Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:15]=2[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]3)[CH2:3][CH2:2]1.[O:17]1CCOCC1>O>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:15]=2[N:14]=[C:13]([CH:16]=[O:17])[CH:12]=[CH:11]3)[CH2:2][CH2:3]1
Reactant: Cc1ccc2cccc(OCC3CC3)c2n1
Reactant: C1COCCO1
Solvent: O
Product: O=Cc1ccc2cccc(OCC3CC3)c2n1
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of 8-(cyclopropylmethoxy)-2-methylquinoline (3.00 g, 14.1 mmol) in dioxane (100 mL) and water (1.0 mL) was added SeO2 (1.87 g, 16.9 mmol). The reaction mixture was stirred at reflux for 2 hours. After cooling to ambient temperature, the solid was removed by filtration and washed with DCM. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (1:4 hexane/DCM) to give 8-(cyclopropylmethoxy)quinoline-2-carbaldehyde (3.1 g, 97.0%) as a solid
Reaction SMILES: [NH3:1].[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]([CH3:28])[C:9]2[O:15][C:14]3[C:16]([Cl:24])=[CH:17][C:18]([NH:20][CH2:21][CH2:22]Cl)=[CH:19][C:13]=3[CH2:12][S:11](=[O:26])(=[O:25])[C:10]=2[CH:27]=1)=[O:5]>CO>[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]([CH3:28])[C:9]2[O:15][C:14]3[C:16]([Cl:24])=[CH:17][C:18]([NH:20][CH2:21][CH2:22][NH2:1])=[CH:19][C:13]=3[CH2:12][S:11](=[O:25])(=[O:26])[C:10]=2[CH:27]=1)=[O:5]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Reactant: N
Solvent: CO
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCN)cc(Cl)c1O2
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Aqueous ammonia solution (2.5 mL, 30%) was added to a solution of Example 56k (0.4 g, 0.93 mmol) in methanol (1 mL). The reaction mixture was sealed under argon in a reactor vessel and kept in an oven at 120° C. for 2 h. It was concentrated and the solid obtained was washed thoroughly with methanol to remove excess ammonia and dried under vacuo. It was treated with a methanolic HCl solution and stirred at 70° C. for 3 h. The reaction mixture was concentrated, treated with 10% aqueous sodium bicarbonate solution and extracted with ethylacetate. The organic layer was washed with water, brine, dried, and purified using flash chromatography (silica gel, 10% methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.340 g, (89.23%); 1H NMR (DMSO-d6): δ 2.70 (s, 3H, CH3), 3.00 (t, 2H, CH2), 3.35 (t, 2H, CH2), 3.90 (s, 3H, OCH3), 5.20 (s, 2H, CH2), 6.40 (t, 1H, NH), 6.80 (s, 2H, Ar), 7.80 (t, 2H, NH2), 8.15 (s, 1H, Ar) and 8.30 (s, 1H, Ar). MS: m/e (CI+) 411 (M+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][N:21]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20]2>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[CH2:22][N:21]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20]3)=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(N)cc2C1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCc1[nH]c(C(=O)Nc2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)nc1Cl
Yield: 64 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (410 mg, 2.36 mmol), thionyl chloride (5 mL), tert-butyl 5-amino-1,3-dihydro-2H-isoindole-2-carboxylate (described in Andronati, S. A.; Krys'ko, A. A.; Chugunov, B. M.; Kabanova, T. A.; Artemenko, A. G.; Russ. J. Org. Chem., 42, 8, 2006, 1174-1182, 0.94 g, 4 mmol) and pyridine (5 mL), to obtain 619 mg of the title compound as a white solid (64%).
Reaction SMILES: [CH:1]1([NH:5][C:6]2[N:7]=[N:8][C:9]([C:12]#[CH:13])=[CH:10][CH:11]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:41]=[CH:40][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[C:24]([C:36]([F:39])([F:38])[F:37])[CH:23]=2)=[O:20])=[CH:17][C:16]=1I>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[C:24]([C:36]([F:38])([F:37])[F:39])[CH:23]=2)=[O:20])=[CH:40][C:41]=1[C:13]#[C:12][C:9]1[N:8]=[N:7][C:6]([NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:11][CH:10]=1
Reactant: C#Cc1ccc(NC2CCC2)nn1
Reactant: CN1CCN(Cc2ccc(NC(=O)c3ccc(Cl)c(I)c3)cc2C(F)(F)F)CC1
Product: CN1CCN(Cc2ccc(NC(=O)c3ccc(Cl)c(C#Cc4ccc(NC5CCC5)nn4)c3)cc2C(F)(F)F)CC1

Procedure:
The title compound was synthesized from N-cyclobutyl-6-ethynylpyridazin-3-amine and 4-chloro-3-iodo-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The product was obtained as a pale yellow solid. Mp: 132-133° C.; 1H NMR (300 MHz, CDCl3) δ: 9.53 (1H, s), 8.10 (1H, s), 8.00 (2H, m), 7.85-7.87 (1H, d, J=6.0 Hz), 7.66-7.69 (1H, d, J=9.0 Hz), 7.43-7.45 (1H, d, J=6.0 Hz), 7.33-7.36 (1H, d, J=9.0 Hz), 6.58-6.61 (1H, d, J=9.0 Hz), 5.56 (1H, s), 4.23-4.25 (1H, m), 3.64 (2H, s), 2.61 (8H, brs), 2.44 (3H, s), 2.43 (2H, m), 1.91-1.97 (2H, m), 1.81-1.86 (1H, brs). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C30H31ClF3N6O: 583.2194. found: 583.2174.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[C:17]1([NH:23][CH2:24][CH2:25][NH2:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>COCCOC>[Cl:1][C:2]1[C:7]([NH:26][CH2:25][CH2:24][NH:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: NCCNc1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Cl
Solvent: COCCOC
Product: Nc1nc(NCCNc2ccccc2)c(Cl)c(-c2ccco2)n1

Procedure:
From 5-chloro-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine and N-phenylethylenediamine in DME. ES-MS m/e (%): 332 (M{37Cl}+H+, 40), 330 (M{35Cl}+H+, 100).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl.[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]23[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH2:19][CH2:18][N:17]2[CH2:16][CH2:15][C:14](=O)[CH2:13]3)=[CH:8][CH:7]=1.[BH3-]C#N.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CO.CCOCC>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]23[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH2:19][CH2:18][N:17]2[CH2:16][CH2:15][CH:14]([N:2]([CH3:3])[CH3:1])[CH2:13]3)=[CH:8][CH:7]=1
Reactant: O=C1CCN2CCc3ccccc3C2(c2ccc(F)cc2)C1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Solvent: CCOCC
Solvent: CO
Product: CN(C)C1CCN2CCc3ccccc3C2(c2ccc(F)cc2)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 24.7 %

Procedure:
To an ice-cold solution of 56 ml (2.16 M, 121 mmoles) of dimethyl amine in methanol is added 8 ml (5.0 N, 40 mmoles) of HCl in methanol. After 5 minutes, 5.9 g (20 mmoles) of 11b-(4-fluorophenyl)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizin-2-one is added. Thereafter, 14 mmoles of NaBH3CN is added. After 24 hours, some molecular sieves are added. 24 hours later, additional molecular sieves are added. After a further 24 hours, an additional 14 mmoles of NaBH3CN is added. After still another 24 hours, 7.5 ml (2.16 M, 16.2 mmoles) of dimethylamine in methanol and 2.0 ml (5.0 N, 10 mmoles) of HCl are added. Three days later, the product is worked-up by pouring it into aqueous sodium carbonate and ether. The mixture is filtered through filter aid; the ether layer is washed with aqueous NaOH, brine and dried (MgSO4). After concentration in vacuo, 6.25 g (96%) of a semi-oily white crystalline solid, i.e., 11b-(4-fluorophenyl)-1,3,4,6,7,11b-hexahydro-N,N-dimethyl-2H-benzo[a]quinolizin-2-amine, is obtained. This product is recrystallized from 100 ml of cyclohexane, yielding 1.6 g of 11b-(4-fluorophenyl)-1,3,4,6,7,11b-hexahydro-N,N-dimethyl-2H-benzo[a]quinolizin-2-amine, m.p. 159°-167° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([N+:13]([O-:15])=[O:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].C(=O)([O-])[O-].[K+].[K+].[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C=O)C>[N+:13]([C:6]1[CH:5]=[CH:4][C:3]([CH2:2][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])([O-:15])=[O:14]
Reactant: COC(=O)c1cc(CBr)ccc1[N+](=O)[O-]
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(CN2CCCCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Methyl 5-(bromomethyl)-2-nitrobenzoate was added to a DMF suspension of potassium carbonate and piperidine, followed by stirring at room temperature to obtain methyl 2-nitro-5-(piperidin-1-ylmethyl)benzoate (Dat, ES: 279). This compound was dissolved in acetic acid, iron powder was added thereto, followed by stirring at 60° C. to obtain methyl 2-amino-5-(piperidin-1-ylmethyl)benzoate (Dat, F: 249). Cyclohexanone and sodium triacetoxyborohydride were added to an acetic acid solution of this compound, followed by stirring at room temperature. By post-treating the reaction liquid, methyl 2-(cyclohexylamino)-5-(piperidin-1-ylmethyl)benzoate was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:14]([CH2:15][O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:13]=[C:12]([C:24]#[C:25][CH2:26][N:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)[C:4]=2[N:5]=[C:6]([CH2:8][CH2:9][CH2:10][CH3:11])[N:7]=1.Cl>CO.O1CCOCC1.CO.CS(C)=O>[CH2:17]([O:16][CH2:15][N:14]1[C:3]2[C:2]([NH2:1])=[N:7][C:6]([CH2:8][CH2:9][CH2:10][CH3:11])=[N:5][C:4]=2[C:12]([C:24]#[C:25][CH2:26][N:27]2[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]2)=[CH:13]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCCc1nc(N)c2c(n1)c(C#CCN1CCN(C(=O)OC(C)(C)C)CC1)cn2COCc1ccccc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CO
Solvent: C1COCCO1
Product: CCCCc1nc(N)c2c(n1)c(C#CCN1CCNCC1)cn2COCc1ccccc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 54.9 %

Procedure:
To a solution of tert-butyl 4-(3-(4-amino-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)prop-2-yn-1-yl)piperazine-1-carboxylate (85 mg, 0.160 mmol) in anhydrous methanol (5 mL) was added 4M hydrogen chloride in 1,4-dioxane (0.5 ml, 2.0 mmol). The reaction was stirred at room temperature for 19 hours. A further 0.5 mL (2.0 mmol) of 4M hydrogen chloride in 1,4-dioxane was added to the reaction. Reaction stirred at room temperature for 2 hours. The reaction was evaporated to dryness under a stream of nitrogen to yield a green oil. The oil was dissolved in MeOH:DMSO (1:1) (2×1 mL) and purified by MDAP (Method B). Appropriate fractions were combined and evaporated in-vacuo to yield the title compound as a pale yellow oil (38 mg).
Reaction SMILES: C(ONC([C:9]1[C:18]([CH3:19])=[C:17]2[C:12]([C:13]([CH3:22])=[CH:14][C:15]([CH3:21])([CH3:20])[NH:16]2)=[CH:11][CH:10]=1)=O)(C)(C)C.[NH2:23]C1C=C2C(C(C)=CC(C)(C)N2)=CC=1>>[NH2:23][C:9]1[C:18]([CH3:19])=[C:17]2[C:12]([C:13]([CH3:22])=[CH:14][C:15]([CH3:21])([CH3:20])[NH:16]2)=[CH:11][CH:10]=1
Reactant: CC1=CC(C)(C)Nc2c1ccc(C(=O)NOC(C)(C)C)c2C
Reactant: CC1=CC(C)(C)Nc2cc(N)ccc21
Product: CC1=CC(C)(C)Nc2c1ccc(N)c2C

Procedure:
Removal of the Boc protective group of 7-tert-butyloxycarbamoyl-1,2-dihydro-2,2,4,8-tetramethylquinoline (400 mg, 1.32 mmol) was effected in the manner similar to that described for 7-amino-1,2-dihydro-2,2,4-trimethylquinoline (EXAMPLE 13), affording 267 mg (quantitative) of the desired aniline as a light reddish oil. Data for 7-amino-1,2-dihydro-2,2,4,8-tetramethylquinoline: 1H NMR (400 MHz, CDCl3) 6.82 (d, 1H, J=8.2 Hz, 5-H), 6.08 (d, 1H, J=8.1 Hz, 6-H), 5.15 (d, 1H, J=1.2 Hz, 3-H), 3.56 (br s, 3H, NH2, NH), 1.95 (D, 3H, J=1.2 Hz, 4-CH3), 1.91 (s, 3H, 8-CH3), 1.27 [s, 6H, 2-(CH3)2].
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[CH2:25]Br>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:25][C:19]2[C:18](=[CH:23][CH:22]=[C:21]([F:24])[CH:20]=2)[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(CBr)c(CBr)c1
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Fc1ccc2c(c1)CN(Cc1ccccc1)C2

Procedure:
A solution of benzylamine (64.3 ml) and triethylamine (164 ml) in toluene (1 L) was added to 1,2-bis(bromomethyl)-4-fluorobenzene (164.1 g) (J. Org. Chem., 1988, 53, 1775-9). This mixture was heated to reflux for 4 h under argon. The reaction mixture was then filtered and the solid was washed with toluene (3×150 ml). The filtrate was evaporated in vacuo and the residue dissolved in dichloromethane (1 L). This solution was washed successively with a saturated solution of potassium carbonate (1 L) and water (0.5 L). The organic extract was dried (MgSO4), concentrated to a volume of 0.5 L and cooled in ice. The unwanted precipitate was filtered off and the filtrate evaporated to a residue which was purified by chromatography over silica gel eluting with a gradient of dichloromethane/ethyl acetate to give the title compound (D7) as an oil (49.3 g). MS electrospray (+ion) 228 (MH+). 1H NMR δ (CDCl3): 7.24-7.42 (5H, m), 7.07-7.12 (1H, m), 6.82-6.89 (2H, m), 3.89 (6H, br, s).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10])([CH3:7])[CH3:6]>S(=O)(=O)(O)O>[CH:5]([C:8]1[CH:14]=[CH:13][C:12]([N+:1]([O-:4])=[O:2])=[CH:11][C:9]=1[NH2:10])([CH3:7])[CH3:6]
Reactant: CC(C)c1ccccc1N
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(C)c1ccc([N+](=O)[O-])cc1N
Reaction time: 0.5 h
Yield: 15.7 %

Procedure:
70% HNO3 (5.1 mL, 84.76 mmol, 1.2 equiv) was added dropwise to a mixture of 2-isopropylaniline (10 mL, 9.55 g, 70.63 mmol, 1 equiv) in 70 mL of conc. sulfuric acid at 0° C. The reaction mixture was stirred at this temperature for 30 minutes and then poured onto ice. The aqueous mixture was extracted with EtOAc (2×150 mL). The organic layers were combined and washed with sat′d NaHCO3. After evaporation, the residue was purified by column chromatography on silica gel using EtOAc/hexanes (3/7) to give 2 g of product (16%) as a dark red oil.
Reaction SMILES: [NH:1]([C:3]([O:5][CH3:6])=[O:4])[NH2:2].N1C=CC=CC=1.[C:13]([CH2:17][C:18](Cl)=[O:19])([CH3:16])([CH3:15])[CH3:14]>ClCCl>[CH3:14][C:13]([CH3:16])([CH3:15])[CH2:17][C:18]([NH:2][NH:1][C:3]([O:5][CH3:6])=[O:4])=[O:19]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: COC(=O)NN
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)NNC(=O)CC(C)(C)C
Yield: 95 %

Procedure:
A solution of 65.5 g of hydrazinecarboxylic acid, methyl ester, 150 ml of dry pyridine and 500 ml of dry dichloromethane was stirred at 0° C. and 100 g of distilled t-butylacetyl chloride was added dropwise. After 2 hours at 0°-5° C. the solvent was removed in vacuo. The residue was taken up in 1.2 liters of ethyl acetate, washed with saturated sodium chloride and filtered through a bed of hydrous magnesium silicate with additional ethyl acetate. The filtrate was concentrated and the solid recrystallized from diisopropyl ether, giving 130 g of 2-(3,3-dimethyl-1-oxobutyl)hydrazinecarboxylic acid, methyl ester as white platelets, mp 83°-84.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11](S(C)(=O)=O)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2].[CH3:30][N:31]([CH2:33][C:34]1[CH:35]=[C:36]([NH2:40])[CH:37]=[CH:38][CH:39]=1)[CH3:32]>CC(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11]([NH:40][C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([CH2:33][N:31]([CH3:32])[CH3:30])[CH:35]=3)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: CN(C)Cc1cccc(N)c1
Solvent: CC(C)O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3cccc(CN(C)C)c3)ncc2c1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 46.3 %

Procedure:
8-Indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (105 mg, 0.25 mmol) and 3-dimethylaminomethyl-phenylamine (38 mg, 0.25 mmol) were combined in iPrOH (2 mL) and heated to 90° C. After 3 h, the reaction mixture was concentrated and purified by preparative HPLC (30 mL/min 5-100% MeCN/H2O gradient over 10 min) and lyophilized to provide 56 mg of 2-(3-Dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.31 (br s, 1H), 8.98 (br s, 1H), 8.51 (s, 1H), 8.39 (s, 1H), 7.00-7.53 (m, 7H), 4.28-4.40 (m, 2H), 3.64 (br s, 2H), 2.88-3.09 (m, 4H), 2.40 (s, 6H), 2.05-2.25 (m, 2H), 1.32-1.40 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([O:9]CC)=O)[N:6]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9])[N:6]=1
Reactant: CCOC(=O)c1coc(Cl)n1
Reactant: Nc1ccccc1
Product: O=C(Nc1ccccc1)c1coc(Cl)n1

Procedure:
Prepared from ethyl 2-chlorooxazole-4-carboxylate (45.4 mg, 0.258 mmol) and aniline (24 mg, 0.258 mmol) as described in Example 154A: 1H NMR (500 MHz, methanol-D4) δ ppm 7.13-7.18 (m, 1H), 7.32-7.38 (m, 2H), 7.65-7.71 (m, 2H), 8.53 (s, 1H). MS (APCI) m/z=223 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-])=O)[CH:8]=2)[C:3]1=[O:15]>C(O)C.O1CCCC1.[Ni]>[NH2:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3](=[O:15])[N:2]([CH3:1])[C:10]2=[O:11]
Reactant: CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: CN1C(=O)c2ccc(N)cc2C1=O

Procedure:
A solution of give 2-methyl-5-nitro-isoindole-1,3-dione (1.1 g, 5.3 mmol) in ethanol/tetrahydrofuran (1:1, 50 mL) is hydrogenated at 45 psi over Raney nickel catalyst. The reaction mixture is filtered through a pad of diatomaceous earth and concentrated to give 5-amino-2-methyl-isoindole-1,3-dione as a yellow cottony solid (0.85 g, 91%).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:6])[CH2:4][CH3:5].[CH2:13](Br)/[CH:14]=[C:15](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])\[CH3:16]>O1CCCC1>[CH3:16]/[C:15](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:14]\[CH2:13][CH:7]([C:3](=[O:6])[CH2:4][CH3:5])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)CC(=O)CC
Reactant: CC(C)=CCC/C(C)=C/CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C/C=C(\C)CCC=C(C)C)C(=O)CC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a suspension of 3.92 g (97.5 mmol, 3 equiv) of 60% NaH in mineral oil (washed three times with pentane) in 200 mL of tetrahydrofuran at 0° C. under argon was added dropwise a solution of 15.3 mL (107 mmol, 3.3 equiv) of ethyl propionylacetate. After 0.5 hour, a solution of 7.04 g (32.4 mmol) of (E)-geranyl bromide in 20 mL of tetrahydrofuran was added dropwise over 45 minutes. The mixture was stirred one hour at 0° C. and one hour at room temperture, quenched with NH4Cl and diluted with 500 mL of diethyl ether. The organic layer was washed with water and brine, and dried over MgSO4 to obtain 20.157 g of crude product as a yellow oil. Purification by flash chromatography on 800 g of silica gel, eluted with 3:97 ethyl acetate:hexanes provided 7.024 g (77%) of pure product as a clear, colorless oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][C:7]=1[NH2:16].CO[C:19](OC)(OC)[CH3:20].Cl.N1C=CC=CC=1>>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=[C:19]1[CH3:20]
Reactant: COC(C)(OC)OC
Reactant: Nc1cnc2ccccc2c1NCCCCl
Agent: Cl
Solvent: c1ccncc1
Product: Cc1nc2cnc3ccccc3c2n1CCCCl
Yield: 77.8 %

Procedure:
Using the general method of Example 1 Part D, N4-(3-chloropropyl)quinoline-3,4-diamine (˜37.6 mmol) was cyclized using 1,1,1-trimethoxyethane (5.43 g, 45.2 mmol) in the presence of pyridine hydrochloride (0.43 g) to provide 7.6 g of 1-(3-chloropropyl)-2-methyl-1H-imidazo[4,5-c]quinoline as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[OH:11].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25](F)[CH:26]=1)[C:22]#[N:23]>CN1C(=O)CCC1.CCOC(C)=O>[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:11][C:3]2[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[C:7]([F:8])[C:2]=2[Cl:1])[CH:26]=1)[C:22]#[N:23]
Reactant: COc1cc(O)c(Cl)c(F)c1
Reactant: N#Cc1cc(F)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1cc(F)c(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 87.9 %

Procedure:
Under a nitrogen atmosphere, 2-chloro-3-fluoro-5-methoxyphenol (50-2) (6.7 g, 37.9 mmol) was diluted in NMP (40 mL, 0.95 M). To this solution Cs2CO3 (24.73 g, 76 mmol) was added and the reaction was allowed to stir at room temperature for 5 minutes. Then, 3-chloro-5-fluorobenzonitrile (11.81 g, 76 mmol) was added to the reaction and it was then heated to 120° C. After 2 hours the reaction was cooled to room temperature and then diluted with EtOAc (40 mL). It was partitioned with water (20 mL) and then extracted with EtOAc (3×30 mL). The organic extracts were then washed with water (3×20 mL) and brine (1×20 mL), dried over sodium sulfate and concentrated. Silica gel chromatography (1%-15% EtOAc/Hexanes) gave 3-chloro-5-(2-chloro-3-fluoro-5-methoxyphenoxy)-benzonitrile (50-4) (10.4 g, 88%).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH:12]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CN(C=O)C>[N+:1]([C:4]1[N:5]=[CH:6][N:7]([CH:12]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: CCCCCCC(Br)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCC(C(=O)OCC)n1cnc([N+](=O)[O-])c1
Reaction time: 0.75 h

Procedure:
4-Nitroimidazole (0.29 moles, 32.9 g in 30 ml DMF was treated portionwise with sodium hydride (0.29 moles, 11.6 g. 60% in mineral oil) and stirred for 45 minutes. Ethyl 2-bromooctanoate (0.29 moles, 73.1 g) was added dropwise over 1 hour. The reaction was stirred overnight at room temperature, poured onto ice water, and extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated to yield 91 g of ethyl 2-(4-nitro-1H-imidazol-1-yl)octanoate. (MS)
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:8][C:7](=[O:9])[O:6][C:4](=[O:5])[CH2:3]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl.[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:10][C:2]([CH3:1])([CH2:3][C:4](=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:8][C:7]([OH:6])=[O:9]
Reactant: CC1(C)CC(=O)OC(=O)C1
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)(CC(=O)O)CC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
A mixture of 3,3-dimethylglutaric anhydride (10.0 g, 70.4 mmol), anhydrous aluminum chloride (23.5 g, 176 mmol) and benzene (100 ml) was heated under reflux for 5 hours. The reaction mixture was poured into ice water, adjusted to pH 1 with a 35% hydrochloric acid and then extracted with ethyl acetate. The extract solution was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 17.4 g of 3,3-dimethyl-5-oxo-5-phenylpentanoic acid.