NH:32][C@@H:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C@H:36]([O:43][C:44]3[CH:45]=[CH:46][C:47]4[N:48]([C:50]([N:53]5[CH2:58][CH2:57][CH2:56][CH2:55][C@@H:54]5[CH3:59])=[N:51][N:52]=4)[CH:49]=3)[CH2:35][CH2:34]2)=[O:31])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])=[C:12]([CH2:27]Cl)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:60][N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:29][C:30]([NH:32][C@@H:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C@H:36]([O:43][C:44]3[CH:45]=[CH:46][C:47]4[N:48]([C:50]([N:53]5[CH2:58][CH2:57][CH2:56][CH2:55][C@@H:54]5[CH3:59])=[N:51][N:52]=4)[CH:49]=3)[CH2:35][CH2:34]2)=[O:31])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])=[C:12]([CH2:27][N:64]3[CH2:65][CH2:66][N:61]([CH3:60])[CH2:62][CH2:63]3)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)cc1CCl)(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)cc1CN1CCN(C)CC1)(C(C)C)C(C)C
Temperature: 50 °C
Yield: 49.8 %

Procedure:
A solution of Intermediate 61f (31.0 mg, 0.04 mmol) in THF (0.4 mL) was treated with 1-methyl-piperazine (41 μL, 0.37 mmol) and the mixture was heated to 50° C. for 64 h. The mixture was evaporated in vacuo and the residue was partitioned between DCM and water. The aqueous layer was then extracted with DCM (2×). The combined organic layers were washed with water (2×), dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-5% [2M NH3 in MeOH] in DCM, to give the title compound as a colorless glass (18 mg, 55%). LCMS (Method 3): Rt 3.64 min, m/z 903.7 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:20][CH2:21][CH2:22][N:23]3C(=O)C4C(=CC=CC=4)C3=O)[N:11]([CH3:19])[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:20][CH2:21][CH2:22][NH2:23])[N:11]([CH3:19])[C:12]=2[C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(SCCN2C(=O)c3ccccc3C2=O)nc(-c2ccc(F)cc2)c1-c1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(SCCN)nc(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
100 ml of HCl 10% are added to 2-{2-[4-(4-fluorophenyl)-1-methyl-5-pyridin-4-yl-1H-imidazol-2-ylsulfanyl]ethyl}isoindole-1,3-dione (2 mmol/0.917 g), and the mixture is stirred at room temperature for 6 h. The mixture is then slowly neutralized using 2N NaOH, resulting in the precipitation of 2-[4-(4-fluorophenyl)-1-methyl-5-pyridin-4-yl-1H-imidazol-2-ylsulfanyl]ethylamine as a white crystalline powder. The precipitate is filtered off with suction and washed with a little ice-cold water and dried over P2O5.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]([C:15]1[CH:24]=[C:23]2[C:18]([C:19](=[O:25])[CH2:20][CH2:21][O:22]2)=[CH:17][CH:16]=1)=[CH2:14].[CH2:26]([C:29]1[CH:37]=[CH:36][C:32]([C:33](F)=[O:34])=[CH:31][CH:30]=1)[CH2:27][CH3:28]>C1COCC1>[CH2:26]([C:29]1[CH:30]=[CH:31][C:32]([C:33]([CH:20]2[C:19](=[O:25])[C:18]3[C:23](=[CH:24][C:15]([CH:13]=[CH2:14])=[CH:16][CH:17]=3)[O:22][CH2:21]2)=[O:34])=[CH:36][CH:37]=1)[CH2:27][CH3:28]
Reactant: CCCc1ccc(C(=O)F)cc1
Reactant: C=Cc1ccc2c(c1)OCCC2=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=Cc1ccc2c(c1)OCC(C(=O)c1ccc(CCC)cc1)C2=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 30.7 %

Procedure:
To a flame-dried 10 mL round-bottom flask under nitrogen charged with butyllithium (2.5 M in hexanes) (0.875 mL, 2.19 mmol) in THF (1 mL) at 0° C. was added diisopropylamine (0.312 mL, 2.19 mmol) dropwise. The solution was stirred at 0° C. for 20 min. The solution was then cooled to −78° C., and 7-vinylchroman-4-one (Preparation 2D, 1.79 M in THF) (1.02 mL, 1.82 mmol) was added dropwise via syringe. The mixture was stirred for 20 min. at −78° C. 4-propylbenzoyl fluoride (0.303 g, 1.823 mmol) in 1 mL of THF was then added dropwise via syringe, and the reaction mixture was stirred at −78° C. for 60 min. and then warmed to room temperature. The reaction was quenched with 1N aqueous hydrochloric acid (5 mL) and extracted with ethyl acetate (3×20 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The yellow residue was purified by flash silica gel chromatography using a mixture of ethyl acetate in hexane (5%-12%) to give 3-(4-propylbenzoyl)-7-vinylchroman-4-one (0.179 g, 0.559 mmol, 31% yield). The compound was triturated with methanol with sonication, filtered, washed with methanol, and dried to give 3-(4-propylbenzoyl)-7-vinylchroman-4-one (0.125 g, 0.390 mmol, 21% yield) as a yellow solid. LC/MS M+1=321.2. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.91 (t, 3H), 1.58-1.68 (m, J=7.42, 7.42, 7.42, 7.42, 7.21 Hz, 2H), 2.65 (t, J=7.63 Hz, 2H) 4.71-4.77 (m, 1H), 4.78-4.83 (m, 1H), 5.20 (dd, J=9.16, 4.99 Hz, 1H), 5.47 (d, J=11.10 Hz, 1H), 6.05 (d, J=17.76 Hz, 1H), 6.73-6.82 (m, 1H), 7.17 (s, 1H) 7.24 (dd, J=8.18, 1.25 Hz, 1H), 7.38 (d, J=8.32 Hz, 2H), 7.73 (d, J=8.05 Hz, 1H), and 7.96 (d, J=8.32 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH2:19][NH2:20])([C:8]2[S:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=2)[CH2:4][CH2:3]1.[F:21][C:22]([F:38])([F:37])[C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](O)=[O:32])[N:24]=1>>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]([CH2:19][NH:20][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][CH:36]=[C:28]([C:25]3[N:24]=[C:23]([C:22]([F:38])([F:37])[F:21])[O:27][N:26]=3)[CH:29]=2)([C:8]2[S:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=2)[CH2:6][CH2:7]1
Reactant: CN1CCC(CN)(c2nc(-c3ccccc3)cs2)CC1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: CN1CCC(CNC(=O)c2cccc(-c3noc(C(F)(F)F)n3)c2)(c2nc(-c3ccccc3)cs2)CC1
Yield: 23 %

Procedure:
This compound was synthesized from (1-methyl-4-(4-phenylthiazol-2-yl)piperidin-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (9 mg, 23% yield): 1H NMR (300 MHz, CDCl3) δ 8.51 (s, 1H), 8.21 (d, J=7.5 Hz, 1H), 7.98 (d, J=7.5 Hz, 1H), 7.86 (d, J=6.3 Hz, 1H), 7.78 (m, 1H), 7.54 (t, J=6.2 Hz, 2H), 7.48 (s, 1H), 7.34-7.25 (m, 2H), 3.86 (s, 2H), 2.69 (m, 2H), 2.57 (m, 4H), 2.34 (s, 3H), 2.13 (m, 2H). MS (ESI) m/z: Calculated for C26H24F3N5O2S: 527.16. found: 528.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:12][CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])=[O:4].[OH-].[Li+]>C1COCC1.CCO.O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)[CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:4]
Reactant: CCOC(=O)CCCC(Nc1cc(-c2ccccc2)sc1C(=O)OC)C1CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COC(=O)c1sc(-c2ccccc2)cc1NC(CCCC(=O)O)C1CCCCC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
To a solution of 3-(1-Cyclohexyl-4-ethoxycarbonyl-butylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester (40 mg, 0.09 mmol, 1.0 equiv) in THF (0.4 mL), EtOH (0.2 mL), water (0.4 mL) was added lithium hydroxide (18.9 mg, 0.45 mmol, 5.0 equiv). The resulting mixture was stirred at 50° C. for 2 hours, after which the organic solvent was removed under vacuum. The resulted solution was neutralized by addition of 1.0 N HCl aq. solution until pH=6. The mixture was extracted with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated to product 30 mg (yield 83%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[O:22]>C(Cl)Cl>[C:21](=[O:22])([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])[O:11][C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)COC(=O)OC(=O)CNC(=O)OC(C)(C)C

Procedure:
One millimole of t-butoxycarbonyl-glycine in 10 ml methylene chloride at 0° is treated successively with one millimole each of triethylamine and isobutyl chloroformate, forming N-(t-butoxycarbonyl)glycyl i-butyl carbonate. To this solution at -78° is added p-nitrobenzyl 5-methoxymethyl 6H-1,3-thiazine-4-carboxylate and then a second millimole of triethylamine. The reaction mixture is allowed to warm to room temperature over one hour, and kept at 25° one hour. The mixture is then washed successively with aqueous pH 2 buffer, water, and aqueous bicarbonate, dried with MgSO4, filtered and evaporated, affording p-nitrobenzyl 7-t-butoxycarbonylamino-3-methoxymethyl decephalosporanate, which may be purified if desired by chromatography on silica gel, eluting with 4:1 chloroform-ethyl acetate.
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[CH3:8][O:9][CH2:10][CH2:11][C:12]1[N:13]([CH2:33][CH2:34][CH3:35])[C:14]2[C:23]3[CH:22]=[CH:21][C:20]([O:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[CH:19][C:18]=3[N:17]=[C:16]([NH2:31])[C:15]=2[N:32]=1.O>C(Cl)(Cl)Cl.C(O)C>[NH2:31][C:16]1[C:15]2[N:32]=[C:12]([CH2:11][CH2:10][O:9][CH3:8])[N:13]([CH2:33][CH2:34][CH3:35])[C:14]=2[C:23]2[CH:22]=[CH:21][C:20]([O:24][CH:25]3[CH2:26][CH2:27][N:28]([C:6]([NH2:5])=[O:7])[CH2:29][CH2:30]3)=[CH:19][C:18]=2[N:17]=1
Reactant: CCCn1c(CCOC)nc2c(N)nc3cc(OC4CCNCC4)ccc3c21
Reactant: C[Si](C)(C)N=C=O
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCO
Product: CCCn1c(CCOC)nc2c(N)nc3cc(OC4CCN(C(N)=O)CC4)ccc3c21
Reaction time: 0.67 h

Procedure:
Trimethylsilylisocyanate (0.225 mL, 1.67 mmol) was added dropwise to a slurry of 2-(2-methoxyethyl)-7-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-ylamine (prepared as described in Part A of Example 388, 0.640 g, 1.67 mmol) in chloroform (16 mL) at 0° C. The reaction mixture was stirred for 40 minutes and water (10 mL) was added. The reaction mixture was stirred vigorously for 2 hours, diluted with 200 mL ethanol, and then concentrated under reduced pressure to approximately 100 mL. Another 100 mL ethanol was added and the solution was evaporated to afford a white solid that was recrystallized from ethanol to provide 0.625 g of 4-{[4-amino-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxamide as granular off-white crystals, mp 207-208.5° C.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)=[O:2].[C:12]([OH:16])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)O
Product: CC(C)(C)OC(=O)c1ccc(C=O)cc1

Procedure:
The starting 4-formylbenzoic acid t-butyl ester was prepared from 4-formylbenzoic acid chloride by esterification with t-butanol.
Reaction SMILES: C([NH:4][C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[CH3:17])(=O)C>Cl>[NH2:4][C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[CH3:17]
Reactant: CC(=O)Nc1c(C)cc(C(=O)O)cc1[N+](=O)[O-]
Agent: Cl
Product: Cc1cc(C(=O)O)cc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
A suspension of 4-acetamido-3-methyl-5-nitrobenzoic acid (38 g, 0.16 mol) in 3N hydrochloric acid (800 mL) was heated at reflux for 8 h and then stirred at room temperature for 8 h. The yellow solid was collected by filtration and transferred to a 2 L flask with a mixture of methylene chloride and methanol. The solvent was evaporated under high vacuum to give the title compound (23 g, 74% yield). 1H-NMR (DMSO-d6, 300 MHz) δ 12.79 (bs, 1H), 8.46 (s, 1H), 7.79 (s, 1H), 7.61 (s, 2H), 2.34 (s, 3H). 13C-NMR (d6-DMSO, 75 MHz) δ 166.0, 147.0, 135.1, 130.0, 126.4, 125.9, 116.7, 17.9. LC/MS: tR=1.23 min, 195 (MH)−.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([NH2:9])[N:3]=1.C(O)(=O)C.[N:14]([O-])=[O:15].[Na+]>O>[NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([N:14]=[O:15])=[C:4]([NH2:9])[N:3]=1
Reactant: Nc1cc(O)nc(N)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(N)c(N=O)c(O)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a solution of 2,6-diamino-4-hydroxypyrimidine (12.9 g, 102.2 mmoles) in 200 ml of a 10% acetic acid solution in water at 80° C. was added dropwise a solution of NaNO2 (7.05 g, 102.2 mmoles) in 20 ml water. A pink precipitate was formed, which was further stirred for 1 hour at 80° C. The reaction mixture was cooled down in the refrigerator overnight. The precipitate was filtered off and dried over P2O5, providing the title compound as a pink powder (15.43 g, yield: 97%). The spectral data are in accordance with literature data (Landauer et al. in J. Chem. Soc. (1953) 3721-3722).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>C(O)C>[Br:1][C:2]1[C:3]([N:9]=[CH:12][N:13]([CH3:15])[CH3:14])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: COC(OC)N(C)C
Reactant: Nc1nc(Br)cnc1Br
Solvent: CCO
Product: CN(C)C=Nc1nc(Br)cnc1Br

Procedure:
A mixture of 3,6-dibromo-pyrazin-2-ylamine (15.37 g, 60.80 mmol) and N,N-dimethylformamide dimethyl acetal (10.1 mL, 76.00 mmol), suspended in ethanol (150 mL), is refluxed for 2 hours. The reaction mixture is evaporated in vacuo affording the title compound. 1H-NMR (400 MHz, CDCl3) δ (ppm) 3.20 (s, 3H), 3.21 (s, 3H), 7.93 (s, 1H), 8.48 (s, 1H). LCMS: Rt 3.81 min (99.1%), m/z (APCI) 307 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[C:4]([NH:6][C:7]([CH3:15])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])=[O:5].CN([CH:24]=[O:25])C>C1COCC1>[Cl:1][C:2]1[C:3]2[C:4](=[O:5])[N:6]([C:7]([CH3:15])([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:8])[CH:24]([OH:25])[C:16]=2[C:17]([Cl:20])=[CH:18][N:19]=1
Reactant: CN(C)C=O
Reactant: CC(C)(NC(=O)c1cc(Cl)cnc1Cl)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(c1ccccc1)N1C(=O)c2c(Cl)ncc(Cl)c2C1O
Yield: 71.7 %

Procedure:
In a similar manner to Step 2 of Example 16, 2,5-dichloro-N-(1-methyl-1-phenylethyl)nicotinamide (400 mg, 1.29 mmol) was dissolved in THF (16 mL), and the solution was treated with n-butyllithium-hexane solution (2.71 mol/L, 1.20 mL, 3.23 mmol) and DMF (0.250 mL, 3.23 mmol), followed by purification by slurry (diisopropylether) and flash column chromatography (hexane/ethyl acetate=60/40 to 50/50) to obtain 4,7-dichloro-1-hydroxy-2-(1-methyl-1-phenylethyl)-1,2-dihydropyrrolo[3,4-c]pyridine-3-one (312 mg, yield 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10].[H-].[Na+].CCCCCC.[NH:33]1[CH:37]=[CH:36][CH:35]=[N:34]1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:33]2[CH:37]=[CH:36][CH:35]=[N:34]2)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10]
Reactant: c1cn[nH]c1
Reactant: O=C(c1ccc(F)cc1Cl)N1Cc2cccn2Cc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(c1ccc(-n2cccn2)cc1Cl)N1Cc2cccn2Cc2ccccc21

Procedure:
In the manner of Example 9's Method 1, employing (2-chloro-4-fluorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.0 g), 60% sodium hydride in oil (0.2 g, degreased with hexane), pyrazole (0.20 g) and dimethylformamide (25 ml), the title compound was obtained as an amorphous solid, MS, m/z: 389.2 (M+H)+, 777.1 (2M+H)+.
Reaction SMILES: [H][H].Cl[C:4]1[C:9]([O:10][CH3:11])=[C:8](Cl)[N:7]=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([O:19]CC3C=CC=CC=3)=[CH:15][CH:14]=2)[N:5]=1.C(N(CC)CC)C.C(O)C>[Pd].O>[CH3:11][O:10][C:9]1[CH:8]=[N:7][C:6]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[N:5][CH:4]=1
Reactant: [H][H]
Reactant: COc1c(Cl)nc(-c2ccc(OCc3ccccc3)cc2)nc1Cl
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: COc1cnc(-c2ccc(O)cc2)nc1
Temperature: 40 °C
Reaction time: 6 h
Yield: 76 %

Procedure:
Hydrogen gas was blown into a mixture of 21 g of 4,6-dichloro-5-methoxy-2-(4-benzyloxyphenyl)pyrimidine, 18.1 g of triethylamine, 3.15 g of 10% palladium-on-carbon, 210 ml of ethanol, and 11 ml of water, followed by stirring at 40° C. for 6 hours. The catalyst was removed by filtration, and the filtrate was poured into 300 ml of water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and distilled to remove ethyl acetate to afford 8.93 g (percent yield: 90.9%) of 5-methoxy-2-(4-hydroxyphenyl)pyrimidine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)=[CH:6][CH:5]=1)([O-])=O.CN(C=O)C.Cl.[OH-].[Na+]>[Fe].O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=[CH:17][C:18]2[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(C=CC=CC=CC=Cc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(C=CC=CC=CC=Cc2ccc(N)cc2)cc1
Temperature: 50 °C

Procedure:
11.28 g of the 1,8-bis(4-nitrophenyl)-1,3,5,7-octatetraene synthesized in Synthesis Example 1 was added to 250 ml of DMF. To this mixture, 22.5 g of iron powder was added, and then diluted hydrochloric acid consisting of 5.6 ml of concentrated hydrochloric acid and 19 ml of water was added with stirring. The mixture was further stirred at 80°~88° C. for 5 hours. The reaction mixture was cooled to 50° C. and was made alkaline by addition of a 10% aqueous solution of sodium hydroxide. Celite was added to the reaction mixture, and then insoluble components were filtered out, together with the Celite, from the reaction mixture, while it was hot. The filterate was diluted with water. As a result, crystals separated out. The crystals were filtered off, washed with water and dried, so that a crude diamino product was obtained. The product was recrystallized from a mixed solvent of DMF and water, whereby 1,8-bis(4-aminophenyl)-1,3,5,7-octatetraene was obtained in the form of dark red plate crystals. The melting point was 262.5°~264.5° C.
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N+:17]([O-])=O)[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[NH2:17][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH2:16][NH:8][CH2:9]2
Reactant: O=[N+]([O-])c1cccc2c1CN(Cc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Product: Nc1cccc2c1CNC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.6 %

Procedure:
11.5 g of 2-benzyl-4-nitroisoindoline was dissolved in 150 ml of methanol and to the solution was added 1.5 g of 10% palladium on carbon. The mixture was stirred under a hydrogen gas stream under atmospheric pressure for one day at room temperature and for another 5 days at 40° C.. The catalyst was removed by filtration and the filtrate was concentrated. The residue was purified by a vacuum distillation (bath temperature: 150°-180° C., pressure: 0.1 mmHg) to obtain 3.74 g of 4-aminoisoindoline.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.ClC1C=CC(Cl)=CC=1C(Cl)=O.S(Cl)(Cl)=O.[CH3:27][O:28][CH2:29][CH2:30][N:31]1[C:35]([CH3:36])=[C:34]([CH3:37])[S:33][C:32]1=[NH:38].CCN(CC)CC>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4](/[N:38]=[C:32]1\[S:33][C:34]([CH3:37])=[C:35]([CH3:36])[N:31]\1[CH2:30][CH2:29][O:28][CH3:27])=[O:6]
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: COCCn1c(C)c(C)sc1=N
Agent: O=C(Cl)c1cc(Cl)ccc1Cl
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1cc(Cl)ccc1Cl
Yield: 25.5 %

Procedure:
The 2,5-dichlorobenzoic acid (Aldrich, 0.28 g, 1.4 mmol) was converted to 2,5-dichlorobenzoyl chloride with 5 mL of thionyl chloride using the method described in Example 134A. The product of Example 126A (0.20 g, 1.1 mmol), Et3N (0.45 mL, 3.2 mmol) and 2,5-dichlorobenzoyl chloride in 15 mL THF were processed using the method described in Example 132 to afford the title compound (0.10 g, 0.28 mmol, 26% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.25 (d, J=1.0 Hz, 3H), 2.28 (d, J=1.0 Hz, 3H), 3.31 (s, 3H), 3.76 (t, J=5.3 Hz, 2H) 4.36 (t, J=5.3 Hz, 2H), 7.28 (d, J=2.4 Hz, 1H), 7.32-7.36 (m, 1H), 7.94 (d, J=2.4 Hz, 1H); MS (DCI/NH3) m/z 359 (M+H)+; Anal. calculated for C15H16Cl2N2O2S: C, 50.15; H, 4.49; N, 7.80. Found: C, 50.22; H, 4.15; N, 7.63.