Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1.[N+:18]([C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:27]([C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=1)(=[O:28])=[O:29])[CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1
Reactant: CN1CC=C(c2c[nH]c3ccc(F)cc23)CC1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Product: CN1CC=C(c2cn(S(=O)(=O)c3cccc([N+](=O)[O-])c3)c3ccc(F)cc23)CC1

Procedure:
(31.0 mg, 56%), from 5-fluoro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4b, 30.1 mg, 0.131 mmol) and 3-nitrophenylsulfonyl chloride (58.1 mg, 0.26 mmol); HRMS-FAB+ for C20H19N3O4SF calculated MH+ : 416.10803; found: 416.10631.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[C:36]([O:40][C:41]([NH:43][C@H:44]1[CH2:48][CH2:47][NH:46][CH2:45]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]>C(Cl)Cl>[C:36]([O:40][C:41](=[O:42])[NH:43][C@H:44]1[CH2:48][CH2:47][N:46]([S:23]([C:21]2[CH:20]=[CH:19][C:8]3[N:9]([CH2:10][CH:11]4[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]4)[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6][C:7]=3[CH:22]=2)(=[O:25])=[O:24])[CH2:45]1)([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)(F)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCC(F)(F)CC2)C1

Procedure:
Following the same procedure in Example 1, step A, using 2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (2 g, 5 mmol), N,N-diisopropylethylamine (3.5 mL, 20 mmol) and (3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (1.4 g, 7.5 mmol) in (10 mL) methylene chloride. The crude product was purified by MPLC on silica gel using 8-70% EtOAc/hexane. Yield: 2.77 g (100%). 1H NMR (400 MHz, METHANOL-D4) δ 1.35 (s, 9 H) 1.52 (d, J=11.72 Hz, 4 H) 1.58 (s, 9 H) 1.62-1.73 (m, 4 H) 1.75-1.81 (m, 1 H) 1.93-2.00 (m, 1 H) 3.03-3.10 (m, 1 H) 3.24-3.29 (m, 2 H) 3.35-3.47 (m, 3 H) 4.40 (d, J=7.42 Hz, 2 H) 7.71-7.78 (m, 2 H) 8.09 (d, J=1.37 Hz, 1 H).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:8]([C:17]([N:21]=[C:22]=[O:23])([CH2:19][CH3:20])[CH3:18])=[N:9][C:10]([N:14]=[C:15]=[O:16])([CH2:12][CH3:13])[CH3:11]>CCCCC>[N:8]([C:17]([NH:21][C:22]([NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:23])([CH2:19][CH3:20])[CH3:18])=[N:9][C:10]([NH:14][C:15]([NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:16])([CH2:12][CH3:13])[CH3:11]
Reactant: CCC(C)(N=C=O)N=NC(C)(CC)N=C=O
Reactant: NC1CCCCC1
Solvent: CCCCC
Product: CCC(C)(N=NC(C)(CC)NC(=O)NC1CCCCC1)NC(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4.7 grams (0.0474 moles) of cyclohexylamine in 30 ml of pentane in a 50 ml erlenmeyer flask cooled in a water bath was added 5.32 grams (0.0237 moles) of 2,2'-azobis(2-isocyanatobutane) (from Example XXXVI) dropwise over 20 minutes while holding the reaction temperature below 30° C. After the addition was complete, the reaction was stirred for an additional 60 minutes at room temperature and filtered. The filter cake was washed with pentane and dried. The dry white solid weighed 4.7 grams (47% crude yield) and melted at 110°-113° C. The product had a strong carbonyl band at 1665 cm-1 and NH peaks at 3320 cm-1 and 3440 cm-1 in its infrared spectrum.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH2:26])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:16]([NH:26][C:10](=[O:12])[C@@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CCCCCCCCCCN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCNC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 42 h

Procedure:
N-(tert-butoxycarbonyl)-L-proline (Aldrich Chemical Company, Milwaukee, Wis.) (137 mg; 0.64 mmol) is dissolved in methylene chloride (3 mL) at ambient temperature. n-Decylamine (120 mg; 0.76 mmol), N,N-diisopropylethylamine (181 mg; 1.40 mmol) and PyBOP (397 mg; 0.76 mmol) are added sequentially. The reaction is stirred for 42 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography using a gradient elution (20%→70% ethyl acetate in hexanes) affording the desired product (12) as an oil. ISMS: MH+ 355.2
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH:6]([C:9]1[NH:19][C:12]2=[CH:13][N:14]=[C:15]([O:17][CH3:18])[CH:16]=[C:11]2[CH:10]=1)([CH3:8])[CH3:7].CN([CH:23]=[O:24])C>>[CH:6]([C:9]1[NH:19][C:12]2=[CH:13][N:14]=[C:15]([O:17][CH3:18])[CH:16]=[C:11]2[C:10]=1[CH:23]=[O:24])([CH3:8])[CH3:7]
Reactant: CN(C)C=O
Reactant: COc1cc2cc(C(C)C)[nH]c2cn1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2c(C=O)c(C(C)C)[nH]c2cn1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
POCl3 (1.1 ml, 12.5 mmol) was added to anhydrous DMF (10 ml) at 0° C. slowly and stirred for 0.5 h. This was added to a solution of 2-isopropyl-5-methoxy-1H-pyrrolo[2,3-c]pyridine (Compound 5, 468 mg, 2.5 mmol) in anhydrous DMF (15 ml) at room temperature. The mixture was then heated to 90° C. for 2 h and cooled to room temperature, quenched cautiously with aqueous Na2CO3, extracted with EtOAc (×4). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound as beige solid.
Reaction SMILES: C([O:3][C:4](=[O:45])[CH:5]([O:7][P:8]([CH2:17][CH2:18][NH:19][C:20]([C:22]1[C:23]2[CH:24]=[CH:25][CH:26]=[N:27][C:28]=2[C:29]([OH:44])=[C:30]2[C:34](=[O:35])[N:33]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[CH2:32][C:31]=12)=[O:21])([O:10]C1C=CC=CC=1)=[O:9])[CH3:6])C.O.[OH-].[Na+]>C(#N)C>[F:43][C:40]1[CH:39]=[CH:38][C:37]([CH2:36][N:33]2[C:34](=[O:35])[C:30]3[C:31](=[C:22]([C:20]([NH:19][CH2:18][CH2:17][P:8]([OH:10])([O:7][CH:5]([CH3:6])[C:4]([OH:45])=[O:3])=[O:9])=[O:21])[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:28]=4[C:29]=3[OH:44])[CH2:32]2)=[CH:42][CH:41]=1
Reactant: CCOC(=O)C(C)OP(=O)(CCNC(=O)c1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CC(OP(=O)(O)CCNC(=O)c1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.3 %

Procedure:
To 2-[(2-{[7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carbonyl]-amino}-ethyl)-phenoxy-phosphinoyloxy]-propionic acid ethyl ester 221 (15 mg, 0.024 mmol) dissolved in acetonitrile (0.10 ml) and water (0.05 ml) was added 1.0 M NaOH (0.072 ml). The reaction mixture was stirred at room temperature for 3 hours, cooled to 0° C., and quenched with 1.0 M HCl (0.1 ml). The mixture was concentrated in vacuo and the resulting residue was redissolved in dimethylsulfoxide, filtered through a glass plug, and purified by reverse phase preparatory HPLC to afford 2-[(2-{[7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carbonyl]-amino}-ethyl)-hydroxy-phosphinoyloxy]-propionic acid 315 (9 mg, 0.014 mmol, 60%). 1H NMR (CD3OD) δ 9.0 (d, 1H), 8.80 (d, 1H), 7.80 (m, 1H), 7.42 (M, 2H), 7.10 (t, 2H), 4.80 (d, 2H), 4.62 (s, 2H), 3.75 (m, 2H), 2.20 (m, 2H), 1.46 (d, 3H). 3P δ 27.8. 19F δ −78.0, −118.0. MS: 532.1 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>C1(C)C=CC=CC=1>[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:27]
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1cccc(Cl)c1
Yield: 81.7 %

Procedure:
0.5 g (0.0026 mol) of 1-benzyl-4-hydroxypiperidine and 0.64 ml (0.0046 mol) of triethylamine were dissolved in 20 ml of toluene and treated with 0.27 ml (0.0021 mol) of 3-chloro-benzoyl chloride. The mixture was boiled at reflux for 6 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.566 g (82%) of 1-benzyl-piperidin-4-yl 3-chloro-benzoate was obtained as a yellow oil. MS: mele (% basic peak)=329 (C19H20CINO2+, 10), 252 (10), 173 (35), 139 (15), 91 (100), 82 (100).
Reaction SMILES: CC(C)([O-])C.[K+].O1CCCC1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=1.Cl[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][C:23]=1[CH:28]=[O:29]>O>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:18][C:22]2[N:26]([CH3:27])[N:25]=[CH:24][C:23]=2[CH:28]=[O:29])=[CH:15][CH:14]=1
Reactant: Cn1ncc(C=O)c1Cl
Reactant: OCc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ncc(C=O)c1OCc1ccc(Cl)cc1
Reaction time: 0.33 h
Yield: 36.6 %

Procedure:
Under cooling in an ice bath, potassium tert-butoxide (217 mg) was added to a tetrahydrofuran (2.8 mL) solution of 4-chlorobenzyl alcohol (217 mg), and the obtained solution was then stirred for 20 minutes. Under cooling in an ice bath, 5-chloro-1-methyl-1H-pyrazol-4-carbaldehyde (200 mg) was added to the reaction solution, and the obtained solution was then stirred for 3 hours. Thereafter, water was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate. The organic layer was washed with a saturated saline, and was then dried over anhydrous magnesium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=80:20 to 60:40), so as to obtain the title compound (127 mg) in the form of a colorless oily substance.
Reaction SMILES: Br[C:2](Br)=[CH:3][CH:4]1[CH2:7][CH:6]([CH2:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH2:5]1.C([Li])CCC.[Si:20]([O:37][CH2:38][CH2:39][CH:40]([C:49](=[O:54])NCOC)[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>O1CCCC1>[Si:20]([O:37][CH2:38][CH2:39][CH:40]([C:49](=[O:54])[C:2]#[C:3][CH:4]1[CH2:7][CH:6]([CH2:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH2:5]1)[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])([C:33]([CH3:34])([CH3:36])[CH3:35])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COCNC(=O)C(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC(=O)OC(C)(C)C
Reactant: CCC(CC)CC1CC(C=C(Br)Br)C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(CC)CC1CC(C#CC(=O)C(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 75.8 %

Procedure:
1-(2,2-Dibromovinyl)-3-(2-ethylbutyl)cyclobutane (9.78 g) and tetrahydrofuran (100 mL) were mixed. To the mixture was added dropwise n-butyllithium (1.65 M in hexane) (39 mL) at −78° C. The mixture was stirred under ambient temperature. To the mixture was added dropwise a solution of tert-butyl 5-(tert-butyldiphenylsilanyloxy)-3-methoxymethylcarbamoylvalerate (10.6 g) in tetrahydrofuran (30 mL) at ice temperature. After stirring at ice temperature for 2 hr., saturated aqueous ammonium chloride (150 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (150 mL, 100 mL). The combined organic layer was washed with water (75 mL) and brine (75 mL, 50 mL), then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (Eluent: ethyl acetate/hexane=1/40→1/30→1/20) to give the title compound (9.70 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18]Br)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O-:28])(=[S:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[K+]>CC(C)=O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18][S:27][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCNC(=O)OCc1ccccc1)NCCBr
Reactant: [O-]C(=S)c1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CCNC(=O)OCc1ccccc1)NCCSC(=O)c1ccccc1
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To the solution of 3-(benzyloxycarbonylamino)-N-(2-bromoethyl)propionamide (10.0 g, 0.03 mol) in acetone (250 ml), acetone (100 ml) solution of potassium thiobenzoate (5.35 g, 0.03 mol) is added. The mixture is stirred for 1 hour and insoluble substance is filtered off. The filtrate is concentrated in vacuo and the residue is dissolved in chloroform. The solution is washed with sodium hydroxide solution, water and then saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solution is concentrated in vacuo to give 7.9 g (68%) of the titled compound.
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:12]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:17][CH2:16]2)=[O:14])=[CH:11][C:10]=1[CH2:27][CH:28]([CH3:30])[CH3:29])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:8][C:9]1[CH:26]=[CH:25][C:12]([C:13]([N:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:19][CH2:20]2)=[O:14])=[CH:11][C:10]=1[CH2:27][CH:28]([CH3:30])[CH3:29]
Reactant: [H][H]
Reactant: CC(C)Cc1cc(C(=O)N2CCN(CC(C)C)CC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)Cc1cc(C(=O)N2CCN(CC(C)C)CC2)ccc1O
Yield: 89.5 %

Procedure:
1-(4-benzyloxy-3-isobutylbenzoyl)-4-isobutylpiperazine (6.78 g) was dissolved in ethanol (250 ml) and then, with 10% palladium charcoal (0.14 g) added thereto, the mixture was stirred at room temperature for 24 hours in a hydrogen gas atmosphere. After the reaction mixture was filtered under a suction, the filtrate was concentrated under a vacuum, thereby yielding 4.73 g of 1-(4-hydroxy-3-isobutylbenzoyl)-4-isobutylpiperazine. In acetone (50 ml), this compound (0.96 g), 2-fluorobenzyl bromide (0.68 g), and potassium carbonate (0.83 g) of were refluxed with stirring for 4 hours. The reaction mixture, with water added thereto, was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine successively, and then dried over sodium sulfate anhydride. The residue obtained after concentration was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2), thereby yielding 0.90 g of the aimed compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:11]2[CH:12]=[N:13][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:15][CH:16]=2)=[CH:9]\[CH3:10])=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:12]=[N:13][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:15][CH:16]=2)[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: C/C=C(\c1ccc(F)cc1)c1cnc(N2CCNCC2)nc1
Agent: [Pd]
Solvent: CO
Product: CCC(c1ccc(F)cc1)c1cnc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.6 %

Procedure:
To a solution of (E)-5-(1-(4-fluorophenyl)prop-1-enyl)-2-(piperazin-1-yl)pyrimidine (170 mg, 0.57 mmol) in methanol (10 mL) was added Pd/C (30 mg). The mixture was exposed to 1 atm hydrogen (balloon) and stirred at RT for 1 h. The mixture was filtrated, and the filtrate was concentrated to an oil, which was purified by combiflash with dichloromethane:methanol=50:1 to give the title compound (racemate, 90 mg, 53%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10]C)=[CH:6][C:4]=1[NH2:5].[Cl:12][C:13]1[CH:21]=[C:20]([O:22]C)[CH:19]=[CH:18][C:14]=1C(O)=O>>[Cl:12][C:13]1[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:14]=1[C:1]1[O:2][C:3]2[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:4]=2[N:5]=1
Reactant: COc1ccc(OC)c(N)c1
Reactant: COc1ccc(C(=O)O)c(Cl)c1
Product: Oc1ccc(-c2nc3cc(O)ccc3o2)c(Cl)c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, from 2,5-dimethoxyaniline, and 2-chloro-4-methoxybenzoic acid and was obtained as a white solid, m.p. 253–255° C.; MS m/e 262 (M+H)+.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[NH:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][C:24](OCC)=[O:25])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1.Cl>CCCCCC.O1CCCC1>[O:25]=[C:24]([CH2:23][O:22][C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][CH:19]=1)[NH:13][CH:14]=[CH:15]2)[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: CCOC(=O)COc1ccc2[nH]ccc2c1
Reactant: COP(C)(=O)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)COc1ccc2[nH]ccc2c1)OC
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
n-Butyl-lithium (21.8ml. of a 2.92M solution in hexane) was added to a solution of dimethyl methylphosphonate (6.2g.) in dry tetrahydrofuran (50ml.) at -78°C. in an atmosphere of argon. After 10 minutes, a solution of ethyl 5-indolyloxyacetate (5.5g.) in dry tetrahydrofuran (50ml.) was added dropwise, and the mixture was stirred for 2 hours at -78°C. The reaction mixture was poured into 2N hydrochloric acid and stirred vigorously for 5 minutes, then the solvents were evaporated under reduced pressure. The residue was shaken with a mixture of ethyl acetate and water, and the organic phase was separated and washed with brine. The solution was dried, the solvents were evaporated and the residue was chromatographed on a column of silica gel MFC (250 g.)using methylene dichloride : ethyl acetate mixtures as eluant, to give dimethyl [2-oxo-3-(indol-5yloxy)propyl]phosphonate as an oil, RF = 0.3 (ethyl acetate).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8].[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[O:26]=[C:25]([NH:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:8])[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:24]([NH:23][C:21](=[O:22])[O:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:28]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nn1cccc1C(=O)Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1cccc1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
2.00 g (9.94 mmol) of 1-amino-N-phenyl-1H-pyrrole-2-carboxamide were dissolved in 50 mL dimethylformamide. To this solution, 2.07 g (10.94 mmol) of (S)-2-(tert-butoxycarbonylamino)propanoic acid (purchased from Aldrich®, cat. no. 13,451-1) and 2.10 g (10.95 mmol) of EDC.HCl were added and the resulting reaction mixture was stirred at room temperature overnight. The solvent was then evaporated under vacuum, the residue was taken up in ethyl acetate and washed with an aqueous solution of sodium bicarbonate and brine, it was dried over magnesium sulphate, filtered and the solvent was evaporated. The product was purified by flash chromatography (0-5%, methanol-dichloromethane). 2.21 g (60% yield) of the final product were obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:9]O)=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].Cl.[NH2:12][CH2:13][CH2:14][SH:15]>Br>[BrH:1].[BrH:1].[Br:1][C:2]1[C:3]([CH2:9][S:15][CH2:14][CH2:13][NH2:12])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: NCCS
Reactant: Cc1ccnc(CO)c1Br
Agent: Br
Agent: Cl
Product: Cc1ccnc(CSCCN)c1Br

Procedure:
A mixture of 3-bromo-2-hydroxymethyl-4-methylpyridine (5.8), cysteamine hydrochloride (3.5 g) and hydrobromic acid (48%, 50 ml) was refluxed for 6 hours and evaporated to dryness. The residue was crystallised from isopropanol/methanol to give 2-(3-bromo-4-methyl-2-pyridylmethylthio)ethylamine dihydrobromide (8.5 g) m.p. 203°-205°.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:16][CH2:17][OH:18])[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:5]=[CH:4]1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([O:18][CH2:17][CH2:16][N:3]1[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:5]=[CH:4]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCCn1cnc2cnc3ccccc3c21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COCCn2cnc3cnc4ccccc4c32)cc1
Reaction time: 1.5 h

Procedure:
Under a nitrogen atmosphere, sodium hydride (16.88 g of 60% in mineral oil, 422 mmol) was added in portions to a solution of 2-(1H-imidazo[4,5-c]quinolin-1-yl)ethanol (60.0 g, 281 mmol) in anhydrous N,N-dimethylformamide (600 mL). The alkoxide was allowed to stir for about 1.5 hours. Benzyl bromide (50.2 mL, 422 mmol) was slowly added over a period of about 30 minutes. The reaction mixture was allowed to stir at ambient temperature overnight. Solvent was removed under reduced pressure. The residue was taken up in ethyl acetate, washed several times with water, washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure to provide 1-[2-(benzyloxy)ethyl]-1H-imidazo[4,5-c]quinoline as a dark oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:23][CH3:24])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:25][C:26]1[C:27]([O:42][CH3:43])=[N:28][C:29]([O:40][CH3:41])=[C:30]([Cl:39])[C:31]=1[C:32](=O)[C:33]([O:35]CC)=O.CC(O)=O>COCCO>[Cl:39][C:30]1[C:29]([O:40][CH3:41])=[N:28][C:27]([O:42][CH3:43])=[C:26]([Cl:25])[C:31]=1[C:32]1[C:33](=[O:35])[N:23]([CH3:24])[C:3]2[N:4]=[C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]([CH2:19][CH3:20])[CH2:21][CH3:22])=[CH:11][CH:10]=3)[N:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CCN(CC)CCOc1ccc(Nc2ncc(N)c(NC)n2)cc1
Reactant: CCOC(=O)C(=O)c1c(Cl)c(OC)nc(OC)c1Cl
Solvent: COCCO
Solvent: CC(=O)O
Product: CCN(CC)CCOc1ccc(Nc2ncc3nc(-c4c(Cl)c(OC)nc(OC)c4Cl)c(=O)n(C)c3n2)cc1
Yield: 51.4 %

Procedure:
A mixture of 0.66 g (2 mmol) of 5-amino-2-[[4-[2-(diethylamino)-ethoxy]phenyl]amino]-4-(methylamino)pyrimidine, 1.23 g (4 mmol) of ethyl 2-(3,5-dichloro-2,6-dimethoxypyridin-4-yl)-2-oxoacetate, and 1 mL of HOAc in 20 mL of 2-methoxyethanol is heated under reflux for 16 hours. Workup as in 6 above gives 0.59 g (51%) of the title compound (Compound 21): mp (EtOH) 239–240° C.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:23]([C:24](O)=[O:25])[C:22]=1[C:30](O)=[O:31].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:30](=[O:31])[C:22]5=[C:21]([F:20])[CH:29]=[CH:28][CH:27]=[C:23]5[C:24]4=[O:25])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C(O)c1cccc(F)c1C(=O)O
Reactant: NCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C1c2cccc(F)c2C(=O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.37 gm, 8.98 mmoles), 3-fluorophthalic acid (1.82 gm, 9.9 moles) and dicyclohexylcarbodiimide (DCC, 5.5 gm, 26.7 mmoles, 2.6 eq) in dichloromethane (DCM, 250 ml) was stirred at room temperature for 18 hrs. The solids were filtered off. The organic solution was concentrated down. The residue was purified on a flash chromatography column (SiO2, 50 gm; eluted with 1% CH3OH:99% DCM, 1.4 liter; 2-6% CH3OH:DCM, 1 liter). The desired product thus obtained weighed 2.64 gm (71%) as an off-white solid. Recrystallization from hot ethanol gave 1.41 gm of white crystals, m.p.=142°-143° C.