Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:30][C:31]1[C:39]([NH2:40])=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([NH2:35])=[O:34].N>N1C=CC=CC=1.CN(C=O)C>[NH2:30][C:31]1[C:32]([C:33]([NH2:35])=[O:34])=[CH:36][CH:37]=[CH:38][C:39]=1[NH:40][C:13](=[O:15])[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:17])[CH3:16]
Reactant: NC(=O)c1cccc(N)c1N
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Agent: N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)Nc1cccc(C(N)=O)c1N
Temperature: 40 °C
Reaction time: 8 h

Procedure:
2-{[(Benzyloxy)carbonyl]amino}-2-methylpropanoic acid (5.18 g, 21.83 mmol) in a mixture of pyridine (25 mL) and DMF (25 mL) was treated with 1,1′-carbonyldiimidazole (3.72 g, 22.92 mmol) and heated at 40° C. for 2 hours. 2,3-Diaminobenzamide dihydrochlolide (4.89 g, 21.83 mmol), prepared as described in WO0026192, was added and the mixture was stirred at room temperature overnight. The solvents were removed under vacuum and the residue was partitioned between ethyl acetate and diluted sodium bicarbonate aqueous solution. The formed slightly yellow solid material was collected by filtration, washed with water and ethyl acetate, and dried to give Example 1A. MS (DCI/NH3) m/z 371 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.NC1CC2CC1CC2.[Cl:22][C:23]1[CH:60]=[CH:59][C:26]([C:27]2[C:32]([C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[C:38]([C:43]5N(CC)[C:46]6[CH:50]=[CH:51][C:52]([C:54](O)=O)=[CH:53][C:45]=6[N:44]=5)[CH:39]=4)[N:34]=3)=[CH:31][C:30]([O:57][CH3:58])=[CH:29][CH:28]=2)=[CH:25][CH:24]=1>>[CH:46]12[CH2:54][CH:52]([CH2:51][CH2:50]1)[CH2:53][CH:45]2[N:44]1[C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N:11]=[C:43]1[C:38]1[CH:39]=[C:40]2[C:35](=[CH:36][CH:37]=1)[N:34]=[C:33]([C:32]1[C:27]([C:26]3[CH:59]=[CH:60][C:23]([Cl:22])=[CH:24][CH:25]=3)=[CH:28][CH:29]=[C:30]([O:57][CH3:58])[CH:31]=1)[CH:42]=[CH:41]2
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCn1c(-c2ccc3nc(-c4cc(OC)ccc4-c4ccc(Cl)cc4)ccc3c2)nc2cc(C(=O)O)ccc21
Agent: NC1CC2CCC1C2
Product: COc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CC5CCC4C5)ccc3n2)c1

Procedure:
The title compound was prepared from Resin 534a and 2-aminonorbornane according to the procedure described in the preparation of Compound 534.
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1C=CC=CC=1.C/C(/C(C)=O)=N\O.[F:28]C1C=CC(C=O)=CC=1>>[F:28][C:17]1[CH:18]=[CH:19][C:14]([C:5]2[O:6][C:7]([CH3:8])=[C:3]([CH2:2][I:1])[N:4]=2)=[CH:15][CH:16]=1
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)/C(C)=N/O
Product: Cc1oc(-c2ccc(F)cc2)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and 4-fluorobenzaldehyde gave 2-(4-fluorophenyl)-4-iodomethyl-5-methyloxazole.
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[Cl:7][CH2:8][C:9]([CH2:14]Cl)([CH3:13])[C:10]([Cl:12])=O.P(Cl)(Cl)(Cl)=O.Cl>O1CCOCC1>[CH3:1][NH:2][C:3]1[S:6][C:13]([C:9]([CH2:10][Cl:12])([CH2:8][Cl:7])[CH3:14])=[N:5][N:4]=1
Reactant: CNC(=S)NN
Reactant: CC(CCl)(CCl)C(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: CNc1nnc(C(C)(CCl)CCl)s1

Procedure:
To a stirred suspension of 34 g of 4-methylthiosemicarbazide in 50 ml of dioxane was added 60 g of α,α-bischloromethyl propionyl chloride, then heated to reflux temperature. Carefully 50 g of phosphorus oxychloride was added and heating continued until HCl evolution ceased. After cooling, the supernatant liquid was decanted from the viscous material that had separated, water was added and the mixture taken to a pH of 10 with sodium hydroxide pellets. No precipitate formed. The solution was extracted with chloroform, the extract was shaken with water then with saturated sodium chloride solution and was then dried over Na2 SO4. The chloroform was removed at reduced pressure and the residue crystallized with a mixture of methylene chloride-petroleum ether to give 27.8 g, m.p. 105°-107° (36%). An analytical sample, m.p. 108°-109°, was prepared from methylene chloride-petroleum ether.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1.[CH3:15][O:16][C:17]1[CH:58]=[C:57]([O:59][CH3:60])[CH:56]=[CH:55][C:18]=1[CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[N:28]([S:45]([C:48]3[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=3)(=[O:47])=[O:46])[C:29]([C:31]3[C:39]4[C:34](=[CH:35][C:36]([O:42][CH3:43])=[C:37]([O:40][CH3:41])[CH:38]=4)[N:33]([CH3:44])[CH:32]=3)=[CH:30][C:23]=12.O>ClCCl>[CH3:15][O:16][C:17]1[CH:58]=[C:57]([O:59][CH3:60])[CH:56]=[CH:55][C:18]=1[CH2:19][N:20]([CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[N:28]([S:45]([C:48]3[CH:49]=[CH:50][C:51]([CH3:54])=[CH:52][CH:53]=3)(=[O:47])=[O:46])[C:29]([C:31]3[C:39]4[C:34](=[CH:35][C:36]([O:42][CH3:43])=[C:37]([O:40][CH3:41])[CH:38]=4)[N:33]([CH3:44])[CH:32]=3)=[CH:30][C:23]=12)[C:11]([NH:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=1)=[O:12]
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: COc1ccc(CNCc2ccnc3c2cc(-c2cn(C)c4cc(OC)c(OC)cc24)n3S(=O)(=O)c2ccc(C)cc2)c(OC)c1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccnc3c2cc(-c2cn(C)c4cc(OC)c(OC)cc24)n3S(=O)(=O)c2ccc(C)cc2)C(=O)Nc2ccc(OC(F)(F)F)cc2)c(OC)c1
Reaction time: 24 h

Procedure:
0.094 cm3 of 4-(trifluoromethoxy)phenyl isocyanate is added to a solution of 0.080 g of (2,4-dimethoxybenzyl)[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amine in 6 cm3 of dichloromethane, under an argon atmosphere, at a temperature in the region of 20° C. The reaction medium is stirred at this same temperature for 24 hours. 2 cm3 of water are added. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. After purification by flash-pack chromatography (SiO2, dichloromethane/methanol 98/02 by volume as eluent), 0.150 g of 1-(2,4-dimethoxybenzyl)-1-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]-3-(4-trifluoromethoxyphenyl)urea is obtained, the characteristics of which are as follows:
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:17]=3[N:16]=[C:15]2[CH2:24][CH3:25])=[CH:10][CH:9]=1)(=[O:4])[CH2:2][CH3:3].[CH3:26][S:27](Cl)(=[O:29])=[O:28].N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:1]([O:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([NH:23][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:22][C:17]=3[N:16]=[C:15]2[CH2:24][CH3:25])=[CH:12][CH:13]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)OCCc1ccc(-n2c(CC)nc3cc(N)ccc32)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)OCCc1ccc(-n2c(CC)nc3cc(NS(C)(=O)=O)ccc32)cc1
Reaction time: 6 h
Yield: 88 %

Procedure:
To a stirred solution of 2-[4-(5-amino-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl propionate (step 4, 1.18 g, 3.50 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (0.40 mL, 5.25 mmol) and pyridine (0.42 mL, 5.25 mmol) at room temperature. After stirring for 6 h, the mixture was poured into 10% aqueous citric acid (100 mL) and extracted with ethyl acetate (100 mL). The aqueous layer was made basic with saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (100 mL). The combined organic extracts were washed with brine (100 mL) and dried (MgSO4), and concentrated to afford 1.28 g (88%) of the title compound as brown amorphous: 1H-NMR (CDCl3) δ 8.47 (1H, s), 7.66 (1H, d, J=1.7 Hz), 7.50 (2H, d, J=8.4 Hz), 7.42 (1H, dd, J=2.0, 8.8 Hz), 7.41 (2H, d, J=8.4 Hz), 7.09 (1H, d, J=8.8 Hz), 4.39 (2H, t, J=7.0 Hz), 3.09 (2H, t, J=6.8 Hz), 3.00 (2H, q, J=7.7 Hz), 2.36 (2H, q, J=7.7 Hz), 1.42 (3H, t, J=7.7 Hz), 1.15 (3H, t, J=7.5 Hz).
Reaction SMILES: [CH:1]1([N:11]2[C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]=[CH:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:22][CH2:23][O:24][CH3:25]>CN(C)C=O>[CH:1]1([N:11]2[C:15]([C:16]([O:18][CH2:22][CH2:23][O:24][CH3:25])=[O:17])=[CH:14][N:13]=[CH:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cncn1C1CCCc2ccccc21
Reactant: COCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOC(=O)c1cncn1C1CCCc2ccccc21
Reaction time: 1 h
Yield: 46.7 %

Procedure:
4.8 Parts of 1-(1,2,3,4-tetrahydro-1-naphthalenyl)-1H-imidazole-5-carboxylic acid are dissolved in 94 parts of warm N,N-dimethylformamide. 0.96 Parts of a sodium hydride dispersion 50% are added portionwise to the thus obtained reaction mixture. Upon complete addition, stirring is continued for 1 hour at room temperature. After the addition of 2.0 parts of 1-chloro-2-methoxyethane, the whole is stirred overnight at 90° C. The reaction mixture is evaporated and the residue is taken up in water. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated, yielding 2.8 parts (46.7%) of (2-methoxyethyl) 1-(1,2,3,4-tetrahydro-1-naphthalenyl)-1H-imidazole-5-carboxylate; mp. 66.8° C. (compound 1.83).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[N:12]1([CH2:18][CH2:19][O:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([NH2:31])=[CH:23][CH:22]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:31][C:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]([O:20][CH2:19][CH2:18][N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[CH:22][CH:23]=1)=[O:8]
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Reactant: COc1cccc(C(=O)O)c1
Product: COc1cccc(C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)c1

Procedure:
Compound is prepared from 3-methoxybenzoic acid and 4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-ylamine according to conditions described in general procedure G. Mp: 105-107° C.; 1H NMR (300 MHz, DMSO-d6) δ 2.57 (t, J=4.8 Hz, 4H), 2.88 (t, J=5.7 Hz, 2H), 3.60 (t, J=4.5 Hz, 4H), 3.85 (s, 3H), 4.31 (t, J=5.4 Hz, 2H), 7.02 (d, J=8.1Hz, 1H), 7.17 (dd, J=2.4 and 8.4 Hz, 1H), 7.42-7.68 (m, 5H), 7.85-7.89 (m, 1H), 8.19-8.22 (m, 1H), 10.24 (s, 1H); MS 407 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=[O:10].C(=O)([O-])[O-].[K+].[K+].[Cl:17]Cl>ClC1C=CC=CC=1Cl.O>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]([Cl:17])=[O:10]
Reactant: ClCl
Reactant: Cc1nn(C)c(Cl)c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Clc1ccccc1Cl
Product: Cc1nn(C)c(Cl)c1C(=O)Cl
Yield: 77 %

Procedure:
Initial charging of 11 g of a 10% solution of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde in 1,2-dichlorobenzene at 10° C., is followed by addition of a solution of 4.6 g of potassium carbonate in 20 ml of water. At 10° C., while illuminating with a mercury lamp, 8 g of chlorine gas are introduced within 1 hour. After the gas introduction has ended, the reaction solution is admixed with water, and the organic phase is removed and washed with water. After removal of the solvent, 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride is obtained in a yield of 77%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:34][C:35]1[CH:36]=[N:37][C:38]2[C:43]([C:44]=1[C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[C:47]([O:53][CH3:54])[C:46]=1[O:55][CH3:56])=[CH:42][C:41]([Cl:57])=[CH:40][CH:39]=2>ClCCl>[C:15]([C:12]1[CH:11]=[C:7]([CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:13]=1[OH:14])[C:8]([NH:34][C:35]1[CH:36]=[N:37][C:38]2[C:43]([C:44]=1[C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[C:47]([O:53][CH3:54])[C:46]=1[O:55][CH3:56])=[CH:42][C:41]([Cl:57])=[CH:40][CH:39]=2)=[O:10])([CH3:17])([CH3:16])[CH3:18]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: COc1ccc(-c2c(N)cnc3ccc(Cl)cc23)c(OC)c1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(-c2c(NC(=O)c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)cnc3ccc(Cl)cc23)c(OC)c1OC
Temperature: 0 °C
Yield: 47.6 %

Procedure:
To a solution of 3,5-di-tert-butyl-4-hydroxybenzoic acid (220 mg) in dichloromethane (20 ml) was dropwise added dicyclohexylcarbodiimide (DCC) (180 mg) under stirring at 0° C. The mixture was stirred at 0° C. for 15 minutes. Then, 3-amino-6-chloro-4-(2,3,4-trimethoxyphenyl) quinoline (250 mg) was added to this mixture. The resultant mixture was stirred at 0° C. for an hour and at room temperature for two days. After the residue was filtered off, the filtrate was diluted with water and extracted with dichloromethane. The dichloromethane layer was washed with an aqueous sodium hydroxide solution, diluted with hydrochloric acid and water in this order and dried (MgSO4). The solvent was removed and the residue was purified by a silica gel column chromatography with hexane-ethyl acetate (3:1, V/V), and then crystallized from isopropyl ether to obtain 3-(3,5-di-tert-butyl-4-hydroxybenzamido)-6-chloro-4-(2,3, 4-trimethoxyphenyl) quinoline (199 mg, 47.6%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](OC(ON=C(C#N)C(N)=O)=O)[CH3:24].C(N(CC)CC)C>C(OCC)(=O)C>[CH2:23]([O:21][C:20](=[O:22])[C@H:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:24]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CCOC(=O)ON=C(C#N)C(N)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 0.33 h
Yield: 103.6 %

Procedure:
To a suspension of N-benzyloxycarbonyl-L-phenylalanine (1.5 g) and 2-ethoxycarbonyloxyimino-2-cyanoacetic acid amide (0.95 g) in ethyl acetate (20 ml), a solution of triethylamine (0.7 ml) in ethyl acetate (5 ml) is dropwise added at -10°C, and the resulting mixture is stirred at the same temperature for 20 minutes and then at room temperature for 2 hours. After allowed to stand over night, the reaction mixture is treated as in Example A to give N-benzyloxycarbonyl-L-phenylalanine ethyl ester (1.7 g) as an oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].CN(C)C=O.[F:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([N+:35]([O-:37])=[O:36])[CH:29]=1>O>[F:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:8][CH2:9][CH2:10][N:11]2[C:15](=[O:16])[C:14]3[C:13](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]2=[O:21])=[C:30]([N+:35]([O-:37])=[O:36])[CH:29]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: O=[N+]([O-])c1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCOc1ccc(F)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 4 h
Yield: 100.4 %

Procedure:
Potassium carbonate (10.8 g, 78.1 mmol) and N-(3-bromopropyl)phthalimide (12.1 g, 45.1 mmol) were added to a N, N-dimethylformamide (DMF) solution (80 ml) of 4-fluoro-2-nitrophenol (6.0 g, 38.2 mmol), and the mixture was stirred at 60° C. for 4 hours. After the reaction mixture was cooled to room temperature, water (200 ml) was added, and the reaction mixture was then cooled with ice. The precipitated insoluble matter was collected by filtration. After being washed with water (50 ml×3), the substance remaining in the filter was air-dried, giving 13.2 g of powdery pale yellow 2-[3-(4-fluoro-2-nitrophenoxy)propyl]isoindole-1,3-dione (yield: 100%).
Reaction SMILES: [CH:1]1([C:5]2[N:13]3[C:8]([C:9](=[O:14])[NH:10][CH:11]=[N:12]3)=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.[I:15]N1C(=O)CCC1=O>CN(C)C=O>[CH:1]1([C:5]2[N:13]3[C:8]([C:9](=[O:14])[NH:10][CH:11]=[N:12]3)=[C:7]([I:15])[N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C1CCC(=O)N1I
Reactant: O=c1[nH]cnn2c(C3CCC3)ncc12
Solvent: CN(C)C=O
Product: O=c1[nH]cnn2c(C3CCC3)nc(I)c12
Temperature: 55 °C

Procedure:
A solution of 7-cyclobutyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (789 mg, 4.15 mmol) and N-iodosuccinimide (NIS, 933 mg, 4.15 mmol) in anhydrous DMF (40 mL) was stirred overnight at rt. An additional 4 eq. of NIS was added and reaction was heated to 55° C. for 6 h. The reaction mixture was concentrated in vacuo and partitioned between DCM and H2O and separated. The aqueous layer was washed with DCM (3×) and the combined organic fractions were washed with 1M sodium thiosulfate (Na2S2O3) (1×), brine (1×), dried over sodium sulfate (Na2SO4), filtered, and concentrated in vacuo. The solid was triturated with 20% EtOAc in DCM and filtered through a fritted Buchner funnel resulting in the title compound as an off-white solid; 1H NMR (DMSO-d6, 400 MHz) δ 1.84-1.96 (m, 1H), 1.98-2.13 (m, 1H), 2.25-2.43 (m, 4H), 3.84-3.96 (m, 1H), 7.87 (s, 1H); MS (ES+): m/z 317.02 (100) [MH+], HPLC: tR=2.62 min (MicromassZQ, polar—5 min).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7]C=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O.CS(O[CH2:25][CH2:26][NH:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[C:35](=[O:49])[NH:36][C:37]1[CH:46]=[C:45]2[C:40]([CH2:41][CH2:42][C:43](=[O:48])[N:44]2[CH3:47])=[CH:39][CH:38]=1)(=O)=O>O>[ClH:34].[Cl:34][C:32]1[CH:31]=[CH:30][C:29]([C:35]([NH:36][C:37]2[CH:46]=[C:45]3[C:40]([CH2:41][CH2:42][C:43](=[O:48])[N:44]3[CH3:47])=[CH:39][CH:38]=2)=[O:49])=[C:28]([NH:27][CH2:26][CH2:25][N:5]2[CH2:6][CH2:7][CH:3]([F:2])[CH2:4]2)[CH:33]=1
Reactant: CN1C(=O)CCc2ccc(NC(=O)c3ccc(Cl)cc3NCCOS(C)(=O)=O)cc21
Reactant: Fc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)CCc2ccc(NC(=O)c3ccc(Cl)cc3NCCN3CCC(F)C3)cc21
Temperature: 40 °C
Reaction time: 15 h
Yield: 49.2 %

Procedure:
3-Fluoropyridine hydrochloride (240 mg) and sodium carbonate (250 mg) were added to a dimethylformamide solution of 2-({5-chloro-2-[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)carbamoyl]phenyl}amino)ethyl methanesulfonate (595 mg), followed by stirring at 40° C. for 15 hours. Water was added to the reaction liquid, followed by extraction with chloroform. The organic layer was dried with magnesium sulfate and then the solution was concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (basic silica gel, chloroform:methanol, 1:0 to 95:5). By treating the resulting free base with 4 M hydrogen chloride/ethyl acetate solution, 4-chloro-2-{[2-(3-fluoropyrrolidin-1-yl)ethyl]amino}-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)benzamide hydrochloride (156 mg) was obtained as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:53]=[CH:52][C:13]([CH2:14][O:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[CH2:22][CH2:23][N:24]([CH2:40][CH2:41][C:42]4[CH:47]=[CH:46][C:45]([C:48]([O:50]C)=[O:49])=[CH:44][CH:43]=4)[CH:25]4[CH2:34][CH2:33][CH2:32][C:31]5[N:30]=[C:29]([C:35]([O:37]CC)=[O:36])[CH:28]=[CH:27][C:26]4=5)=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:54]=1.O.[OH-].[Li+]>C1COCC1.O>[C:48]([C:45]1[CH:46]=[CH:47][C:42]([CH2:41][CH2:40][N:24]([CH2:23][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C:13]2[CH:12]=[CH:11][C:10]([C:8]3[O:9][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:54][C:6]=4[N:7]=3)=[CH:53][CH:52]=2)[CH:25]2[CH2:34][CH2:33][CH2:32][C:31]3[N:30]=[C:29]([C:35]([OH:37])=[O:36])[CH:28]=[CH:27][C:26]2=3)=[CH:43][CH:44]=1)([OH:50])=[O:49]
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccc(C(=O)OC)cc1)CCc1ccccc1OCc1ccc(-c2nc3cc(Cl)ccc3o2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CCN(CCc2ccccc2OCc2ccc(-c3nc4cc(Cl)ccc4o3)cc2)C2CCCc3nc(C(=O)O)ccc32)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
68 mg (0.09 mmol) of ethyl 5-([2-(2-{[4-(5-chloro-1,3-benzoxazol-2-yl)benzyl]oxy}-phenyl)ethyl]-{2-[4-(methoxycarbonyl)phenyl]ethyl}amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 1, Example 63A) were taken up in 4 ml of THF and 2 ml of water, and 12 mg (0.27 mmol) of lithium hydroxide monohydrate were added. The reaction was stirred at 60° C. overnight. After the reaction had gone to completion, the THF was removed on a rotary evaporator and the mixture that remained was diluted with water. The mixture was then acidified to pH 4-5 using acetic acid and extracted repeatedly with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered and concentrated to dryness. This gave 33 mg (0.04 mmol, 48% of theory) of the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][C:23]1[CH:27]=[CH:26][O:25][CH:24]=1)C1C=CC=CC=1.C(N1CCN(CC2C=CC=CC=2)C[C@@H]1CC)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl.CO>[O:25]1[CH:26]=[CH:27][C:23]([CH2:22][CH2:21][C@H:9]2[CH2:10][NH:11][CH2:12][CH2:13][NH:8]2)=[CH:24]1
Reactant: c1ccc(CN2CCN(Cc3ccccc3)[C@@H](CCc3ccoc3)C2)cc1
Agent: CC(Cl)OC(=O)Cl
Agent: CC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Solvent: ClCCCl
Solvent: CO
Product: c1cc(CC[C@H]2CNCCN2)co1
Temperature: 83 °C
Reaction time: 18 h
Yield: 29 %

Procedure:
Dissolve a mixture of (S)-1,4-dibenzyl-2-(2-furan-3-yl-ethyl)-piperazine and (S)-1,4-dibenzyl-2-ethyl-piperazine (2.29 g, 6.35 mmol) in 1,2-dichloroethane (10 mL). Cool on an ice bath and add 1-chloroethyl chloroformate (2.06 ml, 19.1 mmol) dropwise. Remove ice bath and heat to 83° C. for 5.5 h. Concentrate the reaction, dissolve the residue in methanol (50 mL) and heat to reflux for 2 h. Cool to ambient temperature and stir 18 h. Filter and concentrate to a solid. Purify by silica gel chromatography using 7N ammonia in methanol-methylene chloride (2.5%–10%) as the eluent to give 330 mg (29%) of the title compound: mp 112–4° C. Mass spectrum (ion spray): m/z=181 (M+1).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([F:15])[CH:5]=1.[OH:16][CH2:17][C:18]1[C:23]([O:24][CH2:25][C:26](O)=[O:27])=[CH:22][CH:21]=[C:20]([CH3:29])[N:19]=1>>[F:15][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:3][NH:2][C:26](=[O:27])[CH2:25][O:24][C:23]1[C:18]([CH2:17][OH:16])=[N:19][C:20]([CH3:29])=[CH:21][CH:22]=1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Reactant: Cc1ccc(OCC(=O)O)c(CO)n1
Agent: Cl
Product: Cc1ccc(OCC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)c(CO)n1
Yield: 88.1 %

Procedure:
N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide HCl salt (270 mg, 1.00 mmol) was reacted with (2-hydroxymethyl-6-methyl-pyridin-3-yloxy)-acetic acid (200 mg) to give N-(3-fluoro-4-methanesulfonylamino-benzyl)-2-(2-hydroxymethyl-6-methyl-pyridin-3-yloxy)-acetamide (350 mg, 88%) after purification by column chromatography (Hex/EtOAc=10/1).
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][C:5]=2[C:4](=[O:15])OC1=O)[CH:12]=[CH:11][CH:10]=[CH:9]3.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=1>C1(C)C(C)=CC=CC=1.CN(C)C1C=CN=CC=1>[NH2:1][C:6]1[C:5]([C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=2)=[O:15])=[CH:14][C:13]2[C:8]([CH:7]=1)=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: Nc1ccc(Cl)cn1
Reactant: O=c1[nH]c2cc3ccccc3cc2c(=O)o1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1C
Product: Nc1cc2ccccc2cc1C(=O)Nc1ccc(Cl)cn1
Temperature: 150 °C
Reaction time: 13 h
Yield: 8 %

Procedure:
A suspension of 2H-naphth[2,3-d][1,3]oxazine-2,4(1H)-dione (216 mg) and 2-amino-5-chloropyridine (202 mg) in xylene (5 ml) is stirred at 150° C. for 13 hours, and thereto added 4-dimethylaminopyridine (14.4 mg) and the mixture is stirred at 150° C. for another 3 hours. The reaction solution is concentrated under reduced pressure and the resulting residue is suspended in ethyl acetate, and filtered to remove insoluble materials. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1) to give 3-amino-N-(5-chloropyridin-2-yl)-2-naphthamide (24 mg).