Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:17](O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:16])[CH2:11][CH2:12][C:13]([O:15][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])=[O:14])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCCCCCCCCCCCO
Reactant: O=C(O)CCC(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOC(=O)CCC(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 4-(4-nitrophenyl)-4-oxobutyric acid (0.50 g, 2.2 mmol), 1-dodecanol (5.0 ml, 22 mmol), and p-toluenesulfonic acid (50 mg) in tetrahydrofuran (2.5 ml) was stirred 60 hours at room temperature then heated under reflux for 1.5 hours. Concentration of the reaction mixture in vacuo and purification by chromatography or silica gel (200 g) eluting with methylene chloride:hexane (1.1 to 2:1) followed by filtration of the solid product from a small volume of hexane gave, after drying under high vacuum, dodecyl 4-(4-nitrophenyl)-4-oxobutyrate (0.43 g) as a white solid. 1H NMR (DMSO-66, 300 MHz) δ:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.C([NH2:15])(=O)C.C([O-])([O-])=O.[K+].[K+]>>[NH2:15][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Clc1ccnc2ccccc12
Reactant: CC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Nc1ccnc2ccccc12
Temperature: 25 °C
Yield: 60.1 %

Procedure:
A mixture of 4-chloroquinoline (486 mg, 3 mmol), acetamide (2.13 g, 36 mmol) and K2CO3 (2.9 g, 21 mmol) was thoroughly vortexed on a mixer and subjected to microwave irradiation at 175° C. for 1 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water and brine and dried over anhydrous Na2SO4. The solvent was removed in vacuo to yield 4-aminoquinoline as a brown solid (260 mg, 60%). EIMS m/z: 145 ([M+1]+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([CH:12]=O)=[CH:9][CH:8]=1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10](/[CH:12]=[CH:22]/[CH:23]=[O:24])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(-c2ccccn2)s1
Product: O=C/C=C/c1ccc(-c2ccccn2)s1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 5-(2-pyridinyl)-2-thiophenecarboxaldehyde (prepared as described in J. Chem Soc., Perkin Trans. 2 1998, 437) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 216 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:12]12([CH2:22][NH2:23])[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([NH:23][CH2:22][C:12]12[CH2:21][CH:16]3[CH2:15][CH:14]([CH2:20][CH:18]([CH2:17]3)[CH2:19]1)[CH2:13]2)=[O:6]
Reactant: O=C(O)c1cc(O)ccc1Cl
Reactant: NCC12CC3CC(CC(C3)C1)C2
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(O)ccc1Cl

Procedure:
Prepared according to the method of Example 14 from 2-chloro-5-hydroxybenzoic acid (0.3 g) and 1-adamantanemethylamine (0.31 ml) to give the title compound as a white solid (0.15 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[CH3:10][O:11][C:12](=[O:23])[C:13]1[CH:18]=[CH:17][C:16](Cl)=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1.O>CN(C=O)C>[CH3:10][O:11][C:12](=[O:23])[C:13]1[CH:18]=[CH:17][C:16]([S:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COc1ccc(S)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Sc2ccc(OC)cc2)c([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
To a solution of 4-methoxy thiophenol (5 mL, 40.7 mmol) and methyl-3-nitro-4-chlorobenzoate (10.52 g, 48.8 mmol) in DMF (40 mL) was added CsCO3 (26.5 g, 81.4 mmol) and the reaction mixture heated at 80° C. for 3 hours. After cooling, the solution was poured into water and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum to afford the title compound after chromatography on silica gel using ethyl acetate/hexanes as eluent (10.93 g, 80%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([P:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:12])[O:9][CH2:10][CH3:11])[O:5][CH2:6][CH3:7])[CH3:2]>C(O)C.[Ni]>[CH2:1]([O:3][CH:4]([P:8]([CH2:13][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)(=[O:12])[O:9][CH2:10][CH3:11])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOC(OCC)P(=O)(Cc1ccccc1)OCC
Agent: [Ni]
Solvent: CCO
Product: CCOC(OCC)P(=O)(CC1CCCCC1)OCC
Reaction time: 12 h

Procedure:
A solution of 38 bg of ethyl diethoxymethyl(benzyl)phosphinate in 300 ml of absolute ethanol is treated with 20 g of Raney nickel and the suspension is hydrogenated at 110° C. and 150 bar for 12 hours. After this time the mixture is filtered through celite® and the filtrate is evaporated to dryness. Distillation of the residue in high vacuum gives ethyl diethoxymethyl(cyclohexylmethyl)phosphinate of b.p. 120° (10-2 mbar). 'H-NMR (CDCl3): δ (ppm)=, 4.62 (1H, d, CHP), 4.17 (2H, m, CH2OP), 3.84+3.69 (2H, m, 2×CH2OC), 1.88 (3H, m, CH2P+CH), 1.68 (6H, m, 3×CH2), 1.30 (13H, m, 3×CH3 +2×CH2).
Reaction SMILES: [Li]CCCC.[CH3:6][O:7][C:8](=[O:15])[NH:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1.[O:16]1[C:20]2([CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1>C1COCC1>[CH3:6][O:7][C:8](=[O:15])[NH:9][C:10]1[S:11][C:12]([C:23]2([OH:26])[CH2:24][CH2:25][C:20]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:21][CH2:22]2)=[CH:13][N:14]=1
Reactant: COC(=O)Nc1nccs1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)Nc1ncc(C2(O)CCC3(CC2)OCCO3)s1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 28 mL, 70 mmol) was dropped slowly into a solution of thiazol-2-yl-carbamic acid methyl ester (Aldrich, 5.0 g, 31.6 mmol) in THF (100 mL) at −78° C., over 10 min. The reaction was stirred for additional 20 min. at −78° C. A solution of 1,4-dioxa-spiro[4.5]decan-8-one (Aldrich, 7.0 g, 45 mmol) in THF (20 mL) was slowly dropped into the reaction. After addition, the reaction was stirred for an additional 2 hours at −78° C. The reaction was then quenched with diluted NH4Cl solution and warmed to room temperature. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow solid, which was then purified by silica gel column on a CombiFlash® system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=1[O:31][CH3:32].C(O)C>Cl.O>[CH:15]1([N:7]2[CH2:8][CH:9]([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC1CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)C(=O)N2C
Yield: 65.8 %

Procedure:
A mixture of 0.030 g (0.0001 mole) of (rac)-2-chloro-9-cyclopentyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one, 0.017 g (0.0001 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated to 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.028 g of (rac)-4-(9-cyclopentyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-3-methoxy-benzoic acid (I-1) as an off-white solid.
Reaction SMILES: [C:1]([C:4]([CH3:18])([CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([O:7]C)=[O:6])(=[O:3])[CH3:2].[OH-].[K+]>>[C:1]([C:4]([CH3:18])([CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:5]([OH:7])=[O:6])(=[O:3])[CH3:2]
Reactant: COC(=O)C(C)(CCCc1ccccc1)C(C)=O
Agent: [K+]
Agent: [OH-]
Product: CC(=O)C(C)(CCCc1ccccc1)C(=O)O

Procedure:
Analogously to Example 29A, 4.90 g (18.7 mmol) of methyl 2-acetyl-2-methyl-5-phenylpentanoate are reacted with 10.0 ml of a 3.5 M potassium hydroxide solution to give 2-acetyl-2-methyl-5-phenylpentanoic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].CC(C)=O>C(O)C>[CH2:1]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(C=O)c1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Product: COc1cccc(CO)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85.7 %

Procedure:
A solution of 43.00 g (0.18 mole) of 2-benzyloxy-3-methoxy-benzaldehyde of Example 1 in 300 mL of absolute ethanol is treated, with stirring, with 7.56 g (0.20 mole) of sodium borohydride. The temperature rises to 50° C. After one-half hour 10 mL of acetone is added, keeping the temperature at less than 60° C. with cooling. After 15 minutes the volatiles are stripped off at reduced pressure. Ice water (500 mL) is added and the product is extracted into 600 mL of ethyl acetate. The dried (Na2S04) solution is concentrated. The remaining oil is dissolved in 100 mL of warm ether. Petroleum ether is added to turbidity to give 37.70 g (86% yield) of pure product; mp 58°-60° C.
Reaction SMILES: [Li+].[Cl-].[CH2:3]([O:5][C:6](=[O:23])[CH:7]([C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([CH3:22])=[CH:15][N:14]=1)C(OCC)=O)[CH3:4]>CS(C)=O.O>[CH2:3]([O:5][C:6](=[O:23])[CH2:7][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([CH3:22])=[CH:15][N:14]=1)[CH3:4]
Reactant: CCOC(=O)C(C(=O)OCC)c1ncc(C)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1ncc(C)cc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 3 h

Procedure:
LiCl (10.6 g, 0.252 mol) is suspended in a solution of 2-(5-Methyl -3-nitro-pyridin-2-yl)-malonic acid diethyl ester (50 g, 0.168 mol) in DMSO (100 mL) containing water (12 g, 0.678 mol) and is stirred at 150° C. for 3 h. The reaction mixture is cooled, diluted with water (200 mL), and extracted with ethyl acetate. The combined organic phase are washed successively with saturated aqueous NaHCO3, water, brine, dried over Na2SO4, and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 20% EtOAc-hexanes to afford (5-Methyl-3-nitro-pyridin-2-yl)-acetic acid ethyl ester as an oil; 1H NMR (300 MHz, CDCl3) δ 1.23 (t, J=9 Hz, 3H), 4.15 (q, J=9 Hz, 2H), 4.25 (s, 2H), 8.2 (s, 1H), 8.58 (s, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[N:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.C1CCCCC=1>>[CH3:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[N:11]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[N:10]=[C:9]2[C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=1
Reactant: CCCCCn1nc(-c2ccc(OC)cc2)c2cccc(C)c21
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: CCCCCn1nc(-c2ccc(O)cc2)c2cccc(C)c21
Yield: 43 %

Procedure:
Prepared according to Method D step C from 3-(4-methoxyphenyl)-7-methyl-1-pentyl-1H-indazole (0.105 g, 0.34 mmol), boron tribromide (0.094 mL, 1.0 mmol) and 0.3 mL of cyclohexene to give the product (0.043 g) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](OC(=O)C(C)(C)C)[N:6]=[C:5]2[C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[NH:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH:3]=2)[NH:7][N:6]=1
Reactant: CC(C)(C)C(=O)On1nc(-c2ccc[nH]2)c2cc(N)ccc21
Reactant: O=C(Cl)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc2[nH]nc(-c3ccc[nH]3)c2c1)c1ccncc1
Yield: 104.1 %

Procedure:
2,2-Dimethyl-propionic acid 5-amino-3-(1H-pyrrol-2-yl)-indazol-1-yl ester (0.38 mmol) was coupled with isonicotinoyl chloride (0.4 mmol) (Aldrich, Milwaukee, Wis.) and triethylamine in DCM at 0° C. to give 120 mg of the titled compound as a light yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[C:16]([CH:17]([CH3:19])[CH3:18])=[C:15]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[N:14]=[C:13]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[N:12]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[CH:17]([C:16]1[C:11]([C:9]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH:2]=[O:1])=[O:10])=[N:12][C:13]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[N:14][C:15]=1[O:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)([CH3:19])[CH3:18]
Reactant: COc1ccc(COc2nc(OCc3ccc(OC)cc3)c(C(C)C)c(C(=O)c3cccc(CO)c3)n2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: COc1ccc(COc2nc(OCc3ccc(OC)cc3)c(C(C)C)c(C(=O)c3cccc(C=O)c3)n2)cc1
Reaction time: 1 h
Yield: 94.4 %

Procedure:
A mixture of (3-hydroxymethyl-phenyl)-[5-isopropyl-2,6-bis-(4-methoxy-benzyloxy)-pyrimidin-4-yl]-methanone (1.9 g, 3.52 mmol), pyridinium chlorochromate (1.14 g, 5.28 mmol), and dried celite (1 g) in dichloromethane (20 ml) was stirred for 1 hr. at room temperature. The mixture was then filtered through a short silica gel pad and the pad was washed with EA. The combined filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:4)) to afford 1.75 g (74%) of a pale yellow syrup. 1H NMR (200 MHz, CDCl3) δ 1.19 (6H, d, J=7.4 Hz), 2.88 (1H, m), 3.79 (3H, s), 3.83 (3H, s), 5.29 (2H, s), 5.45 (2H, s), 6.77-6.95 (4H, m), 7.28-7.42 (4H, m), 7.65 (1H, m), 8.11-8.28 (3H, m), 10.03 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].[Cl-].[NH4+].O>[Fe].CO>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:11](=[O:13])[CH3:12])[CH:4]=1
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CC(=O)c1cc(N)ccc1Cl
Temperature: 70 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
2.01 g (10.1 mmol) of 1-(2-chloro-5-nitro-phenyl)-ethanone, 2.54 g (47.5 mmol) of ammonium chloride and 1.99 g (35.7 mmol) of iron powder were added to a mixture of 6 mL of water and 12 mL of methanol. The slurry was stirred at 70° C. for 1 h, and then cooled down, filtered through a pad of celite and concentrated down under reduced pressure. The residue was taken up in 60 mL ethyl acetate and 60 mL of water. The aqueous layer was extracted with 40 mL of ethyl acetate and the combined organic layers were evaporated under reduced pressure. The residue was filtered through a pad of silica gel eluting with a 7:3 mixture of ethyl acetate-hexanes to give 1.6 g (94%) of the pure product as a white solid. LC-MSD, m/z for C8H8ClNO [M+H]+=170.0, 172.0;
Reaction SMILES: FC(F)(F)C(O)=[O:4].[CH2:8]([N:15]1[CH:20]2[CH2:21][CH2:22][CH:16]1[CH:17]=[C:18]([C:23]1[C:24]([O:31]C(C)(C)C)=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27])[CH2:19]2)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>S(=O)(=O)(O)O>[CH2:8]([N:15]1[CH:20]2[CH2:21][CH2:22][CH:16]1[CH:17]=[C:18]([C:23]1[C:24]([OH:31])=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]([NH2:27])=[O:4])[CH2:19]2)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)Oc1c(C#N)cccc1C1=CC2CCC(C1)N2Cc1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: O=S(=O)(O)O
Product: NC(=O)c1cccc(C2=CC3CCC(C2)N3Cc2ccccc2)c1O
Temperature: 65 °C

Procedure:
Trifluoroacetic Acid (50 mL) and sulfuric acid (20 mL) were added to crude 3-(8-benzyl-8-aza-bicyclo[3.2.1]oct-2-en-3-yl)-2-tert-butoxy -benzonitrile (37.53 g, 0.101 mol) and the reaction mixture was heated at 65° C. overnight, poured into ice water and neutralized to pH 7. The aqueous layer was extracted EtOAc (3×) and the solvent was evaporated. The reaction mixture was purified by silica gel chromatography (10 min 7% MeOH:DCM, 10 min 10% MeOH: DCM, ramping to 20% MeOH:DCM over 30 min) to provide the title compound (22.15 g). (m/z): [M+H]+ calcd for C21H22N2O2 335.17; found 335.4
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]#[C:12][C:13]2[N:18]=[C:17]([C:19]([OH:21])=O)[CH:16]=[CH:15][CH:14]=2)[CH:2]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[Cl:44][C:45]1[CH:54]=[CH:53][CH:52]=[C:51]([CH3:55])[C:46]=1[C:47]([NH:49][NH2:50])=[O:48]>CN(C)C=O>[Cl:44][C:45]1[CH:54]=[CH:53][CH:52]=[C:51]([CH3:55])[C:46]=1[C:47]([NH:49][NH:50][C:19]([C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([C:12]#[C:11][C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:18]=1)=[O:21])=[O:48]
Reactant: Cc1cccc(Cl)c1C(=O)NN
Reactant: O=C(O)c1cccc(C#Cc2cnc3ccccc3c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cccc(Cl)c1C(=O)NNC(=O)c1cccc(C#Cc2cnc3ccccc3c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 6-[(quinolin-3-yl)ethynyl]pyridine-2-carboxylic acid (0.05 g, 0.2 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.04 g, 0.2 mmol) and 1-hydroxybenzotriazole (0.03 g, 0.2 mmol) in N,N-dimethylformamide (10 ml) was stirred at ambient temperature for 1 hr. 2-chloro-6-methylbenzohydrazide (0.03 g, 0.2 mmol) was added and the mixture stirred for 12 hrs at ambient temperature. Concentration and trituration of the residue with water produced a solid which was filtered, washed with water and dried in vacuo. Leaching the product with methanol and drying in vacuo gave N′-(2-Chloro-6-methylbenzoyl)-6-[2-(3-quinolyl)ethynyl]pyridine-2-carboxylic acid hydrazide as a white solid.
Reaction SMILES: [C:1]1([CH2:7][S:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:18][C:19]3[O:20][C:21]([C:24]4[N:25](C(OC(C)(C)C)=O)[C:26]5[C:31]([CH:32]=4)=[CH:30][CH:29]=[CH:28][CH:27]=5)=[CH:22][N:23]=3)[CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[C:24]1[C:21]1[O:20][C:19]([NH:18][C:14]2[CH:13]=[C:12]([NH:11][S:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:10])[CH:17]=[CH:16][CH:15]=2)=[N:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2cnc(Nc3cccc(NS(=O)(=O)Cc4ccccc4)c3)o2)cc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Cc1ccccc1)Nc1cccc(Nc2ncc(-c3cc4ccccc4[nH]3)o2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.4 %

Procedure:
To a stirred solution of tert-butyl 2-(2-((3-(phenylmethylsulfonamido) phenyl)amino) oxazol-5-yl)-1H-indole-1-carboxylate 28 (0.24 g, 0.441 mmol) in anhydrous CH2Cl2 (20 mL) was added 1:1 mixture of CH2Cl2:Trifluoroaceticacid (10 mL) at room temperature. Reaction was stirred for 1.5 hour at ambient temperature. It was quenched with aq. saturated NaHCO3 and CH2Cl2 layer was separated. After evaporation of solvent, crude product was purified using MPLC silica column (Biotage) (Acetone/hexane as an eluent) to obtain N-(3-((5-(1H-indol-2-yl)oxazol-2-yl)amino)phenyl)-1-phenyl methane sulfonamide 29 (0.14 g, 71% yield).
Reaction SMILES: [C:1]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]([CH3:26])[NH:8][C:7]=1[CH2:27][SH:28])([O:3][CH2:4][CH3:5])=[O:2].[CH2:29]=[O:30]>CO>[C:1]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]([CH3:26])[NH:8][C:7]=1[CH2:27][S:28][CH2:29][OH:30])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C1=C(C)NC(CS)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reactant: C=O
Solvent: CO
Product: CCOC(=O)C1=C(C)NC(CSCO)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 3,5-dicarboethoxy-6-methyl-2-mercaptomethyl-4-(m-nitrophenyl)-1,4-dihydropyridine in MeOH (25 ml) is added with a 37% formaldehyde aqueous solution (6 ml, 79 mmol.). The obtained solution is refluxed for 1.5 hours. The solvent is evaporated under reduced pressure and the residue is dissolved in ethyl acetate (50 ml). The organic phase is washed (3×60 ml), separated, dried on Na2SD4, filtered and the solvent is evaporated under reduced pressure; the oily residue is crystallized from isopropyl ether, obtaining 3 g of 3,5-dicarboethoxy-4-(m-nitro-phenyl)-6-methyl-2-(hydroxymethylthiomethyl)-1,4-dihydropyridine, m.p. 113°-114° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20]Cl)[CH:14]=[CH:13][C:10]=1[CH:11]=[O:12].C([O-])([O-])=O.[K+].[K+]>C(O)CCC.O>[Cl:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:14]=[CH:13][C:10]=1[CH:11]=[O:12]
Reactant: CN1CCNCC1
Reactant: O=Cc1ccc(OCCCCl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: CN1CCN(CCCOc2ccc(C=O)c(Cl)c2)CC1
Yield: 63.6 %

Procedure:
N-Methylpiperazine (2.16 g, 21.5 mmol), 2-chloro-4-(3-chloro-propoxy)-benzaldehyde (3.19 g, 10.8 mmol), K2CO3 (4.46 g, 32.3 mmol), and KI (1.02 g, 5.38 mmol) were stirred in n-butanol (22 mL) at 90° C. for 18 h. The reaction mixture was diluted with water and then extracted three times with EtOAc. The combined extracts were dried (Na2SO4), filtered, and concentrated, yielding the crude product, which was purified by Method 1 to afford 2.04 g (63%) of an orange oil. 1H NMR (400 MHz, CD3OD): 10.3 (s, 1H), 7.86 (d, J=8.0, 1H), 7.08 (d, J=2.0, 1H), 7.00 (dd, J=8.0, 2.0, 1H), 4.15 (t, J=8.0, 2H), 3.00-2.30 (br s, 10H), 2.29 (s, 3H), 2.05-1.90 (m, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[N:14]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CC#N>[CH3:27][O:26][C:22]1[CH:21]=[C:20]([NH:19][C:15]2[N:14]=[C:13]([C:9]3[S:8][C:7]([NH:6][C:4](=[O:5])[CH2:3][CH2:2][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[N:11][C:10]=3[CH3:12])[CH:18]=[CH:17][N:16]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(Nc2nccc(-c3sc(NC(=O)CCBr)nc3C)n2)c1
Reactant: C1COCCN1
Solvent: CC#N
Product: COc1cccc(Nc2nccc(-c3sc(NC(=O)CCN4CCOCC4)nc3C)n2)c1

Procedure:
By treatment of 3-bromo-N-{5-[2-(3-methoxyphenylamino)-pyrimidin-4-yl]-4-methyl-thiazol-2-yl}-propionamide with morpholine. Anal. RP-HPLC: tR=13.6 min (0-60% MeCN, purity>94%). 1H-NMR (DMSO-D6) δ: 1.20 (m, 2H, CH2), 2.48 (m, 4H, CH2), 2.58 (s, 3H, CH3), 3.41-3.57 (m, 6H, CH2), 3.79 (s, 3H, CH3), 6.52 (d, 1H, J=7.0 Hz, Ph-H), 7.07 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.15 (t, 1H, J=7.3 Hz, Ph-H), 7.22 (m, 1H, Ph-H), 7.62 (brs, 1H, Ph-H), 8.46 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 9.58 (brs, 1H, NH). MS (ESI+) m/z 456.01 [M+H]+ (C22H26N6SO3 requires 454.55).