Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:61])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([C@@H:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:60])[CH:48]([NH:55][C:56]([O:58][CH3:59])=[O:57])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].COC(N[C@H](C1C=CC=CC=1)C(O)=O)=O>>[CH3:1][O:2][C:3](=[O:61])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:32]=[CH:33][C:34]([C:37]5[NH:38][C:39]([C@H:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:60])[CH:48]([NH:55][C:56]([O:58][CH3:59])=[O:57])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)=[CH:35][CH:36]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Agent: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Product: COC(=O)NC(C(=O)N1CCC[C@@H]1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Yield: 65 %

Procedure:
This compound was prepared following the procedure for [1-(2-{5-[6-(4-{2-[1-(2S)-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using (R)-methoxycarbonylamino-phenyl-acetic acid (0.02 g, 0.09 mmol, 1.5 equiv.) to provide [1-(2-{5-[6-(4-{2-[1-(2R)-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.03 g, 65%) as a white powder. LCMS-ESI+: calc'd for C47H50N8O6: 822.4 (M+). Found: 823.8 (M+H+). 1H-NMR: 400 MHz, (CDCl3): (Mixture of rotomers) 7.62-8.02 (m, 9H), 7.36-7.43 (m, 6H), 7.22 (s, 2H), 6.01 (s, 1H), 5.29-5.53 (m, 4H), 4.35 (t, 1H), 3.73-3.87 (m, 2H), 3.68 (s, 3H), 3.63 (s, 3H), 3.22 (q, 2H), 2.82-2.96 (m, 2H), 2.37 (m, 1H), 2.23 (m, 2H), 1.90-2.11 (m, 4H), 0.87-0.93 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[CH2:5]I.[CH2:12]([O:14][P:15]([O:19]CC)[O:16][CH2:17][CH3:18])[CH3:13]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[CH2:5][P:15](=[O:19])([O:16][CH2:17][CH3:18])[O:14][CH2:12][CH3:13]
Reactant: Fc1cc(CI)cc(F)c1F
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1cc(F)c(F)c(F)c1)OCC
Temperature: 135 °C
Reaction time: 8 h

Procedure:
3,4,5-trifluorobenzyl iodide (5.075 g, 22.55 mmol) was combined with triethylphosphite (11.6 mL, 67.7 mmol) and the mixture heated and stirred at 135° C. overnight. The mixture was put under hi-vacuum and heated to 70° C. for 12 hours. The final product was a clear oil (6.10 g, 96% yield). 1H NMR (400.14 MHz, CDCl3) δ 6.93 (m, 2H), 4.07 (quint, J=7.10 Hz, 4H), 3.06 (d, J=21.7 Hz, 2H), 1.28 (t, J=7.05 Hz, 6H). 13C{1H} NMR (100.62 MHz, CDCl3) δ 150.8 (dddd, J=249.7, 9.8, 3.8, 3.8 Hz, 2C), 138.74 (dtd, J=250.6, 15.2, 3.9 Hz), 128.2-127.9 (m), 113.9-113.6 (m, 2C), 62.30 (d, J=6.74 Hz, 2C), 32.93 (d, J=139.8 Hz), 16.20 (d, J=6.01 Hz, 2C). 31P{1H} NMR (202.45 MHz, CDCl3): δ 24.96. Analysis calculated (found) %: C 46.82 (46.72), H 5.00 (4.96). MS (FAB, m/z): 269 (M+, 100%). Exact mass calculated (found) for [M+H]+, m/z): 269.05544 (269.05616).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH:10]1[CH:15]([CH3:16])[C:14](=[CH2:17])[CH2:13][CH2:12][NH:11]1.[CH2:18]([O:22]C=O)CCC>>[CH:18]([N:11]1[CH2:12][CH2:13][C:14](=[CH2:17])[CH:15]([CH3:16])[CH:10]1[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:22]
Reactant: C=C1CCNC(Cc2ccccc2OC)C1C
Reactant: CCCCOC=O
Product: C=C1CCN(C=O)C(Cc2ccccc2OC)C1C

Procedure:
8 g (34 mmol) of 2-(2-methoxyphenyl)methyl-3-methyl-4-methylene-piperidine 16 as base and 30 mL of n-butylformate were used. Yield: 9.1 g (100%) as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:17](OC([O-])=O)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CC#N>[C:20]([O:19][C:17]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: OCCC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 93.6 %

Procedure:
Amine preparation: To a solution of 4-piperidine ethanol (540 mg) in MeCN (8 mL) was added triethylamine (0.70 mL) followed by tert-butyl dicarbonate (1.00 g). The mixture was stirred at room temperature for 22 h and partitioned between 0.5 M hydrochloric acid and ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and the solvent evaporated to give 4-(2-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (897 mg). This was dissolved in THF (14 mL) and sodium hydride added (172 mg; 60% dispersion in mineral oil) at 0° C. After 30 min iodomethane (0.97 mL) was added and the mixture stirred for 22 h. The mixture was diluted with ethyl acetate and washed with water, brine and dried (MgSO4). The solvent was evaporated and the residue purified by flash chromatography to give 4-(2-methoxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (724 mg). To a solution of 4-(2-methoxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (284 mg) in DCM (5 mL) was added 2M hydrogen chloride in diethyl ether (5.0 mL) and the mixture stirred for 21 h. The solvent was evaporated to give the desired amine as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:10](=[O:26])[N:11]([O:22][CH2:23][O:24][CH3:25])[C:12]2([CH2:19][CH2:18][N:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[C:13]=1[OH:14].C(N(CC)CC)C.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:10](=[O:26])[N:11]([O:22][CH2:23][O:24][CH3:25])[C:12]2([CH2:15][CH2:16][N:17]([O:20][CH3:21])[CH2:18][CH2:19]2)[C:13]=1[O:14][C:37]([CH:34]1[CH2:36][CH2:35]1)=[O:38]
Reactant: COCON1C(=O)C(c2cc(C)ccc2C)=C(O)C12CCN(OC)CC2
Reactant: O=C(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCON1C(=O)C(c2cc(C)ccc2C)=C(OC(=O)C2CC2)C12CCN(OC)CC2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.5 %

Procedure:
To a solution of 3-(2,5-dimethyl-phenyl)-4-hydroxy-8-methoxy-1-methoxymethoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one (compound P2ii.2) (200 mg, 0.55 mmol), triethylamine (0.153 ml, 111 mg, 1.10 mmol) and a catalytic amount of 4-dimethylaminopyridine in tetrahydrofuran (6 ml) at 0° C. was added cyclopropanecarboxylic acid chloride (0.066 ml, 75 mg, 0.72 mmol) dropwise. The suspension was stirred at 0° C. for 10 minutes, and at room temperature for one hour. The reaction mixture was evaporated, diluted with ethyl acetate and filtered to remove salts. The filtrate was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/hexane 1:2) to afford 200 mg of an oily product. This material was triturated with diethyl ether, filtered and dried. Yield: 190 mg of cyclopropanecarboxylic acid 3-(2,5-dimethyl-phenyl)-8-methoxy-1-methoxymethoxy-2-oxo-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester (title compound P1ii.4) as a white solid, mp 114-116° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:25]=[C:24]([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH:23]=[CH:22][C:6]=1[CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH3:18])=[C:12]([O:19][CH3:20])[CH:11]=1.N1C=CC=CC=1.[C:38](Cl)(=[O:40])[CH3:39]>ClCCl>[C:38]([NH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:25]=[C:24]([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH:23]=[CH:22][C:6]=1[CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH3:18])=[C:12]([O:19][CH3:20])[CH:11]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)Cl
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCCN)cc(OC)c1C
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCCNC(C)=O)cc(OC)c1C
Reaction time: 1.5 h
Yield: 34.2 %

Procedure:
To a solution of compound 44a (21 mg, 0.05 mmol) and pyridine (0.008 mL, 0.1 mmol) in dichloromethane (1 mL) was added acetyl chloride (0.004 mL, 0.055 mmol). The reaction mixture was stirred for 1.5 h, and additional acetyl chloride (0.004 mL) was added. After an additional 5 min, the reaction was quenched by addition of water and concentrated. The residue was purified by reverse phase HPLC (C18 column, water/acetonitrile gradient containing 0.1% TFA) to afford compound 45a (8 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.[Li]CCCC.CON(C)[C:20](=[O:30])[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:22][CH3:23].O>C1COCC1>[CH3:11][O:10][CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:20](=[O:30])[CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH3:23])=[CH:3][CH:4]=1
Reactant: COCOc1ccc(Br)cc1
Reactant: CCC(C(=O)N(C)OC)c1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCC(C(=O)c1ccc(OCOC)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
To a stirred solution of 13 (99.0 g, 0.46 mol) in anhydrous THF (750 mL) was added n-BuLi (1.6 M in hexanes, 310 mL, 0.50 mol) dropwise at −78° C. The reaction mixture was stirred for 30 min and 14 (90.1 g, 0.43 mol) dissolved in THF (500 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 1 h and then slowly warmed to 0° C. H2O (500 mL) was added and the volatiles were removed under reduced pressure. The residue was extracted with Et2O (3×500 mL) and the combined extracts were washed with water (500 mL) and brine (500 mL). The mixture was dried over MgSO4 and concentrated. The residue was recrystallized from hexanes to afford 97.6 g (80%) of 15 as white needles. 1HNMR (400 MHz, DMSO-d6): δ 0.79 (t, J=7.3 Hz, 3H), 1.68 (h, J=7.0 Hz, 1H), 2.03 (h, J=7.0 Hz, 1H), 3.32 (s, 3H), 4.65 (t, J=7.3 Hz, 1H), 5.21 (s, 2H), 7.03 (d, J=8.8 Hz, 2H), 7.15 (t, J=7.1 Hz, 1H), 7.23-7.30 (m, 4H), 7.98 (d, J=8.8 Hz, 2H).
Reaction SMILES: [CH2:1]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(=O)([O-])[O-].[Na+].[Na+].C(O)C.Cl[CH2:28][C:29]#[N:30]>CO>[CH2:10]([N:9]([CH2:28][C:29]#[N:30])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: N#CCCl
Reactant: CCCCCCCCNCCCCCCCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CCCCCCCCN(CC#N)CCCCCCCC
Yield: 70 %

Procedure:
73.9 g (0.3 mol) of di-n-octylamine were initially introduced together with 31.8 g (0.3 mol) of sodium carbonate into 240 ml of absolute ethanol. At room temperature, 22.9 g (0.3 mol) of chloroacetonitrile were added and the mixture was stirred at reflux until starting material could no longer be detected by means of thin-layer chromatography (stationary phase: silica gel; mobile phase: methanol). The reaction mixture was filtered off and the filtrate was evaporated to dryness on a rotary evaporator. The residue was subjected to fractional distillation. At 145° C. and 0.04 mbar a fraction is obtained which is pure according to NMR spectroscopy. 58.4 g (0.21 mol) of di-n-octylaminoacetonitrile were isolated in the form of a clear liquid, corresponding to a yield of 69%.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)=[CH:5][NH:4][N:3]=1.[CH2:20]([O:22][C:23](=[O:34])[C:24](=[CH:30]OCC)[C:25](OCC)=[O:26])[CH3:21].[O-]CC.[Na+].C(O)C.Cl>O.C(O)C>[CH2:13]([C:10]1[CH:9]=[CH:8][C:7]([C:6]2[CH:5]=[N:4][N:3]3[C:25]([OH:26])=[C:24]([C:23]([O:22][CH2:20][CH3:21])=[O:34])[CH:30]=[N:1][C:2]=23)=[CH:12][CH:11]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1n[nH]cc1-c1ccc(Cc2ccccc2)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnc2c(-c3ccc(Cc4ccccc4)cc3)cnn2c1O
Yield: 99.7 %

Procedure:
A mixture of 3-amino-4-(4-benzylphenyl)pyrazole (0.75 g), ethoxymethylenemalonic diethylester (1.30 g) and ethanol (30 ml) was stirred under heating reflux for 48 hours. After cooling, sodium ethoxide -ethanol was added, and was stirred at room temperature for 12 hours. Then, at 0° C., 10% hydrochloric acid was added to adjust to acid, and water (50 ml) was added and stirred for 30 minutes. The precipitate was separated by filtration, washed with water, and dried to give the title compound (1.12 g).
Reaction SMILES: C[N:2]1C(=O)CCC1.N.Br[C:10]1[CH:18]=[C:17]([Cl:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][CH3:21])[N:15]=2)[CH:11]=1>C(OCC)(=O)C.[Cu](I)I>[Cl:19][C:17]1[C:16]2[C:12](=[CH:13][N:14]([CH2:20][CH3:21])[N:15]=2)[CH:11]=[C:10]([NH2:2])[CH:18]=1
Reactant: CN1CCCC1=O
Reactant: CCn1cc2cc(Br)cc(Cl)c2n1
Agent: I[Cu]I
Agent: N
Solvent: CCOC(C)=O
Product: CCn1cc2cc(N)cc(Cl)c2n1
Temperature: 80 °C
Reaction time: 10 h

Procedure:
Copper oxide (I) (200 mg), NMP (7 mL), and concentrated aqueous ammonia (7 mL) were added to 5-bromo-7-chloro-2-ethyl-2H-indazole obtained in the above-described Step 1 (1.43 g), and the reaction solution was stirred in a microwave reactor at 80° C. for 10 hours. The reaction solution was cooled to room temperature, and diluted with ethyl acetate. Thereafter, the reaction solution was washed successively with water four times and then with a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum, and the resultant was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain 7-chloro-2-ethyl-2H-indazol-5-amine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([Cl:13])=[N:7][C:8](Cl)=[CH:9][C:10]=1[CH3:11])=[O:4].C([O-])([O-])=O.[K+].[K+].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:6]([Cl:13])=[N:7][C:8]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:9][C:10]=1[CH3:11])=[O:4]
Reactant: C1COCCN1
Reactant: COC(=O)c1c(C)cc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(C)cc(N2CCOCC2)nc1Cl
Yield: 30.4 %

Procedure:
A solution of 5.2 g (23.7 mmol) 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid methylester, 3.94 g (28.5 mmol) K2CO3 and 2.06 ml (23.7 mmol) morpholine in DMF (48 ml) was heated to 60° C. for 16 h. Then the mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 4:1) provided 1.95 g (7.2 mmol, 30%) 2-chloro-4-methyl-6-morpholino-pyridine-3-carboxylic acid methylester.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH3:14])[C:8]=1[NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH3:6].C(O)(=O)C.N([O-])=O.[Na+]>O>[CH2:5]([C:7]1[CH:12]=[C:11]([N+:1]([O-:4])=[O:2])[CH:10]=[C:9]([CH2:13][CH3:14])[C:8]=1[NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)(=[O:17])=[O:18])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CCc1cccc(CC)c1NS(=O)(=O)c1ccc(C)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCc1cc([N+](=O)[O-])cc(CC)c1NS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 115 ml nitric acid (d=1.42) in water (900 ml) are added successively 129.9 g (0.43 moles) of N-(2,6-diethylphenyl)-p-toluenesulfonamide, glacial acetic acid (900 ml) and sodium nitrite (3.2 g). The mixture is boiled on a steam bath for 1.5 hours, then poured into ice water (2 l). The precipitate is filtered washed with water and air-dried to give crude N-(2,6-diethyl-4-nitrophenyl)-p-toluenesulfonamide.
Reaction SMILES: Cl[C:2]1[C:13]2=[C:14]3[N:9]([CH:10]([CH3:16])[CH2:11][C:12]2=[O:15])[CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:6](=[O:20])[C:5]3=[CH:4][C:3]=1[Cl:21].[CH2:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH3:23]>COCCO>[Cl:21][C:3]1[CH:4]=[C:5]2[C:14]3[N:9]([CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:6]2=[O:20])[CH:10]([CH3:16])[CH2:11][C:12](=[O:15])[C:13]=3[C:2]=1[N:27]1[CH2:28][CH2:29][N:24]([CH2:22][CH3:23])[CH2:25][CH2:26]1
Reactant: CC1CC(=O)c2c(Cl)c(Cl)cc3c(=O)c(C(=O)O)cn1c23
Reactant: CCN1CCNCC1
Solvent: COCCO
Product: CCN1CCN(c2c(Cl)cc3c(=O)c(C(=O)O)cn4c3c2C(=O)CC4C)CC1
Reaction time: 2 h
Yield: 80 %

Procedure:
3.26 g (0.01 mole) of 8, 9-dichloro-5-methyl-6, 7-dihydro-1,7-dioxo-1H, 5H-benzo[ij]quinolizine-2-carboxylic acid was suspended in 30 ml of methyl cellosolve, 3.43 g (0.03 mole) of N-ethylpiperazine was added thereto, and this mixture was stirred at 100°-110° C. for 2 hours. The resulting reaction solution was evaporated to dryness under reduced pressure. 30 ml of methanol was added to the resulting residue and this mixture was stirred. The insoluble matter was collected by filtration and recrystallized from ethanol to obtain 3.23 g (80.0% yield) of 9-chloro-5-methyl-8-(4-ethyl-1-piperazinyl)-6,7-dihydro-1, 7-dioxo-1H, 5H-benzo[ij]quinolizine-2-carboxylic acid in the form of yellow crystals. These crystals had a melting point of 295°-298° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[C:7]([CH3:13])[C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:17])=O>CN(C=O)C.ClCCl>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[C:7]([CH3:13])[C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(F)c(F)cc(F)c1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(F)c(F)cc(F)c1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A solution of 5.8 g (30.5 mmol) of 2,4,5-trifluoro-6-methylbenzoic acid, 4.7 g (37.0 mmol) of oxalyl chloride, and 100 ml of dichloromethane was treated with three drops of DMF. The reaction mixture was stirred at room temperature for two hours, then concentrated to give 6.3 g of the title compound as an oily solid. The product was used "as is" in the next step.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:8]2[C:18]([CH2:22]O)=[CH:19][CH:20]=[CH:21][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:26])=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:8]2[C:18]([CH2:22][Cl:26])=[CH:19][CH:20]=[CH:21][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cccc(CO)c2n1Cc1ccccc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCc1nc2cccc(CCl)c2n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 2-n-butyl-1-(2-chlorophenyl)methyl-7-hydroxymethyl-1H-benzimidazole (1.01 g, 2.76 mmol) in methylene chloride (50 mL) was added thionyl chloride (0.61 mL). The resulting solution was stirred at ambient temperature for one hour, the solvent was evaporated, the residue triturated with toluene and then petroleum ether, and the white crystals (1.06 g) of 2-n-butyl-7-chloromethyl-1-(2-chlorophenyl)methyl-1H-benzimidazole were isolated and washed well with ether to give the title compound as the hydrochloride salt; mp 180°-184° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1.Br[CH2:15][C:16]([C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1)=O>>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:11]=[CH:10][C:6]([C:7]2[O:8][CH:15]=[C:16]([C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=3)[N:9]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccc(C(=O)CBr)cc1
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1
Product: CCOC(=O)c1ccc(-c2coc(-c3ccc(C(F)(F)F)cc3)n2)cc1
Yield: 21 %

Procedure:
In the same manner as in Example 1, 4-trifluoromethylbenzamide was reacted with ethyl 4-bromoacetylbenzoate to obtain ethyl 4-[2-(4-trifluoromethylphenyl)-4-oxazolyl]benzoate. The product was recrystallized from ethanol. Yield: 21%. Pale yellow prisms. Melting Point: 168 to 170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([I:9])[CH:3]=1.[CH:10]1[CH:15]=[CH:14][C:13]([CH:16](Br)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:16]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]=1[I:9])([C:13]1[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: Nc1ccc(Cl)cc1I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(NC(c2ccccc2)c2ccccc2)c(I)c1
Temperature: 45 °C
Yield: 95.5 %

Procedure:
To a solution of 4-chloro-2-iodoaniline (16.5 g, 65.1 mmol) in DMF (250 mL) at rt were added α-bromodiphenylmethane (21.5 g, 84.6 mmol) and iPr2NEt (23 mL, 130 mmol) and the reaction mixture was heated at 45° C. overnight. After the volatile was removed under reduced pressure, the residue was dissolved in EtOAc, washed with water (3×) and brine and dried over MgSO4. Purification on SiO2 column chromoatography (hexanes to 5% EtOAc/hexanes) gave the desired Benzhydryl-(4-chloro-2-iodo-phenyl)-amine (26.1 g, 97% yield) as a yellowish solid.
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH3:12])=[N:10][N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]=2[NH2:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(N=[C:23]=[O:24])C>N1C=CC=CC=1>[CH3:12][C:11]1[C:7]2[C:1]3[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=3[C:23](=[O:24])[NH:19][C:8]=2[N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]=1
Reactant: Cc1nn(-c2ccccc2)c(N)c1C1=CCCCC1
Reactant: CCN=C=O
Solvent: c1ccncc1
Product: Cc1nn(-c2ccccc2)c2[nH]c(=O)c3c(c12)CCCC3
Yield: 35.3 %

Procedure:
To a solution of EXAMPLE 7A (1.26 g, 5 mmol) in pyridine (10 mL) was added ethyl isocyanate (1.18 mL, 15 mmol). The solution was heated at reflux for 7 hours, cooled, concentrated and the residue triturated with methanol. The solid was collected by filtration, washed with methanol and dried to give 493 mg (35%) of the title compound. 1H NMR (DMSO-d6) 1.72-1.83 (m, 4H), 2.49-2.55 (m, 2H), 2.57 (s, 3H), 3.05 (t, J=5.2 Hz, 2H), 7.24 (t, J=7.4 Hz, 1H), 7.43-7.53 (m, 2H), 8.19 (d, J=7.7 Hz, 2H), 11.27 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.CCN(CC)CC.[CH2:17]=[O:18].Cl>CC#N>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([OH:9])[C:3]=1[CH:17]=[O:18]
Reactant: Oc1cc(F)cc(F)c1
Reactant: C=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=Cc1c(O)cc(F)cc1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of commercially available 3,5-difluorophenol (3.000 g; 23.10 mmol), anh. magnesium chloride MgCl2 (6.587 g; 69.20 mmol), and NEt3 (8.04 ml; 57.70 mmol) in anh. MeCN (100 ml) was stirred at rt, under nitrogen, for 20 min. Paraformaldehyde (3.459 g; 115.00 mmol) was then added, and the resulting mixture was heated to 80° C., under nitrogen, for 1.5 h. After cooling to rt, aq. 1N HCl (80 ml) was added, and the aq. layer was extracted with AcOEt. The mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 2,4-difluoro-6-hydroxybenzaldehyde as a yellow oil. LC-MS (conditions A): tR=0.67 min.; no ionisation.