Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([O:15]CC)=O)[N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([Mg]Br)=[CH:21][CH:20]=1.C1COCC1.Cl.[Na+].[Cl-]>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[O:15])[N:3]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)c1nc(Cl)c2cccc(F)c2n1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)c1nc(Cl)c2cccc(F)c2n1
Temperature: -40 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
To a solution of ethyl 4-chloro-8-fluoroquinazoline-2-carboxylate (360 mg, 1.42 mmol) in THF (20 mL) at −40° C. was added 1M 4-fluorophenylmagnesium bromide/THF (1.7 mL, 1.7 mmol) and the mixture was stirred at −40° C. for 3 h. After this time, and additional portion of 1M 4-fluorophenylmagnesium bromide/THF (0.3 mL, 0.3 mmol) was added and the mixture was stirred at −40° C. for 2 h. To the mixture was added 0.5N HCl to give pH ˜2, and then saturated aq NaCl (50 mL) was added, and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford (4-chloro-8-fluoroquinazolin-2-yl)(4-fluorophenyl)methanone (0.4 g, 93%). 1H NMR (300 MHz, DMSO-d6) δ 7.04-7.25 (m, 1 H), 7.31-7.58 (m, 2 H), 7.70-8.36 (m, 4 H); LC-MS (ESI) m/z 305 (M+H)+, 327 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[S:5][C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1.O>C(O)C.COC(O)C.[Ni]>[CH3:1][C:2]1[N:3]=[C:4]([NH:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[S:5][C:6]=1[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=1
Reactant: CCOC(=O)CNc1nc(C)c(Cc2ccc([N+](=O)[O-])cc2)s1
Agent: [Ni]
Agent: COC(C)O
Solvent: O
Solvent: CCO
Product: CCOC(=O)CNc1nc(C)c(Cc2ccc(N)cc2)s1
Yield: 72.8 %

Procedure:
9.2 g of ethyl (4-methyl-5-(4-nitrobenzyl)thiazol-2-yl)aminoacetate in 500 ml of an ethanol/methoxyethanol mixture are hydrogenated at normal pressure and room temperature in the presence of Raney nickel. After filtration of the catalyst and concentration of the reaction medium, a brown oil is obtained which is taken up with acidified water, the aqueous phase is extracted with chloroform and then rendered basic and the precipitate obtained is filtered off to give 6.1 g of ethyl (4-methyl-5-(4-aminobenzyl)thiazol-2-yl)aminoacetate in the form of a brown solid melting at 116° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][N:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([C:26]2([C:31]([F:34])([F:33])[F:32])[CH2:30][CH2:29][NH:28][CH2:27]2)[CH:21]=[C:22]([Cl:25])[C:23]=1[Cl:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[C:20]([C:26]2([C:31]([F:34])([F:33])[F:32])[CH2:30][CH2:29][N:28]([C:2]3[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][N:3]=3)[CH2:27]2)[CH:21]=[C:22]([Cl:25])[C:23]=1[Cl:24]
Reactant: FC(F)(F)C1(c2cc(Cl)c(Cl)c(Cl)c2)CCNC1
Reactant: CCOC(=O)c1cnc(Cl)nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Temperature: 100 °C
Yield: 95 %

Procedure:
Ethyl 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate (1.2 g) [see J. Med. Chem., 43, 3995 (2000)], 3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)pyrrolidine (1.5 g), and potassium carbonate (0.7 g) were added to N,N-dimethylformamide (50 mL) and the mixture was heated at 100° C. for 5 hours. After cooling, the reaction solution was poured over ice water, and then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was then purified by a silica gel chromatography to obtain the title compound (2.4 g, 95%).
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[CH3:2].[OH-:20].[Na+]>S(=O)(=O)(O)O.O>[CH2:18]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6](=[O:20])[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[CH3:19].[O:20]=[NH:3]
Reactant: [OH-]
Reactant: CCN(CC)CC#CCCCc1cccc(OC)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCN(CC)CCC(=O)CCCc1cccc(OC)c1
Product: N=O

Procedure:
Add mercuric sulphate (0.45 g) to a swirled solution of 1-diethylamino-6-m-methoxyphenylhex-2-yne (8.5 g) in concentrated sulphuric acid (2.5 cc) and water (25 cc). Keep the solution under nitrogen at 75°C for 1 hour, then cool, make basic with 10% aqueous sodium hydroxide, and filter through glass wool to remove mercuric oxide. Extract product with ether and wash and dry the ethereal solution. Remove the solvent to obtain the crude ketoamine 1-diethylamino-6-m-methoxyphenylhexan-3-one, infrared absorption peak at 1710 μ. Distil under reduced pressure with partial elimination of diethylamine, to obtain a mixture of the ketoamine 1-diethylamino-6-m-methoxyphenylhexan-3-one and the vinyl ketone 6-m-methoxyphenylhex-1-en-3-one (7.1 g, ca. 76%), b.p. 140°-145°C/0.1 mm; infrared absorption peaks at 5.85 and 5.95 μ, the ketoamine predominating.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[CH2:44]([N:51]1[CH2:56][CH2:55][CH:54]([NH2:57])[CH2:53][CH2:52]1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(Cl)(Cl)Cl.O>[CH2:44]([N:51]1[CH2:56][CH2:55][CH:54]([NH:57][C:36]([NH:20][C:19]2[CH:21]=[C:22]([CH3:23])[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][C:18]=2[CH3:24])=[O:42])[CH2:53][CH2:52]1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)NC4CCN(Cc5ccccc5)CC4)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (140 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 1-benzyl-4-piperidineamine (89 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (124 mg, yield 74%).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][C:5]2[S:8][CH:9]=[N:10][C:4]=2[CH2:3]1.C([Li:15])CCC.[C:16](=[O:18])=[O:17]>O1CCCC1.CCCCCC>[CH3:1][CH:2]1[NH:7][CH2:6][C:5]2[S:8][C:9]([C:16]([O-:18])=[O:17])=[N:10][C:4]=2[CH2:3]1.[Li+:15]
Reactant: O=C=O
Reactant: CC1Cc2ncsc2CN1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1Cc2nc(C(=O)[O-])sc2CN1
Product: [Li+]
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
In anhydrous tetrahydrofuran (200 ml), 6-methyl -4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (6.43 g) was dissolved, followed by the dropwise addition of a solution (1.47M, 34.00 ml) of n-butyl lithium in n-hexane at an external temperature of −78° C. The resulting mixture was stirred for 40 minutes without changing the temperature. Then a carbon dioxide gas was blown into the reaction mixture for 1 hour. After warming up to room temperature, the reaction mixture was concentrated under reduced pressure, whereby the title compound (9.42 g, quant.) was obtained as a pale brown foamy solid.
Reaction SMILES: C([Li])CCC.[Br-].[OH:7][CH2:8][CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1>C1COCC1.O>[F:30][C:31]1[CH:38]=[CH:37][C:34](/[CH:35]=[CH:10]/[CH2:9][CH2:8][OH:7])=[CH:33][CH:32]=1
Reactant: OCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OCC/C=C/c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 47.6 %

Procedure:
n-Butyllithium (1.6M in H, 100 ml) was added dropwise to a stirred suspension of (3-hydroxypropyl)triphenylphosphonium bromide (32.1 g) in dry THF (200 ml) cooled to 0° C. under nitrogen. A solution of 4-fluorobenzaldehyde (9.93 g) in dry THF (100 ml) was added dropwise and the mixture stirred under nitrogen at 0° C. for 30 min and at room temperature for a further 1.5 h. The mixture was carefully diluted with water (25 ml), the solvent evaporated in vacuo at 40° and the residue partitioned between EA (200 ml) and water (200 ml). The aqueous phase was re-extracted with EA (200 ml), the organic phases combined, dried and evaporated in vacuo to give a brown oil. Purification by FCC eluting with CX-ER (1:1) gave the title compound as a colourless oil (6.33 g). T.l.c. (CX-ER 1:1) Rf 0.13
Reaction SMILES: FC(F)(F)[C:3](OC(=O)C(F)(F)F)=[O:4].CN(C)C=O.[Br:19][C:20]1[N:21]=[C:22]2[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:23]2=[N:24][C:25]=1[CH3:26]>ClCCl>[Br:19][C:20]1[N:21]=[C:22]2[C:29]([CH:3]=[O:4])=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:36])([CH3:35])[CH3:37])[C:23]2=[N:24][C:25]=1[CH3:26]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1nc2c(ccn2COCC[Si](C)(C)C)nc1Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc2c(nc1Br)c(C=O)cn2COCC[Si](C)(C)C
Yield: 84.8 %

Procedure:
Trifluoroacetic anhydride (10.2 mL, 60.8 mmol) was added dropwise, with cooling (ice bath), to N,N-dimethylformamide (24 mL) under an argon atmosphere. The cooling bath was removed for 15 min to facilitate stirring and then replaced. A solution of 2-bromo-3-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine (3.47 g, 10.1 mmol) in dichloromethane (5 mL) was added dropwise. The cooling bath was removed; the mixture was stirred for 15 min, then set in a bath at 45° C. and stirred for 16 h. The mixture was cooled, then poured onto ice water (200 mL) containing sodium carbonate (13 g) and extracted four times with ether. The combined ether extracts were washed twice with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography on (silica, 20% ethyl acetate in hexanes) gave 2-bromo-3-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (3.17 g, 84%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm −0.09 (s, 9H), 0.85 (t, J=8.0 Hz, 2H), 2.71 (s, 3H), 3.58 (t, J=8.0 Hz, 2H), 5.68 (s, 2H), 8.87 (s, 1H), 10.04 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Cl[CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[N:24]1>>[N:23]1([CH2:22][N:7]2[C:8]([C:9](=[O:18])[C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]2=[O:19])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[N:24]1
Reactant: ClCn1nnc2ccccc21
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(Cn2nnc3ccccc32)c(=O)[nH]c1=O
Yield: 33.5 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 1-chloromethyl-1H-benzotriazole were reacted by the same way with the example 1 to obtain the titled compound (135 mg, yield: 33.5%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=2)=[O:8])=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)C(C)C)C.[NH2:39][C:40]([CH3:55])([CH2:43][O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[C:51]([F:54])([F:53])[F:52])[C:41]#[N:42]>ClCCl.CN(C)C1C=CN=CC=1>[C:7]([C:9]1[CH:10]=[CH:11][C:12]([C:15]([NH:39][C:40]([C:41]#[N:42])([CH3:55])[CH2:43][O:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[C:51]([F:53])([F:54])[F:52])=[O:17])=[CH:13][CH:14]=1)(=[O:8])[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: CC(N)(C#N)COc1ccccc1C(F)(F)F
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C#N)(COc1ccccc1C(F)(F)F)NC(=O)c1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66.9 %

Procedure:
330 mg of benzophenone-4-carboxylic acid are dissolved in 6 ml of dichloromethane, then 283 mg of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 18 mg of 4-dimethylaminopyridine and 222 mg of ethyldiisopropylamine are added, and stirred for 20 minutes at room temperature. 300 mg of 2-amino-2-methyl-3-(2-trifluoromethylphenoxy)-propionitrile are subsequently added, and the mixture stirred for a further 40 hours. Afterwards, the mixed solution is washed with an aqueous sodium bicarbonate solution, then with a 1 n hydrochloric acid solution and finally with a saturated sodium chloride solution. The organic phase is then separated, dried with sodium sulphate, filtered and concentrated by evaporation. After recrystallisation in diethylether, the residue yields 372 mg of the title compound with a melting point of 121-123° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[Br:30][C:31]1[C:32]([O:39][CH3:40])=[N:33][CH:34]=[C:35]([CH:38]=1)[CH:36]=O>C1COCC1>[Br:30][C:31]1[C:32]([O:39][CH3:40])=[N:33][CH:34]=[C:35](/[CH:36]=[CH:2]/[O:3][CH3:4])[CH:38]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ncc(C=O)cc1Br
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CO/C=C/c1cnc(OC)c(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
A solution of (methoxymethyl)triphenylphosphonium chloride (737 mg, 2.15 mmol) in THF (10 mL) at −78° C. was added t-BuOK (1 M in THF, 2.15 mL, 2.15 mmol) and stirred at 0° C. for 30 mins, then added dropwisely a solution of 5-bromo-6-methoxynicotinaldehyde (310 mg, 1.435 mmol) in THF (6 mL) at 0° C. via cannulation. The mixture was stirred and gradually warmed to rt overnight. The mixture was concentrated and the residue was purified via a flash column using 50% ethyl acetate in hexanes as an eluent. The product containing fractions were concentrated to give (E)-3-bromo-2-methoxy-5-(2-methoxyvinyl)pyridine (296.9 mg, 85% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)Cl>[CH2:1]([O:3][C:4]1[N+:5]([O-:22])=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2]
Reactant: CCOc1cc2ccccc2cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOc1cc2ccccc2c[n+]1[O-]
Temperature: 25 °C
Yield: 69.9 %

Procedure:
3-Ethoxyisoquinoline (1.5 g, 8.7 mmol) was taken up in DCM (45 mL) at 0° C. mCPBA (77%, 4.1 g, 18.3 mmol) was added slowly and the resulting solution allowed to warm to rt overnight. The reaction volume was doubled with additional DCM and washed with 1M NaOH. Following separation and extraction with DCM, the combined organics were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo to afford 3-ethoxyisoquinoline N-oxide (1.15 g, 69%) as a white low melting solid that was used without further purification. LCMS found 190.05 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([NH2:22])=[CH:11][CH:10]=1)C1C=CC=CC=1.CO[C:25](OC)(OC)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([C:25]2[N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:13]3=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]3[N:22]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(OC)(OC)c1ccccc1
Reactant: Nc1ccc(OCc2ccccc2)nc1Nc1ccccc1
Product: Oc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2n1

Procedure:
From 6-(benzyloxy)-N2-phenylpyridine-2,3-diamine and trimethyl orthobenzoate, prepared in a similar manner as the one described in Example 1.117, the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.61 (d, J=8.3 Hz, 1H), 7.29-7.57 (m, 10H), 8.00 (d, J=8.6 Hz, 1H), 11.07 (broad s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:13]([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)(N1C=CN=C1)=O.O.[CH2:26]1[CH2:30]O[CH2:28][CH2:27]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:22]([CH3:21])[C@H:23]2[C@H:24]([N:20]3[CH2:13][CH2:9][CH2:4][CH2:5]3)[CH2:6][C:7]3[C:27](=[CH:26][CH:30]=[CH:3][CH:2]=3)[CH2:28]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CN(C(=O)Cc1ccc(Cl)c(Cl)c1)[C@@H]1Cc2ccccc2C[C@H]1N1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,4-Dichlorophenylacetic acid (1.05 %) and carbonyldiimidazole (856 mg) were dissolved in dry THF (20 ml). This solution was cannulated into a stirred suspension of the above product (1.0 g) in methylene chloride (20 ml) at 0° . The mixture was allowed to warm to room temperature and stirred overnight. Water (50 ml) and methylene chloride (100 ml) were added and the organic layer was separated, washed with brine, dried, and evaporated to give a crude product which was chromatographed (silica gel; CH2Cl2 : CH3OH=40:1) to yield the pure free base of the title compound (1.2 g). Its naphthalenesulfonate was recrystallized from ethyl acetate: 2-propanol; m.p. 161°-164°.
Reaction SMILES: C(OC([N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:20])[CH:17]=2)[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=O)C1C=CC=CC=1>CC(O)=O.Br>[ClH:27].[CH2:33]([O:32][C:30](=[O:31])[CH2:29][O:28][C:22]1[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=1[CH:12]1[C:13]2[C:18](=[CH:17][C:16]([F:20])=[CH:15][CH:14]=2)[CH2:19][NH:11]1)[CH3:34]
Reactant: CCOC(=O)COc1ccc(Cl)cc1C1c2ccc(F)cc2CN1C(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: CCOC(=O)COc1ccc(Cl)cc1C1NCc2cc(F)ccc21
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (±)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-5-fluoro-1,3-dihydro-isoindole-2-carboxylic acid benzyl ester (165 mg, 0.34 mmol, 1.0 eq.) in AcOH (3.0 mL), 33% hydrobromic acid in acetic acid (3.0 mL) was added. The mixture was stirred at r.t. for 2 hours. The reaction mixture was concentrated in vacuo. The residue was stirred in 1.25M HCl in ethanol (5.0 mL) at r.t. for 18 hours. The reaction mixture was concentrated in vacuo to give the desired salt as a colorless oil.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1.[C:20]1(=O)[CH2:23][CH2:22][CH2:21]1.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.CC(C)=O.ClCCl>[C:5]([C:20]1([NH:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:13]=2)[CH2:23][CH2:22][CH2:21]1)#[N:6]
Reactant: Nc1ccc(CCCC(=O)O)cc1
Reactant: O=C1CCC1
Reactant: C[Si](C)(C)C#N
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#CC1(Nc2ccc(CCCC(=O)O)cc2)CCC1
Reaction time: 15 h
Yield: 86 %

Procedure:
Trimethylsilyl cyanide (0.50 g, 5 mmol) was added dropwise to a mixture of 4-(4-aminophenyl)-butyric acid (0.537 g, 3 mmol), cyclobutanone (0.35 g, 5 mmol) and sodium sulfate (1 g) in 1,4-dioxane (10 ml). The mixture was stirred for 15 hours. After filtration to eliminate sodium sulfate, the medium was concentrated under vacuum to obtain a brown liquid which was subjected to chromatography (dichloromethane:acetone, 50:50) to yield 4-[4-(1-Cyanocyclobutylamino)-phenyl]-butyric acid (91) (0.665 g, 2.58 mmol, 86%) as a yellowish solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:26][C@H:27]([C:34]([NH:36][C@H:37]([CH:42]=NNC(N)=O)[CH2:38][CH:39]([CH3:41])[CH3:40])=[O:35])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)=[O:25])[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([OH:52])CCC.C(O)(=O)C>O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:26][C@H:27]([C:34]([NH:36][C@H:37]([CH:42]=[O:52])[CH2:38][CH:39]([CH3:40])[CH3:41])=[O:35])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)=[O:25])[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@@H](C=NNC(N)=O)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1
Reactant: CCCCO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)C[C@@H](C=O)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1

Procedure:
A solution of 200 mg. of N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-histidyl-L-leucinal semicarbazone in 2 ml. of the upper layer of a 4:1:5 by volume mixture of 1-butanol, glacial acetic acid and water was subjected to partition chromatography on a Sephadex (trade mark) G-25 column (column size: 2.5 cm. inner diameter×100.5 cm. length) and eluted with the same solvent as above. Fractions coloured with Pauli's reagent and 2,4-dinitrophenylhydrazine were collected and the solvent was removed under reduced pressure from the collected fractions. When diethyl ether was added to the residue, there were obtained 96 mg. of the desired compound as a white powdery solid, melting at 106°-108° C.; [α]22 -49.0° (C=0.5, methanol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][C:13]([N+:21]([O-:23])=[O:22])=[C:12]2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][C:27]=1[F:34].O>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][C:13]([N+:21]([O-:23])=[O:22])=[C:12]2[NH:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][C:27]=1[F:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(N)c(F)c1
Reactant: COc1cc2ncc([N+](=O)[O-])c(Cl)c2cc1OCc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2ncc([N+](=O)[O-])c(Nc3ccc(C#N)cc3F)c2cc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
6-Benzyloxy-4-chloro-7-methoxy-3-nitroquinoline (6.75 g, 19.58 mmol) and 4-amino-3-fluorobenzonitrile (2.46 g, 18.1 mmol) were dissolved in glacial acetic acid (106 ml) and stirred at 50° C. for 18 h overnight. The suspension obtained was subsequently added to water (1 l) and stirred for a further 30 min. The precipitate formed was filtered off with suction, rinsed with water and dried in vacuo, giving 4-(6-benzyloxy-7-methoxy-3-nitro-quinolin-4-ylamino)-3-fluorobenzonitrile (6.69 g, 15.06 mmol) as solid. MS: 445.1 (M+H+), TLC (HPTLC): Rf=0.31 (cyclohexane/ethyl acetate 2:1, parts by volume).
Reaction SMILES: C1(C[O:8][C:9]2[C:14]([O:15]CC3C=CC=CC=3)=[CH:13][N:12]=[C:11]([CH:23]=[O:24])[CH:10]=2)C=CC=CC=1.[H][H]>CN(C)C=O.[Pd]>[OH:15][C:14]1[C:9](=[O:8])[CH:10]=[C:11]([CH:23]=[O:24])[NH:12][CH:13]=1
Reactant: O=Cc1cc(OCc2ccccc2)c(OCc2ccccc2)cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=Cc1cc(=O)c(O)c[nH]1
Yield: 76.7 %

Procedure:
To a solution of 4,5-bis(phenylmethoxy)-2-pyridinecarboxaldehyde (1.9 g, 6.0 mmol) in 25 ml of dry dimethylformamide was added 0.2 g of palladium on charcoal catalyst and hydrogen was bubbled through the mixture for three hours. The catalyst was removed by filtration, the solvent distilled off in vacuo and the residue triturated with ether to give 0.64 g of the title compound, melting point 174°-177° C., dec.