Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)[C:7](=[O:12])[C:8]([F:11])([F:10])[F:9].[H][H]>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]([CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=1)[C:7](=[O:12])[C:8]([F:11])([F:10])[F:9]
Reactant: O=C(N(CCc1ccc([N+](=O)[O-])cc1)Cc1cccc(Cl)c1)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(CCN(Cc2cccc(Cl)c2)C(=O)C(F)(F)F)cc1
Yield: 65 %

Procedure:
To a solution of the product of step (b) (3.89 g, 10.05 mmol) in ethyl acetate (100 ml) was added 5% Pd/C. The mixture was hydrogenated at 50 psig for 1.4 hours, until the theoretical amount of hydrogen was taken up. The catalyst was filtered and the filtrate concentrated to an oil. This was purified by chromatography (silica gel, methylene chloride: n-hexane (1:1)) to yield 2.33 g of pure N-(3-chlorobenzyl)-N-(2-(4-aminophenyl)ethyl)trifluoroacetamide as a thick oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH2:11]([O:18][C:19]1[C:20]([O:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[K+].O>CO>[CH2:11]([O:18][C:19]1[C:20]([O:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)=[C:21]([CH:22]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:8][CH:9]=2)[OH:23])[CH:24]=[CH:25][CH:26]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Clc1cnc2[nH]ccc2c1
Reactant: O=Cc1cccc(OCc2ccccc2)c1OCC1CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OC(c1cccc(OCc2ccccc2)c1OCC1CC1)c1c[nH]c2ncc(Cl)cc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 53.6 %

Procedure:
A mixture of 5-chloro-1H-Pyrrolo[2,3-b]pyridine (4, 0.68 g, 4.46 mmol, prepared as described in Example 4), 3-benzyloxy-2-cyclopropylmethoxy-benzaldehyde (130, 1.2 g, 4.25 mmol), and potassium hydroxide (0.68 g, 11 mmol) in methanol (50 mL) was stirred at room temperature for 4 days. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was collected, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide compound as a white solid (131, 0.99 g, 54%). MS (ESI) [M+H+]+=435.21.
Reaction SMILES: Br[CH2:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:24]([C:25]#[N:26])=[CH:23][CH:22]=[C:8]3[C:9]3([CH2:15][CH2:14][N:13](C(=O)C(F)(F)F)[CH2:12][CH2:11]3)[O:10][C:5]=2[CH:4]=1.[CH3:29][O-:30].[Na+]>>[CH3:29][O:30][CH2:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:24]([C:25]#[N:26])=[CH:23][CH:22]=[C:8]3[C:9]3([CH2:11][CH2:12][NH:13][CH2:14][CH2:15]3)[O:10][C:5]=2[CH:4]=1
Reactant: N#Cc1ccc2n1-c1ccc(CBr)cc1OC21CCN(C(=O)C(F)(F)F)CC1
Reactant: C[O-]
Agent: [Na+]
Product: COCc1ccc2c(c1)OC1(CCNCC1)c1ccc(C#N)n1-2
Temperature: 25 °C
Reaction time: 5 h
Yield: 24.9 %

Procedure:
7′-(Bromomethyl)-1-(2,2,2-trifluoroacetyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]-benzoxazine]-1′-carbonitrile (53.2 mg, 0.117 mmol) was treated with sodium methoxide (36 mg, 0.67 mmol) at room temperature. The mixture was allowed to stir for 5 h at room temperature before it was concentrated under reduced pressure. The residue was taken up in ethyl acetate, filtered, and concentrated to give 7′-(methoxymethyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-carbonitrile (9.0 mg, 4%). ESI-MS m/z calc. 309.2. found 310.3 (M+1)+; Retention time 0.97 minutes (3 min run).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:43])[C@@H:12]([NH:21][C:22](=[O:42])[C@@H:23]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:41])[CH3:40])=[CH:34][CH:33]=2)[NH:24]C(OC(C)(C)C)=O)[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[S:8][CH:9]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:43])[C@@H:12]([NH:21][C:22](=[O:42])[C@@H:23]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:41])[CH3:40])=[CH:34][CH:33]=2)[NH2:24])[C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccc(NC(C)=O)cc2)[C@@H](C)c2ccccc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](N)c2ccc(NC(C)=O)cc2)[C@@H](C)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a cold solution of 2-{(2S,3S)-2-[(R)-2-(4-acetylamino-phenyl)-2-tert-butoxycarbonylamino-acetylamino]-3-phenyl-butyryl-amino}-thiazole-4-carboxylic acid methyl ester (107 mg, 0.175 mmol) in dichloromethane (6 mL), was added trifluoroacetic acid (4 mL). The reaction mixture was stirred at room temperature for 45 minutes, followed by removal of volatiles in vacuo. To the residue was added diethyl ether (10 mL) and the resulting suspension was separated by centrifugation. The solid was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give crude 2-{(2S,3S)-2-[(R)-2-(4-acetylamino-phenyl)-2-amino-acetylamino]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester which was used immediately in the following step of the synthesis.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5](=[O:12])[C:4]2[CH:13]=[C:14]([C:17]#[N:18])[CH:15]=[CH:16][C:3]1=2.[Cl-].[NH4+].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C=O>[CH3:1][N:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5](=[O:12])[C:4]2[CH:13]=[C:14]([C:17]3[NH:23][N:22]=[N:21][N:18]=3)[CH:15]=[CH:16][C:3]1=2
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1c2ccc(C#N)cc2c(=O)c2cccnc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c2ccc(-c3nnn[nH]3)cc2c(=O)c2cccnc21
Reaction time: 20 h
Yield: 72.7 %

Procedure:
A mixture of 5 g of 10-methyl-5-oxo-5H,10H-benzo[b][1,8]naphthyridine-7-carbonitrile, 50 ml of dimethylformamide, 1.45 g of ammonium chloride and 1.8 g of sodium azide is heated with stirring at 110° C to 120° C for 20 hours. After cooling, crystals are filtered off and added to a dilute hydrochloric acid, and the mixture is stirred. The crystals are filtered off, washed with water and recrystallized from dimethylformamide to give 4.3 g of 10-methyl-7-(5-1H-tetrazolyl)-5-oxo-5H,10H-benzo[b][1,8]naphthyridine melting at 321° C with decomposition.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C:11](=[O:13])[CH:10](C(OCC)=O)[CH:9]1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.S(=O)(=O)(O)O>[CH2:1]([N:8]1[CH:9]([CH3:19])[CH2:10][C:11](=[O:13])[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1C(=O)CN(Cc2ccccc2)C1C
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC1CC(=O)CN1Cc1ccccc1
Temperature: 90 °C
Yield: 45.9 %

Procedure:
A suspension of ethyl 1-benzyl-2-methyl-4-oxo-3-pyrrolidinecarboxylate (3.4 g, 13 mmol) in water (95 ml) and sulfuric acid (5 ml) was heated to 90° C. overnight. The mixture was allowed to cool was neutralized with sodium carbonate, extracted with methylene chloride. The combined organic layer filtered through a plug of silica gel and concentrated to give 1-benzyl-5-methyl-3-pyrrolidinone (1.13 gm, 46%) as a yellow oil, MS (M+H)+=190.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[C:6]([C:18]#[N:19])[CH:5]=1>ClCCl.C(O)(=O)C>[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[C:6]([C:18]#[N:19])[C:5]=1[Br:1]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1C#N
Reactant: BrBr
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1ccc(N)c(Br)c1C#N
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 128.9 %

Procedure:
A solution of bromine (25.1 mmol) in dichloromethane (1.3 mL) was added dropwise, under an argon atmosphere, to a solution of amine II (27.9 mmol) in acetic acid (325 mL). After 2.5 h of stirring at room temperature, the solvent was removed in vacuo. The excess of acetic acid was co-evaporated with heptane to afford the expected compound III (10.1 g, quantitative yield) as a beige solid; mp 163° C.; IR (KBr) νmax/cm−1 3327, 2826, 2605, 2566, 2236, 1955, 1716, 1610, 1561, 1496, 1481, 1398, 1369, 1280, 1238, 1193, 1153, 1059, 963, 906, 838; 1H NMR (300 MHz, DMSO-d6) δ 9.05 (s, 1H, NH), 7.11 (d, 1H, J=8.7 Hz), 7.05 (d, 1H, J=8.7 Hz), 6.01 (s, 2H, NH2), 1.43 (s, 9H); 13C NMR (75 MHz, DMSO-d6) δ 153.6, 144.1, 131.6, 126.9, 119.6, 116.1, 112.8, 107.8, 79.5, 28.1; HRMS calcd for C12H15N3O2Br (M+H+): 312.0348, found 312.0354.
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([C:7]2[CH:31]=[C:30]([OH:32])[C:10]3[C:11]4[CH2:29][CH2:28][S:27][C:12]=4[C:13]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[O:14][C:9]=3[CH:8]=2)[CH3:6])[CH2:3][CH2:2]1.[O:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40](O)=[O:41])[CH2:35][CH2:34]1.C1(N=C=NC2CCCCC2)CCCCC1>>[CH:1]1([CH2:4][CH:5]([C:7]2[CH:31]=[C:30]([O:32][C:40](=[O:41])[CH2:39][N:36]3[CH2:37][CH2:38][O:33][CH2:34][CH2:35]3)[C:10]3[C:11]4[CH2:29][CH2:28][S:27][C:12]=4[C:13]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[O:14][C:9]=3[CH:8]=2)[CH3:6])[CH2:3][CH2:2]1
Reactant: CCCCCCC1(CCCCCC)Oc2cc(C(C)CC3CC3)cc(O)c2C2=C1SCC2
Reactant: O=C(O)CN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCCCCCC1(CCCCCC)Oc2cc(C(C)CC3CC3)cc(OC(=O)CN3CCOCC3)c2C2=C1SCC2

Procedure:
By reacting 7-(3-cyclopropyl-2-propyl)-1,2-dihydro-9-hydroxy-4-oxo-4H-thieno[2,3-c] [1]benzopyran with n-hexyl magnesium bromide, using the procedure described above in Example 8, there is obtained 7-(3-cyclopropyl-2-propyl)-4,4-di(1-hexyl)-1,2-dihydro-9-hydroxy-4H-thieno[2,3-c] [1]benzopyran. The benzopyran is then reacted with morpholinoacetic acid and dicyclohexylcarbodiimide according to the method of Example 9 to yield the desired ester.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([C:7]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)[CH3:6])=[O:4].[CH2:22]([NH2:25])[CH2:23][NH2:24].C(N(CC)CC)C>C(O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:7]2[N:5]([CH3:6])[C:3](=[O:4])[CH2:2][N:24]3[CH2:23][CH2:22][NH:25][C:9]3([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]=2[CH:17]=1
Reactant: CN(C(=O)CCl)c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: NCCN
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1C(=O)CN2CCNC2(c2ccccc2)c2cc(Cl)ccc21

Procedure:
A solution of 6.4 g. (20 mmole) of 2-(2-chloro-N-methylacetamido)-5-chlorobenzophenone, 12.0 g. (0.2 mole) of ethylenediamine, 50 ml. of triethylamine and 250 ml. of ethanol was heated at reflux for 20 hours. The reaction mixture was concentrated to a residue which was partitioned between ether and water. The ether layer was washed with water, dried and concentrated to a small amount of liquid which was treated with a small amount of ethanol to give upon standing the above-titled product as colorless crystals, m.p. 164°-167°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:20][CH3:21])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:22])[N:7]([CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1)[CH2:20][CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(CCOc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCN(CCOc1ccc(N)cc1)C(=O)OC(C)(C)C
Yield: 113.4 %

Procedure:
A solution of ethyl-[2-(4-nitro-phenoxy)-ethyl]-carbamic acid tert-butyl ester (825 mg, 2.36 mmol) (from step B above) and 150 mg of 10% palladium-on-carbon in ethanol (25 mL) was hydrogenated at 20 psi in a Parr shaker for 1 hour. The mixture was filtered through Celite™ and the solvent was evaporated to give 750 mg (100%) [2-(4-amino-phenoxy)-ethyl]-ethyl-carbamic acid tert-butyl ester.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:12][CH2:13][CH2:14][OH:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N:16]([O-])=[O:17].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>Cl.O>[OH:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:12][CH2:13][CH2:14][OH:15])[C:6]1[CH:11]=[CH:10][C:9]([N:16]=[O:17])=[CH:8][CH:7]=1
Reactant: OCCCN(CCCO)c1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=Nc1ccc(N(CCCO)CCCO)cc1
Reaction time: 1 h

Procedure:
N,N-bis(3-hydroxypropyl) aniline (10.46 g) was dissolved in hydrochloric acid (20cm3) at 0-5° C. and sodium nitrite (3.45 g) in water(15cm3) was added dropwise. The mixture was stirred for 1 hr, water (10cm3) was added, made alkaline with sodium carbonate, separated in to an oil and water layer. The oil was dissolved in dichloromethane and the solvent removed to leave N,N-bis(3-hydroxypropyl)4-nitrosoaniline as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[C:10]2[C:9](=[O:17])[NH:8][C@@H:7]3[CH2:18][N:19](C(OC(C)(C)C)=O)[CH2:20][C@H:6]3[C:5]=2[CH:4]=1)[CH3:2].[ClH:28]>C(OCC)C>[ClH:28].[CH2:1]([C:3]1[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[C:10]2[C:9](=[O:17])[NH:8][C@@H:7]3[CH2:18][NH:19][CH2:20][C@H:6]3[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(c(C(F)(F)F)c1)C(=O)N[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]21
Agent: Cl
Solvent: CCOCC
Product: CCc1cc2c(c(C(F)(F)F)c1)C(=O)N[C@@H]1CNC[C@@H]21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86 %

Procedure:
To a solution of (3aS,9bR)-tert-butyl 8-ethyl-5-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate, the second eluting peak from Example 45, Part H (63 mg, 0.16 mmol) in 2 mL of diethyl ether was added 1 mL of 12 N HCl. The resulting mixture was stirred vigorously for 5 min at ambient temperature and then was concentrated and dried in vacuo. The resulting white solid was triturated twice with diethyl ether and dried in vacuo to afford 45 mg (86%) of the title compound of Example 46 as a white solid. 1H NMR (DMSO-D6): δ 9.83 (broad s, 1H), 9.64 (broad s, 1H), 8.89 (s, 1H), 7.66 (s, 1H), 7.43 (s, 1H), 3.95-3.90 (m, 1H), 3.63-3.58 (m, 1H), 3.51-3.45 (m, 1H), 3.34-3.28 (m, 1H), 3.21-3.10 (m, 2H), 2.73 (q, 2H, J=7.7 Hz), 1.21 (t, 3H, J=7.7 Hz). LRMS (ESI): 285.2 (M+H)+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16](I)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[C:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)(=[O:21])[CH3:20]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16]([C:25]4[CH:26]=[CH:27][C:22]([C:19](=[O:21])[CH3:20])=[CH:23][CH:24]=4)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Ic1ccnc(Nc2ccc3c(c2)OCCO3)c1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CC(=O)c1ccc(-c2ccnc(Nc3ccc4c(c3)OCCO4)c2)cc1
Temperature: 90 °C

Procedure:
Following the similar procedure described for Example 401(c), the mixture of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-iodo-pyridin-2-yl)-amine (Example 401 (b), 0.73 g, 2.1 mmol), tetrakis (triphenylphosphine) palladium (0) (Aldrich Chemical Company) (0.12 g, 0.11 mmol), 4-actylphenylboronic acid (Aldrich Chemical Company) (0.41 g, 2.5 mmol) and 1,2-dimethoxyethane (20 mL) gave, after heated at 90° C. overnight and purification on a Biotage 40M column (3:1 hexane:EtOAc), the title compound as a light-orange solid. MS (ESI, pos. ion) m/z: 347 (M+1). Mp: 178.0-180.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][O:13][NH:14][C:15](=[O:17])[CH3:16].[I:18]CC(Cl)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][O:13][NH:14][C:15](=[O:17])[CH2:16][I:18]
Reactant: COc1ccc2[nH]cc(CONC(C)=O)c2c1
Reactant: O=C(Cl)CI
Product: COc1ccc2[nH]cc(CONC(=O)CI)c2c1

Procedure:
By carrying out the procedure in the same manner as for the synthesis of the compound of Example 13, but replacing the acetic acid chloride with iodoacetic acid chloride, the title compound is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[O:17][CH2:16][CH2:15][CH:14]2[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][CH2:32][C:33]2[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)=[CH:27][CH:26]=1)([CH3:24])[CH3:23]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[O:17][CH2:16][CH2:15][CH:14]2[C:19]([N:31]([C:28]1[CH:29]=[CH:30][C:25]([CH:22]([CH3:24])[CH3:23])=[CH:26][CH:27]=1)[CH2:32][C:33]1[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCOc2c(OCc3ccccc3)cccc21
Reactant: COc1ccc(CNc2ccc(C(C)C)cc2)cn1
Product: COc1ccc(CN(C(=O)C2CCOc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)cc2)cn1
Yield: 70.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 8-(benzyloxy)chroman-4-carboxylic acid (0.47 g) and (4-isopropylphenyl)[(6-methoxypyridin-3-yl)methyl]amine 0.43 g) as starting materials, 8-benzyloxy-N-(4-isopropylphenyl)-N-[(6-methoxypyridin-3-yl)methyl]chroman-4-carboxamide (0.61 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:13]O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: CO
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Agent: Cl
Product: COC(=O)c1cc(N)ccc1Cl
Reaction time: 16 h

Procedure:
A solution of 10 g of 2-chloro-5-(amino)benzoic acid in 250 mL of methanol was saturated with HCl (gas) and stirred for 16 h. The solution was concentrated in vacuo, diluted with water, made neutral with 5N NaOH and extracted twice with ether. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated to afford 10 g of title compound as a slightly pink solid.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].[N:22]1[C:30](N)=[C:29]2[C:25]([N:26]=[CH:27][NH:28]2)=[N:24][CH:23]=1>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:30]1[N:22]=[CH:23][N:24]=[C:25]2[C:29]=1[N:28]=[CH:27][NH:26]2)(=[O:3])[CH3:2]
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Reactant: Nc1ncnc2nc[nH]c12
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2ncnc3[nH]cnc23)c1=O
Yield: 1.3 %

Procedure:
To a stirred solution of 250 mg (0.870 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (12 mL), adenine (235 mg, 1.740 mmol) was added. The resulting mixture was stirred and refluxed during two days. The solvent was evaporated and the residue purified by column chromatography (silica gel, dichloromethane/methanol 95:5) and preparative HPLC/MS to yield the title compound (4.4 mg, 1.4% yield).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(O[C:40]([N:42]1[CH2:47][CH2:46][CH:45]([NH2:48])[CH2:44][CH2:43]1)=O)(C)(C)C.CCN(C(C)C)C(C)C>ClCCl>[CH3:40][N:42]1[CH2:47][CH2:46][CH:45]([NH:48][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[N:1]=[CH:2][NH:3][C:4]=3[CH:9]=2)=[O:12])[CH2:44][CH2:43]1
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2ccc3nc[nH]c3c2)CC1
Reaction time: 3 h

Procedure:
Step 1 (Amide Coupling): 5-Benzimidazole carboxylic acid (0.50 g, 3.1 mmol), EDC.HCl (0.72 g, 3.7 mmol) and HOBt (0.58 mg, 3.7 mmol) in dichloromethane (11 mL) was stirred at room temperature for 10 minutes. 4-Amino-piperidine-1-carboxylic acid tert-butyl ester (0.70 g, 3.4 mmol) and DIPEA (0.59 ml, 3.4 mmol) were added and the mixture was stirred for 3 hours. The mixture was then partitioned between EtOAc and sat. aqueous Na2CO3. The layers were separated and the aqueous layer was extracted with EtOAc (×3). The combined organic layers were washed with water, brine and dried (MgSO4). The solvent was evaporated in vacuo to give 3H-benzoimidazole-5-carboxylic acid (1-methyl-piperidin-4-yl)-amide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([OH:25])=O)[N:21]=1)=[CH:5]2.[NH2:26][CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([NH:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:25])[N:21]=1)=[CH:5]2
Reactant: NCCCN1CCOCC1
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Product: O=C(C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1)NCCCN1CCOCC1
Yield: 35 %

Procedure:
The compound (50 mg, 0.13 mmol) prepared in Example 27 and 4-(3-aminopropyl)morpholine instead of morpholine were reacted according to the same procedure as Example 73 to give the title compound (23 mg, Yield 35%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH2:18]O)[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:21].O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH2:18][Cl:21])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1ccc(-c2nccc3c(CO)cccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1ccc(-c2nccc3c(CCl)cccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.8 %

Procedure:
1-(4-Methylphenyl)-5-hydroxymethylisoquinoline (7.5 g) was dissolved in 80 ml of chloroform, and 12.5 g of phosphorus pentachloride was added under ice cooling. The mixture was stirred at room temperature for 1 hour, and 100 ml of water was added. The mixture was stirred for 30 minutes, and neutralized with potassium carbonate. The chloroform layer was washed in water, and dried. The solvent was distilled off, and the residue was recrystallized from methanol to afford 8.6 g of 1-(4-methylphenyl)-5-chloromethylisoquinoline as slightly yellow prisms having a melting point of 119.8° to 120.1° C.
Reaction SMILES: [Na].[CH:2]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[NH2:10][C:11]1[N:16]=[C:15](Cl)[CH:14]=[C:13]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:12]=1>>[NH2:10][C:11]1[N:16]=[C:15]([O:9][CH2:8][CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH:14]=[C:13]([NH:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:12]=1
Reactant: OCC1CCCCC1
Reactant: Nc1nc(Cl)cc(NCc2ccccc2)n1
Agent: [Na]
Product: Nc1nc(NCc2ccccc2)cc(OCC2CCCCC2)n1
Temperature: 180 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
To a stirred solution of sodium (0.025 g, 1.09 mmol) in cyclohexylmethanol (5 ml, 43 mmol) under nitrogen at 100° C., was added 2-amino-6-benzylamino-4-chloropyrimidine (0.2 g, 0.86 mmol), and the mixture was stirred at 180° C. for 2 h. After removal of solvents, the residue was redissolved in methanol, filtered and the filtrate was evaporated to dryness. The crude product was purified by chromatography on silica, employing petrol: ethyl acetate (8:2) as eluent, to give the title product as a yellow solid (0.13 g, 49%); δH (200 MHz, d6-DMSO) 0.96-1.15 (5H, m, C6H11), 1.23-1.34 (6H, m, C6H11), 4.03 (2H, br s, OCH2), 4.51 (2H, d, C6H5CH2, J=5.31 Hz), 5.12 (1H, s, C(5)H), 6.56 (2H, br s, NH2), 7.20 (1H, br s, NH), 7.28-7.39 (5H, m, C6H5); m/z (+EI) 312 (M+, 100%), 229 (M+-C6H11, 45), 216 (MH+-C6H11CH2, 53), 91 (72).