Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:10]2[C:5](=[CH:6][C:7]([NH:14][C:15]([C:17]3[CH:22]=[N:21][CH:20]=[CH:19][N:18]=3)=O)=[C:8]([N+:11]([O-])=O)[CH:9]=2)[NH:4][C:3]1=[O:23]>[Pd].C(O)C>[CH3:1][C:2]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:10]2[C:5](=[CH:6][C:7]3[NH:14][C:15]([C:17]4[CH:22]=[N:21][CH:20]=[CH:19][N:18]=4)=[N:11][C:8]=3[CH:9]=2)[NH:4][C:3]1=[O:23]
Reactant: CCOC(=O)C1(C)C(=O)Nc2cc(NC(=O)c3cnccn3)c([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1(C)C(=O)Nc2cc3[nH]c(-c4cnccn4)nc3cc21
Temperature: 60 °C
Reaction time: 1 h

Procedure:
3.2 g. (8.3 mmol) 3-methyl-3-ethoxycarbonyl-5-nitro-6-(2-pyrazinoylamino)-indolin-2-one in 100 ml. ethanol are hydrogenated in 100 ml. ethanol in the presence of 0.5 g. 10% palladium on charcoal. After completion of the take up of hydrogen, the solution is filtered off from the catalyst, the ethanol is evaporated off and the residue is stirred for 1 hour in glacial acetic acid at 60° C. The glacial acetic acid is evaporated, the residue is taken up in water, filtered and recrystallized from ethanol. There are obtained 1.8 g (65% of theory) of the title compound, m.p. 288°-290° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C@@H:4]([NH2:29])[CH2:5][NH:6][C:7](=[O:28])[CH2:8][CH2:9][NH:10][C:11](=[O:27])[CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C(N(CC)CC)C.[C:38]1([S:44](Cl)(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>ClCCl>[CH3:1][O:2][C:3](=[O:30])[C@@H:4]([NH:29][S:44]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:46])=[O:45])[CH2:5][NH:6][C:7](=[O:28])[CH2:8][CH2:9][NH:10][C:11](=[O:27])[CH2:12][CH2:13][CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:18][CH2:19]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)[C@@H](N)CNC(=O)CCNC(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CNC(=O)CCNC(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1)NS(=O)(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
The compound (120 mg) obtained in the above (5) is dissolved in dichloromethane (3 ml), and thereto are added triethylamine (98 μl) and benzenesulfonyl chloride (54 μl) at room temperature, and the mixture is stirred for 30 minutes. Triethylamine (98 μl) and benzenesulfonyl chloride (81 μl) are further added, and the mixture is stirred for 90 minutes. The mixture is evaporated under reduced pressure to remove the solvent, and to the residue is added ethyl acetate. The mixture is washed successively with 1N hydrochloric acid (twice), a saturated brine (once), a saturated aqueous sodium hydrogen carbonate solution (twice) and a saturated brine (twice), and dried over anhydrous magnesium sulfate. The desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (silica gel; 20 g, solvent; chloroform-methanol=30:1 to 10:1). The fractions containing the title compound are concentrated under reduced pressure to give the title compound (151 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].C1C(=O)N([Br:22])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:22][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:9][CH2:10][C:11]([F:13])([F:12])[F:14])[CH:4]=1
Reactant: Cc1ccc(F)c(OCC(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)cc1OCC(F)(F)F

Procedure:
A mixture of 2.68 g (12.8 mmol) of 1-fluoro-4-methyl-2-(2,2,2-trifluoro-ethoxy)-benzene, 2.3 g (12.9 mmol) of NBS and 140 mg of dibenzoylperoxide in 60 ml of CCl4 was refluxed for 6 hours. Solvent was removed and the crude residue was used without any further purification for the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([C:24]([O:26]CC)=[O:25])=[C:5]2[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>>[CH:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:10][CH:9]=2)[C:5]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:6]1[C:24]([OH:26])=[O:25])([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1C(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1ccc2c(c1)c(-c1ccccc1)c(C(=O)O)n2C(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared from ethyl 5-amino-1-benzhydryl-3-phenyl-1H-indole-2-carboxylate and methanesulfonyl chloride followed the procedure of Example 1 Step 3 as an off-white solid: 1H NMR (DMSO-d6) δ 2.85 (s, 3H, 6.79 (d, J=9.0 Hz, 1H, 6.95 (dd, J=9.0, 2.0 Hz, 1H, 7.19 (d, J=7.4 Hz, 4H, 7.30-7.50 (m, 12H, 7.91 (s, 1H, 9.37 (s, 1H, 13.21 (br s, 1H; MS (ESI) m/z 495 [M-H]−; HRMS calcd for C29H25N2O4S: 497.1533; found (ESI+): 497.1522; Anal. calcd for C29H24N2O4S.0.7H2O: C, 68.41; H, 5.03; N, 5.50. Found: C, 68.32; H, 4.91; N, 5.70.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][NH2:8].[S:9]1[CH2:15][C:13](=[O:14])[NH:12][C:10]1=S.C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][NH:8][C:10]1[S:9][CH2:15][C:13](=[O:14])[N:12]=1
Reactant: Cc1ccsc1CN
Reactant: O=C1CSC(=S)N1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccsc1CNC1=NC(=O)CS1
Temperature: 0 °C
Reaction time: 72 h
Yield: 31.3 %

Procedure:
To a solution of 3-methyl-thiophen-2-ylmethylamine (700 mg, 5.5 mmol) and rhodanine (732 mg, 5.5 mmol) in acetonitrile (30 mL) was added diisopropylethylamine (DIEA) (1.91 mL, 11 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (1.52 g, 5.6 mmol) was added in one portion. After addition, the suspension was allowed to warm to room temperature and stirred for 3 days. The resulting black solids were filtered through a plug of celite and washed with acetonitrile (200 mL) and ethyl acetate (250 mL). The filtrates were removed under the vacuum and the crude residue was dissolved in dichloromethane (150 mL) and washed with water and brine solution. After drying over magnesium sulfate, the filtrate was removed under the vacuum and the residue was dissolved in dichloromethane (10 mL) and diluted with hexanes (10 mL). After overnight storage in the refrigerator, the solids were collected by filtration and washed with dichloromethane. After drying in air, 390 mg (31.5% yield) of 2-[(3-methyl-thiophen-2-ylmethyl)-amino]-thiazol-4-one was isolated as a light yellow amorphous solid: EI-HRMS m/e calcd for C9H10N2OS2 (M+) 226.0235, found 226.0232.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][O:4][N:3]=1.[Br:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[N:18]1[C:27]2[C:22](=[CH:23][C:24]([S:28](Cl)(=[O:30])=[O:29])=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]1=[O:32].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Br:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[N:18]1[C:27]2[C:22](=[CH:23][C:24]([S:28]([NH:1][C:2]3[CH:6]=[CH:5][O:4][N:3]=3)(=[O:30])=[O:29])=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]1=[O:32]
Reactant: Nc1ccon1
Reactant: O=c1ccc2cc(S(=O)(=O)Cl)ccc2n1-c1ccc(C(F)(F)F)cc1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1ccc2cc(S(=O)(=O)Nc3ccon3)ccc2n1-c1ccc(C(F)(F)F)cc1Br
Reaction time: 0.5 h
Yield: 33.2 %

Procedure:
A solution of 3-aminoisoxazole (0.380 ml, 5.14 mmol) and 1-(2-bromo-4-(trifluoromethyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonyl chloride (1.200 g, 2.57 mmol) in 10 mL THF was cooled to 0° C. and was treated with LHMDS 1N in THF (2.57 ml, 2.57 mmol). After stirring for 30 minutes, the reaction mixture was concentrated. Purification of the crude residue by reverse phase column chromatography [Puriflash C18, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 1-(2-bromo-4-(trifluoromethyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.438 g, 0.852 mmol, 33.1% yield) with minor impurities. m/z (ESI) 514.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][CH2:13][O:14][CH3:15])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:16][CH:17]([CH3:23])[CH2:18][S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([CH2:12][CH2:13][O:14][CH3:15])[CH2:7][CH2:8][N:9]([S:19]([CH2:18][CH:17]([CH3:23])[CH3:16])(=[O:21])=[O:20])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CC(C)CS(=O)(=O)Cl
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Solvent: c1ccncc1
Product: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)CC(C)C)CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 40.4 %

Procedure:
4-(2-Methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (1 g) was dissolved in pyridine (15 ml) under an argon atmosphere at RT and 2-methyl-propane-1-sulfonyl chloride (0.728 g) was added and the mixture was stirred for 60 h at RT. The pyridine was evaporated off, the residue dissolved in AcOEt, washed with 0.05M HCl and brine. The layers were separated, the organic layer dried over sodium sulphate and concentrated. The crude product was purified by flash chromatography (AcOEt/heptane, gradient from 0 to 25%,) to give the desired 4-(2-methoxy-ethyl)-1-(2-methyl-propane-1-sulfonyl)-piperidine-4-carboxylic acid ethyl ester (0.63 g) as a yellow oil. MS (ESI): 336.18 (MH+).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([CH2:23][C@H:24]([NH:29]C(OC(C)(C)C)=O)[C:25]([O:27][CH3:28])=[O:26])[CH:19]=[CH:20][C:21]=1[CH3:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[NH2:29][C@@H:24]([CH2:23][C:18]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:16]([O:15][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:17]=1)[C:25]([O:27][CH3:28])=[O:26].[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2]
Reactant: COC(=O)[C@H](Cc1ccc(C)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](N)Cc1ccc(C)c(OCc2ccccc2)c1

Procedure:
To TFA (5 mL) was added to a solution of (S)-methyl 3-(3-(benzyloxy)-4-methylphenyl)-2-((tert-butoxycarbonyl)amino)propanoate (1.0 g, 2.5 mmol) in DCM (10 mL) at 0° C. with stirring. The mixture was stirred for 1 h and then concentrated to dryness. The residue was azeotroped with EtOAc (10 mL×3) to remove residual TFA and afford crude (S)-methyl 2-amino-3-(3-(benzyloxy)-4-methylphenyl)propanoate as its TFA salt.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].[NH4+].[OH-].O=P(Cl)(Cl)[Cl:25]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:25])=[C:6]2[CH:5]=[N:4]1)=[CH:14][CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=3)[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1nccc1Nc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCn1ncc2c(Cl)c3ccc([N+](=O)[O-])cc3nc21
Temperature: 0 °C
Yield: 82 %

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl) -4-nitroanthranilic acid (3.4 g, 12.32 mmol) and POCl3 (20 ml) was refluxed for 8 hours. The reaction mixture was poured into ice-water, neutralized with concentrated NH4OH and the resulting solid was collected by filtration, washed with water and dried to afford 2.8 g (82%) of 1-ethyl-4-chloro-7-nitro-1H-pyrazolo[3,4-b]quinoline.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[OH:4].[C:26]1([C:37](O)=[O:38])[CH:27]=[CH:28][CH:29]=[C:30]2[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[OH:4][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH:2]([NH:1][C:37]([C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=12)=[O:38])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:24])([F:25])[CH:21]([F:22])[F:23])[CH:14]=1
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(O)cc1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(O)cc1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-{(1RS,2SR)-2-amino-1-hydroxy-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propyl}phenol (125 mg, 0.35 mmol) in acetonitrile (30 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (66 mg, 0.35 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (100 mg, 0.52 mmol) and 1-hydroxybenzotriazole hydrate (53 mg, 0.35 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from chloroform-hexane to give the objective substance (162 mg, 88%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1O)([O-:3])=[O:2].O=P(Cl)(Cl)[Cl:13]>C1(C)C=CC=CC=1>[Cl:13][C:9]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnccc1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cnccc1Cl
Temperature: 25 °C
Yield: 75 %

Procedure:
To a suspension of 3-nitropyridin-4-ol (4.342 g, 31 mmol) in toluene (60 mL) was added POCl3 (11.6 mL, 124.4 mmol) at 0° C. The resulting mixture was warmed to room temperature, then heated to 110° C. for 14 hours. After cooling to room temperature, the solvent was removed in vacuo and the residue was poured into ice, and basified with saturated aqueous NH4Cl solution. The mixture was extracted with EtOAc (40 mL×2). The combined organic layers was washed with water, brine, dried (MgSO4) and concentrated to a brown oil, which solidified on standing. (3.68 g, 75% yield).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3].CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][NH:38][CH:39]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:35]2[CH:36]=[N:37][NH:38][CH:39]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4cn[nH]c4)cc23)CC1

Procedure:
Following the general procedure of Example 66, a mixture of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1H-indazol-3-yl]-1-piperidinecarboxylate (Intermediate 5) (30 mg, 0.07 mmols), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (41 mg, 0.21 mmols), cesium carbonate (150 mg), and Pd(PPh3)4 (10 mg) in dioxane/water (3/1, 4 mL) were reacted to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[N:6][CH:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(Cl)CCl.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)Cc1cncc(Br)c1
Reactant: C1COCCN1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(Cc1cncc(Br)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 95 %

Procedure:
To a solution of (5-bromopyridin-3-yl)acetic acid (1.00 g, 4.63 mmol) and morpholine (0.50 mL, 5.73 mmol) in DCM (50 mL) was added EDC (1.78 g, 9.30 mmol) and 1-hydroxybenzotriazole (1.25 g, 9.26 mmol). The reaction mixture was allowed to stir at rt for 50 min and then diluted with DCM (50 mL) and 1N HCl (100 mL). The organic solution was separated and discarded. The aqueous solution was neutralized with sat. aq. NaHCO3 (100 mL) and was extracted with DCM (3×50 mL). The organic solutions were combined, dried over MgSO4, filtered and concentrated to give 4-[(5-bromopyridin-3-yl)acetyl]morpholine (1.26 g, 4.40 mmol, 95%) as a light brown solid. LCMS (FA): Rt=1.11 min, m/z=287.0 (M+H).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH2:15]([Li])CCC.IC>O1CCCC1>[CH3:15][CH:9]1[CH2:8][CH2:7][CH2:6][CH:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]1=[O:3]
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: [Li]CCCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1CCCC(C)C1=O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (5.0 g, 0.125 mol) in tetrahydrofuran (250 mL) was added a solution of ethyl 2-oxocyclohexanecarboxylate (19.9 mL, 0.125 mol) in tetrahydrofuran (30 mL) whilst maintaining the temperature of the mixture between 10° C. and 15° C. by means of an ice bath. After stirring at 5° C. for 1 hour, butyl lithium (52.5 mL, 2.5 M solution in hexanes, 131 mmol) was added dropwise while maintaining the temperature below 12° C. After stirring at 5° C. for 30 minutes, iodomethane (7.8 mL, 125 mmol) was added. The reaction mixture was stirred at 5° C. for 1.5 hours and then quenched with a saturated solution of ammonium chloride. The mixture was diluted with ethyl ether, washed with water. The organic extracts were dried over magnesium sulfate and concentrated. The resulting residue was distilled (100–110° C., 0.1 torr) to obtain the title compound as a colorless oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10](=[O:13])[CH2:11][CH3:12].[F:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[C:17]([O:24][CH3:25])[CH:16]=1>CCCCCCC.CCOC(C)=O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[NH:8][CH2:9][C:10](=[O:13])[CH2:11][CH3:12])=[C:17]([O:24][CH3:25])[CH:16]=1
Reactant: CCC(=O)CNc1cnccc1I
Reactant: COc1cc(F)ccc1B(O)O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCC(=O)CNc1cnccc1-c1ccc(F)cc1OC

Procedure:
The title compound was prepared in analogy to Example 72, from 1-(4-iodo-pyridin-3-ylamino)-butan-2-one and 4-fluoro-2-methoxyphenylboronic acid (CAS RN 179899-07-1) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Yellow oil (43%). MS (ESI): m/z=289.134 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[CH:21]=[C:20]([CH2:22][CH3:23])[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:16]2[CH:21]=[C:20]([CH2:22][CH3:23])[S:19][C:17]=2[N:18]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: CCc1cc2c(Cl)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of 3-nitrobenzylamine with 2,4-dichloro-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-ethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]=[C:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH3:16])=[O:14].Br[CH2:18][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21]>C1(C)C=CC=CC=1>[CH3:21][C:20]([CH3:23])([CH3:22])[CH2:19][CH2:18][C:9]1([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:11][CH2:12][C:8]1=[O:7]
Reactant: CC(C)(C)CCBr
Reactant: COC(=O)C1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)C1(CCC(C)(C)C)CCCC1=O
Temperature: 25 °C

Procedure:
117.0 g (846.0 mmol) of potassium carbonate are added to a solution consisting of 40.0 g (281.7 mmol) of methyl 2-oxocyclopentanecarboxylate in 160 ml of dry toluene. 93 g (563.4 mmol) of 1-bromo-3,3-dimethylbutane are then added dropwise, and the mixture is stirred at reflux for 14 hours. After the reaction has ended the mixture is cooled to room temperature and filtered off through Celite. The product is concentrated under reduced pressure and purified by column chromatography (silica gel 100-200 mesh, mobile phase: ethyl acetate 5%/petroleum ether). This gives 48 g (75% of theory) of methyl 1-(3,3-dimethylbutyl)-2-oxocyclopentanecarboxylate.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.Cl[C:12]1[N:13]=[CH:14][CH:15]=[C:16]2[C:20]([CH3:21])=[C:19]([CH2:22][CH3:23])[NH:18][C:17]=12>>[CH2:22]([C:19]1[NH:18][C:17]2=[C:12]([N:2]3[CH2:3][CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:1]3)[N:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[CH3:21])[CH3:23]
Reactant: c1ccc2c(c1)CCNC2
Reactant: CCc1[nH]c2c(Cl)nccc2c1C
Product: CCc1[nH]c2c(N3CCc4ccccc4C3)nccc2c1C
Temperature: 140 °C
Reaction time: 8 h

Procedure:
1,2,3,4-Tetrahydroisoquinoline (1 ml) was added to 7-chloro-2-ethyl-3-methyl-1H-pyrrolo[2,3-c]pyridine (850 mg, 4.37 mmol) prepared in Preparation 28. The reaction mixture was stirred overnight at 140° C., cooled to room temperature, and then purified with silica gel column chromatography to give 660 mg of the titled compound as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=O)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].O(C1C=CC(P2(=S)SP(=S)(C3C=CC(OC4C=CC=CC=4)=CC=3)[S:32]2)=CC=1)C1C=CC=CC=1>COCCOC.C1COCC1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](=[S:32])[NH2:15])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(C(N)=O)cc1
Reactant: S=P1(c2ccc(Oc3ccccc3)cc2)SP(=S)(c2ccc(Oc3ccccc3)cc2)S1
Solvent: COCCOC
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(C(N)=S)cc1
Yield: 105.3 %

Procedure:
To stirring suspension of 4-(heptyloxy)benzamide (1.24 g, 5.29 mmol) in DME (20 mL) and THF (10 mL) was added 2,4-bis(4-phenoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (2.80 g, 5.29 mmol). The reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated onto silica and purified by column chromatography (0-60% EA in iso-hexanes) to afford 1.4 g (62%) of 4-(heptyloxy)benzothioamide as a yellow waxy solid. LCMS-ESI (m/z) calculated for C14H21NOS: 251.4; found 252.0 [M+H]+, tR=3.13 min. (Method 6).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:14])[CH:5]=[C:6]([Cl:13])[C:7]=1[C:8]([Cl:12])=[C:9]([Cl:11])[Cl:10].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:33]N1C(=O)CCC1=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:13])[C:7]=1[C:8]([Cl:12])=[C:9]([Cl:10])[Cl:11])[CH2:14][Br:33]
Reactant: Cc1cc(Cl)c(C(Cl)=C(Cl)Cl)c(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: ClC(Cl)=C(Cl)c1c(Cl)cc(CBr)cc1Cl

Procedure:
From the reaction of 3,5-dichloro-4-(trichlorovinyl)toluene (2.15 g), dibenzoyl peroxide (0.33 g), and N-bromosuccinimide (2.05 g) in 85 ml of benzene at reflux as in Example 30, 3,5-dichloro-4-(trichlorovinyl)benzyl bromide is obtained. This material (2.7 g) and sodium azide (0.8 g) in ethanol (25 ml) is heated for 2 hours. The crude product is chromatographed on silica gel to give pure 3,5-dichloro-4-(trichlorovinyl)benzyl azide.