Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]([N:14]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:21](O)=[O:22])=[O:13])([CH3:10])([CH3:9])[CH3:8].[CH3:34][O:35][C:36](=[O:50])[CH2:37][CH2:38][CH2:39][NH:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[C:47](=[O:49])[NH2:48].CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:34][O:35][C:36](=[O:50])[CH2:37][CH2:38][CH2:39][N:40]([C:21](=[O:22])[C:20]1[CH:24]=[C:25]([Cl:27])[CH:26]=[C:18]([O:17][CH2:16][CH2:15][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:13])[C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[CH:19]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[C:47](=[O:49])[NH2:48]
Reactant: COC(=O)CCCNc1ccccc1C(N)=O
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)c1ccccc1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.2 %

Procedure:
2M Oxalyl chloride solution in dichloromethane (0.090 ml) and DMF (0.01 ml) were added to a suspension of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.060 g) in anhydrous dichloromethane (1 ml). The reaction was stirred at room temperature for 2 h then 4-(2-carbamoyl phenylamino)-butyric acid methyl ester (0.037 g), DMAP (0.002 g) and DIPEA (0.078 ml) were added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was removed and the organic phase washed with saturated aqueous sodium bicarbonate solution, water and dried with brine and over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with ethyl acetate:cyclohexane (9:1 v/v), neat ethyl acetate and dichloromethane:methanol (9:1) to give the title compound as a colourless gum (0.031 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH2:9]([OH:11])[CH3:10]>>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([O:11][CH2:9][CH3:10])[CH:7]=1
Reactant: CCO
Reactant: Brc1cncc(Br)c1
Product: CCOc1cncc(Br)c1
Yield: 60 %

Procedure:
The title compound was synthesized from 3,5-dibromopyridine and ethanol using the procedure described in Example 53, step (a) in 60% yield. 1H NMR (CDCl3) δ 8.27 (bs, 1H), 8.23 (bs, 1H), 7.33 (m, 1H), 4.06 (q, 2H, J=7.0 Hz), 1.43 (t, 3H, J=7.0 Hz).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.[OH-].[K+].[CH2:25](Cl)Cl>>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:25][NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: ClCCl
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: Nc1ccccn1
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc2c(c1)c1c(n2CNc2ccccn2)CCN(C)C1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 1.00 mmol) and 2-aminopyridine (188 mg, 2.00 mmol) in DCM (2 mL) was added powdered KOH (392 mg, 7.00 mmol), and the reaction mixture was stirred at 85° C. for 2 h. The progress of reaction was monitored by TLC and LCMS. DCM was removed under reduced pressure. Water was added to the residue and extracted with EtOAc (2×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to afford crude material, which was purified by reverse phase HPLC to yield (2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-ylmethyl)-pyridin-2-yl-amine. 1H NMR (CDCl3, freebase) δ (ppm): 8.1 (d, 1H), 7.38 (m, 2H), 7.18 (s, 1H), 7.0 (d, 1H), 6.6 (t, 1H), 6.3 (d, 1H), 5.57 (s, 2H), 5.26 (bs, 1H), 3.8 (s, 2H), 3.1 (t, 2H), 3.0 (t, 2H), 2.6 (s, 3H), 2.4 (s, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].CN1CCCC1=O.[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>O>[C:22]([NH:26][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)N
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
To a mixture of 5.22 g of 4-fluoro-3-nitro-benzo trifluoride and 25 ml of N-methylpyrrolidone was added 3.88 g of tert-butylamine, and the mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into water, the deposited solid was collected by filtration. This solid was washed with water, then, dried under reduced pressure, to obtain 5.35 g of N-tert-butyl-2-nitro-4-trifluoromethylaniline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[CH2:16][CH2:15][CH2:14][N:12]3[CH:13]=2)=[CH:5][CH:4]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:27]([O:26][C:24]([N:17]1[CH:22]=[CH:21][CH:20]([C:13]2[N:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[N:10][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH:19]=[CH:18]1)=[O:25])[CH3:28]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(-c2cn3c(n2)CCC3)cc1
Reactant: c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)N1C=CC(c2c(-c3ccc(OC)cc3)nc3n2CCC3)C=C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 2.8 g (13.1 mmoles) of 2-(4-methoxyphenyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazole, prepared as described above, and 6.2 g (78.4 mmoles) of dry pyridine in 30 ml of dry CH2Cl2 was treated dropwise over 1 hour at 5° C. under argon atmosphere with 4.25 g (39.2 mmoles) of ethyl chloroformate. After stirring for 1 hour an additional 3.1 g (39.2 mmoles) of pyridine was added, followed by 2.15 g (19.8 mmoles) of ethyl chloroformate added over 2 hours. The mixture was stirred overnight at 25° C., then poured into ice water made alkaline with Na2CO3 and extracted with CH2Cl2. The organic phase was sequentially washed with 0.2 N HCl, water, and aqueous K2CO3 solution, dried over Na2SO4 and stripped in vacuo to afford the titled compound as an amber resin.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][N:11]=1.[I:19]I.O>C1COCC1>[F:9][C:10]1[C:15]([I:19])=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][N:11]=1
Reactant: CC(C)c1ccc(F)nc1
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1cnc(F)c(I)c1
Reaction time: 0.5 h

Procedure:
To a stirring solution of 9.2 mL of LDA (lithium diisopropylamide) (2.0M solution in THF/heptane/ethylbenzene) in 20 mL of THF at −78° C. was added 2-fluoro-5-isopropylpyridine in 40 mL of THF dropwise over a period of 20 min. After 30 min. 4.39 g (17.3 mmol) of iodine in 25 mL of THF was added. After 2 h at −78° C. with the light off, 20 mL of water was added, and the cold bath was removed. Water (80 mL) was added and 9 g of sodium thiosulfate was added in 3 portions. Diethyl ether was added, and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (5% Et2O/hexanes) provided 1.83 g of 2-fluoro-3-iodo-5-isopropylpyridine with some impurity.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.CN(C)CCCCCCN(C)C.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>C(#N)C.O>[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)(=[O:42])=[O:41])=[CH:36][CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CN(C)CCCCCCN(C)C
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 8 h
Yield: 117 %

Procedure:
Tert-butyl 4-hydroxypiperidine-1-carboxylate (2.22 g, 10.0 mmol) was dissolved in acetonitrile (40 ml), to which triethylamine (2.74 ml, 19.7 mmol) and N,N,N′,N′-tetramethyl-1,6-diaminohexane (0.57 ml, 2.64 mmol) were added, and the mixture was cooled in an ice-bath. p-Toluenesulfonyl chloride (2.75 g, 14.4 mmol) was added to this mixture, which was allowed to return to room temperature and stirred overnight. Water was poured into the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) to afford tert-butyl 4-(toluene-4-sulfonyloxy)piperidine-1-carboxylate (4.16 g, yield 89%) as a pale yellow powder.
Reaction SMILES: [OH:1][C:2]([CH3:8])([CH2:6][CH3:7])[C:3](O)=[O:4].S(Cl)(Cl)=O.[C:13]1([S:19]([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C>CC(N(C)C)=O>[C:13]1([S:19]([C:22]2[CH:23]=[CH:24][C:25]([NH:26][C:3](=[O:4])[C:2]([OH:1])([CH3:8])[CH2:6][CH3:7])=[CH:27][CH:28]=2)(=[O:20])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Reactant: CCC(C)(O)C(=O)O
Agent: C
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CCC(C)(O)C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 2-hydroxy-2-methyl butyric acid (0.76 g, 6.4 mmol) in dry dimethylacetamide (15 ml) was stirred under a nitrogen atmosphere at -10° C. Thionyl chloride (0.76 g, 6.4 mmol) was added and the resulting mixture was allowed to stir at -10° C. for 1 hour. 4-Phenylsulfonylaniline (1.0 g, 4.29 mmol) was then added and the reaction mixture was stirred at -10° C. for a further 15 mins. The solution was then allowed to warm to room temperature where it was stirred overnight. The reaction mixture was poured onto water, extracted with ethyl acetate, and the combined ethyl acetate portions were washed with water, and brine. After drying (Na2SO4) the ethyl acetate was removed by evaporation. Crystallization from ethyl acetate/hexane yielded the title tertiary carbinol (0.89 g, 62.5%) as a colorless crystalline solid; mp=163.0°-165.0° C. 1H-NMR (250 MHz, d6 -DMSO): 0.82 (t, J=7 Hz, 3H, CH3), 1.32 (s, 3H, CH3), 1.56 (m, J=7 Hz, 1H, CH2), 1.76 (m, J=7 Hz, 1H, CH2), 5.65 (s, 1H, OH), 7.64 (m, 3H, ArH), 7.91 (m, 4H, ArH, 8.01 (d, J=11.1 Hz, 2H, ArH), 9.98 (s, 1H, NH). MS (CI, CH4): 334(M+1, 100).
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[C:5]([OH:25])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36]>CN(C)C=O.C(OCC)(=O)C.O>[F:26][CH:2]([F:1])[O:3][C:4]1[C:5]([O:25][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)CBr
Reactant: CCOC(=O)c1c(/C=C/c2cccc(OC(F)F)c2O)nc2sccn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(/C=C/c2cccc(OC(F)F)c2OCC(C)(C)C)nc2sccn12
Temperature: 110 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
To a stirred solution of Intermediate 6 (1.60 g, 4.209 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added cesium carbonate (2.74 g, 8.418 mmol) followed by 1-bromo-2,2-dimethylpropane (1.60 mL, 12.629 mmol) at room temperature. The resulting suspension was stirred at 110° C. overnight under nitrogen atmosphere. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (200 mL) and water (100 mL). The layers were separated. Aqueous layer was extracted with ethyl acetate (2×50 mL) and the combined organic layers were washed with brine (2×50 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure. The residue obtained after the evaporation of the solvent was purified by silica gel column chromatography using 10% ethyl acetate in petroleum ether to obtain 1.20 g of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.07 (s, 9H), 1.39 (t, J=6.9 Hz, 3H), 3.57 (s, 2H), 4.35-4.42 (m, 2H), 7.18 (t, J=74.7 Hz, 1H), 7.20-7.25 (m, 2H), 7.47 (d, J=3.9 Hz, 1H), 7.52-7.58 (m, 1H), 7.73 (d, J=16.2 Hz, 1H), 7.90 (d, J=16.2 Hz, 1H), 8.10-8.16 (m, 1H); APCI-MS (m/z) 451.10 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[N:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[S:9][C:10]=1[CH2:11][CH3:12])[CH3:2].[CH:24]([N-]C(C)C)(C)C.[Li+].CI>O1CCCC1>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([C:6]1[N:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=2)[S:9][C:10]=1[CH2:11][CH3:12])[CH3:24])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CC
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1CC
Temperature: 25 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-acetic acid ethyl ester (2.02 g, 6.13 mmol) is dissolved into anhydrous tetrahydrofuran (THF) (10 mL) and lithium diisopropylamide (LDA) is slowly added at room temperature. This solution is allowed to stir at room temperature and monitored by TLC. After complete conversion, methyl iodide (582 mg, 4.00 mmol) is added slowly and the reaction is followed by TLC. After 18 h., the reaction is not complete, but is quenched with saturated ammonium chloride solution and diluted with diethyl ether. The two phases are separated and the organic layer is washed with water and brine, dried over anhydrous sodium sufate, then concentrated and purified using flash column chromatography (10% EtOAc/Hexanes). The pure 2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propionic acid ethyl ester (1.30 g, 3.64 mmol) is obtained in 59% yield.
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([C:13]2[NH:17][C:16]([C:18]3([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:15][N:14]=2)[CH:7]=1.[CH2:28]([N:30]=[C:31]=[O:32])[CH3:29]>C(N(CC)CC)C>[CH2:28]([NH:30][C:31](=[O:32])[O:12][C:9]1[CH:10]=[CH:11][C:6]([CH3:5])=[CH:7][C:8]=1[C:13]1[NH:17][C:16]([C:18]2([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)[CH2:19][CH2:20][CH2:21][CH2:22]2)=[N:15][N:14]=1)[CH3:29]
Reactant: Cc1ccc(O)c(-c2nnc(C3(c4cccs4)CCCC3)[nH]2)c1
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCNC(=O)Oc1ccc(C)cc1-c1nnc(C2(c3cccs3)CCCC2)[nH]1

Procedure:
A chloroform solution (2.7 ml) of 4-{4-methyl-[5-(1-(2-thienyl)cyclopentyl]-4H-1,2,4-triazol-3-yl}phenol (40 mg), triethylamine (103 μl), and ethyl isocyanate (57 μl) was heated at 60° C. for 5 hours. The solvent was removed by evaporation and a small amount of ethyl acetate was added to the residue. The resulting white solid was collected by filtration and washed with diethyl ether to obtain 4-{4-methyl-[5-(1-(2-thienyl)cyclopentyl]-4H-1,2,4-triazol-3-yl}phenyl ethylcarbamate (30 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:8][NH:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:7][CH2:6]1)=[O:4].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1.[C:26]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:2][C:3]([C:5]1([CH2:8][N:9]([C:18]2[C:19]([N+:23]([O-:25])=[O:24])=[CH:20][N:21]=[C:16]([Cl:15])[N:17]=2)[CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:7][CH2:6]1)=[O:4])[CH3:26]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C1(CNC2CCCC2)CC1
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(CN(c2nc(Cl)ncc2[N+](=O)[O-])C2CCCC2)CC1

Procedure:
Reaction of 1-cyclopentylaminomethyl-cyclopropanecarboxylic acid methyl ester with 2,4-dichloro-5-nitropyrimidine and K2CO3 in acetone gave 1-{[(2-Chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-methyl}cyclopropanecarboxylic acid ethyl ester. Treatment with NH4Cl and iron powder in ethanol gave 1-{[(5-Amino-2-chloro-pyrimidin-4-yl)-cyclopentyl-amino]-methyl}-cyclopropanecarboxylic acid ethyl ester
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH3:10].Cl.[O:12]([NH2:14])[CH3:13]>>[CH3:13][O:12][N:14]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[C:3]([CH3:10])[CH:4]=1
Reactant: CON
Reactant: Cc1cc(C=O)ccc1F
Agent: Cl
Product: CON=Cc1ccc(F)c(C)c1

Procedure:
Reaction of 4-fluoro-3-methyl-benzaldehyde with methoxylamine hydrochloride as described in the preparation of compound 1-A gave the title oxime ether as a clear oil after chromatography on silica gel (elution hexane-ethyl acetate 8:2) (100% yield). 1HNMR indicated a 9:1 mixture of E- and Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 2.29 (3H, broad s, CH3), 3.96 (3H, s, OCH3), 7.0 (1H, m, aromatic), 7.34 (1H, m, aromatic), 7.4 (1H, m, aromatic), 8.0 (1H, s, CH).
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>N1C=CC=CC=1.C(OCC)(=O)C>[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([O:1][CH:2]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:19][CH:20]=2)[CH2:3][O:4][C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=[CH:7][N:6]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)c1ccc(C(O)COc2ncnc3ccccc23)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC(COc2ncnc3ccccc23)c2ccc(C(C)(C)C)cc2)cc1
Reaction time: 4 h

Procedure:
A 15 ml round bottom flask is charged with 4-(2-hydroxy-2-(4-tert-butylphenyl) ethoxy) quinazoline (0.25 g, 0.77 mmol) is dissolved in pyridine (5 ml). p-Toluenesulfonyl chloride (0.15 g, 0.79 mmol) is then added to it and the mixture stirred for 4 hours. The reaction mixture is diluted with ethyl acetate, washed with 5% copper sulfate solution and then with water and dried. After removing the solvent on the rotary evaporator the crude is purified by flash chromatography using silica gel (ethyl acetate/hexanes)to give the product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9][CH2:10][C:11]2[NH:20][C:14]3=[N:15][CH:16]=[C:17](Br)[CH:18]=[C:13]3[N:12]=2)[N:3]=1.[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([C:17]2[CH:18]=[C:13]3[N:12]=[C:11]([CH2:10][CH2:9][C:4]4[N:3]=[C:2]([NH2:1])[CH:7]=[C:6]([CH3:8])[CH:5]=4)[NH:20][C:14]3=[N:15][CH:16]=2)=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cc(N)nc(CCc2nc3cc(Br)cnc3[nH]2)c1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(N)nc(CCc2nc3cc(-c4ccc(OCc5ccccc5)cc4)cnc3[nH]2)c1
Yield: 43.5 %

Procedure:
The title compound is synthesized according to General Procedure A. 100 mg of 2-[2-(2-amino-4-methylpyridin-6-yl)ethyl]-6-bromo-3H-imidazo[4,5-b]pyridine in 5.0 ml dioxane, 903 μl Na2CO3 solution, 78 mg of 4-benzoxyphenylboronic acid, 13 mg of PdCl2(PCy3)2, 110° C. for 70 h, 20 ml of CH2Cl2/H2O, 120 mg of crude title compound is purified by recrystallization from 5.0 ml isopropyl alcohol to yield 57 mg of the pure title compound as colorless solid. M.p. 225° C. ESI-MS: 436.3 (MH+). TLC: Rf=0.35 (dichloromethane/methanol 10:1).
Reaction SMILES: CN1CCC(C2C=CC=CC=2)=CC1.[CH3:14][C:15]1[NH:16][CH2:17][CH2:18][C:19]2([C:25]3[CH:30]=[CH:29][CH:28]=[C:27](OC)[CH:26]=3)[C:24]=1[CH2:23][CH2:22][CH2:21][CH2:20]2>>[CH3:14][C:15]1[NH:16][CH2:17][CH2:18][C:19]2([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:24]=1[CH2:23][CH2:22][CH2:21][CH2:20]2
Reactant: COc1cccc(C23CCCCC2=C(C)NCC3)c1
Agent: CN1CC=C(c2ccccc2)CC1
Product: CC1=C2CCCCC2(c2ccccc2)CCN1

Procedure:
Following the above procedure but substituting 1-methyl-4-(3-methoxyphenyl)-1,2,5,6-tetrahydropyridine for 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine, there was prepared 1-methyl-4a-(3-methoxyphenyl)-2,3,4,4a,5,6,7,8-octahydroisoquinoline. The compound distilled in the range 144°-6° C. at 0.1 torr.; yield 19.3 g.
Reaction SMILES: [OH-].[Na+].O.[Cl:4][C:5]1[CH:6]=[C:7]([CH:37]=[CH:38][C:39]=1[Cl:40])[C:8]([NH:10][C:11]1([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12]1=[O:29])=[O:9].C(O)C>O1CCCC1>[Cl:4][C:5]1[CH:6]=[C:7]([CH:37]=[CH:38][C:39]=1[Cl:40])[C:8]([NH:10][C:11]1([CH2:30][CH2:31][C:32]([OH:34])=[O:33])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12]1=[O:29])=[O:9]
Reactant: CCOC(=O)CCC1(NC(=O)c2ccc(Cl)c(Cl)c2)C(=O)N(CCCc2ccccc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCC1(NC(=O)c2ccc(Cl)c(Cl)c2)C(=O)N(CCCc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 95.8 %

Procedure:
1.5 ml of 4N sodium hydroxide and 5 ml of water were added to a mixed solution of 1.20 g of ethyl 3-[3-(3,4-dichlorobenzoylamino)-2,3-dihydro-2-oxo-1-(3-phenylpropyl)-1H-indol-3-yl]propionate, 20 ml of ethanol and 5 ml of tetrahydrofuran. The mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, diluted with water, then made acidic with 10% hydrochloric acid and extracted with ethyl acetate. After the extract was dried, the solvent was removed by evaporation. The residue was recrystallized from ethanol-ethyl acetate to afford 1.09 g of 3-[3-(3,4-dichlorobenzoylamino)-2,3-dihydro-2-oxo-1-(3-phenylpropyl)-1H-indol-3-yl]propionic acid as colorless needles. Melting point: 242° to 243° C., IR (Nujol) (cm-1): 3285, 1715, 1690, 1675, 1615, FAB-MS (m/z): 513 & 511 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][CH:10]=[CH:11][N:12]=1.C(O)(=O)C.[Br:17]Br.C([O-])(O)=O.[Na+]>O>[Br:17][C:10]1[S:9][C:8]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:12][CH:11]=1
Reactant: BrBr
Reactant: c1ccc(Nc2nccs2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Brc1cnc(Nc2ccccn2)s1
Reaction time: 0.25 h

Procedure:
To a flask containing pyridin-2-yl-thiazol-2-yl-amine (5-2, 3.92 g, 0.0221 mol) was added acetic acid. Bromine (1.14 mL, 0.0221 mol) was then added dropwise to the stirred solution at ambient temperature. The reaction was stirred for 15 min, resulting in an orange-white precipitate. At 15 min, 100 mL H2O were added and solid NaHCO3 introduced, causing a large amount of foaming. The product was obtained as a tan colored precipitate, which was washed with 1.5L H2O and dried under high vacuum overnight. 1H NMR (DMSO-d6): δ 11.53 (bs, 1H), 8.31 (d, 1H, J=3.3 Hz), 7.73 (t, 1H, J=7.6 Hz), 7.45 (s, 1H), 7.05 (d, 1H, J=8.4 Hz), 6.96 (t, 1H, J=5.5 Hz). Mp: 210-212° C. (dec). [M+H]+=255.9.
Reaction SMILES: [Br:1][C:2]1[C:3]([N+:16]([O-])=O)=[CH:4][C:5]2[O:9][CH:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:6]=2[CH:15]=1.[NH4+].[Cl-]>CO.C1COCC1.O.[Fe]>[NH2:16][C:3]1[C:2]([Br:1])=[CH:15][C:6]2[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][O:9][C:5]=2[CH:4]=1
Reactant: CCOC(=O)c1coc2cc([N+](=O)[O-])c(Br)cc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1coc2cc(N)c(Br)cc12
Yield: 67.6 %

Procedure:
A mixture of crude compound ethyl 5-bromo-6-nitrobenzofuran-3-carboxylate (95 g, 302 mmol), iron filings (50.67 g, 907 mmol) and NH4Cl (97 g, 1.82 mol) in MeOH-THF—H2O (2:2:1, 1000 mL) were stirred at reflux for 3 hours. After being filtered and concentrated in vacuum, the residue was purified by column chromatography (eluted with PE:EA from 20:1 to 10:1) to furnish ethyl 6-amino-5-bromobenzofuran-3-carboxylate (58.00 g, yield: 68%). 1H-NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.85 (s, 1H), 7.03 (s, 1H), 5.55 (br s, 2H), 4.31 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H).