Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:23])[CH2:16][C:17]([CH2:19][O:20][CH2:21][CH3:22])=O)[CH3:13].[CH2:24]([O:26][C:27](=[O:32])/[CH:28]=[C:29](\[NH2:31])/[CH3:30])[CH3:25]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:28]([C:27]([O:26][CH2:24][CH3:25])=[O:32])=[C:29]([CH3:30])[NH:31][C:17]=1[CH2:19][O:20][CH2:21][CH3:22])=[O:23])[CH3:13]
Reactant: CCOCC(=O)CC(=O)OCC
Reactant: CCOC(=O)/C=C(/C)N
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: CCOCC1=C(C(=O)OCC)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC)=C(C)N1
Yield: 70 %

Procedure:
15 g of 3-nitrobenzaldehyde, 18 g of γ-ethoxyacetoacetic acid ethyl ester and 13 g of β-aminocrotonic acid ethyl ester are heated in 60 ml of ethanol for about 5 hours, the mixture is cooled and the product is filtered off and rinsed with cold ethanol. 2-Ethoxymethyl-6-methyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is obtained, in the form of light yellow crystals of melting point 120°-122°C, in a yield of 70% of theory.
Reaction SMILES: [C:1]1([N:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=O)[CH3:21])[N:15]=2)[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:23]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[C:1]1([N:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[N:31][C:30]3[CH:32]=[CH:33][C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:28][CH:29]=3)[CH3:21])[N:15]=2)[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: CC(=O)c1cccc(C(C)=Nc2cccc3ccccc23)n1
Solvent: Cc1ccccc1
Product: CC(=Nc1ccc(C(C)(C)C)cc1)c1cccc(C(C)=Nc2cccc3ccccc23)n1
Reaction time: 16 h

Procedure:
Monoimine (6, 1.25 g, 4.34 mmol) and 4-tert-butylaniline (0.65 g, 4.34 mmol) were dissolved in 50 ml of toluene. To this solution, molecular sieves (4 Å) were added. After standing for 16 hours the mixture was filtered. The solvent was removed in vacuo. The residue was recrystallised from ethanol. Yield 0.44 g (24%) of mixed diimine (7, 96% purity by NMR). H-NMR (CDCl3) δ 8.51 (d, 1H, Py-Hm), 8.38 (d, 1H, Py-Hm), 7.91 (t, 1H, Py-Hp), 7.86 (d, 1H, ArH), 7.78 (d, 1H, ArH), 7.63 (d, 1H, ArH), 7.4-7.6 (m, 5H, ArH), 6.8-6.9 (m, 3H, ArH), 2.43 (s, 3H, Me), 2.37 (s, 3H, Me), 1.34 (s, 9H, But).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][N:12](C(=O)[C@@H]3CCCN3S(C3C=CC4C(=CC=CC=4)C=3)(=O)=O)[C:11]3[CH:34]=[CH:35][CH:36]=[CH:37][C:10]=3[S:9]2)=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:13][NH:12][C:11]3[CH:34]=[CH:35][CH:36]=[CH:37][C:10]=3[S:9]2)=[CH:6][CH:7]=1
Reactant: O=C([C@@H]1CCCN1S(=O)(=O)c1ccc2ccccc2c1)N1C[C@@H](c2ccc(Cl)cc2)Sc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Clc1ccc([C@@H]2CNc3ccccc3S2)cc1
Temperature: 0 °C
Yield: 58.7 %

Procedure:
(R)-2-(4-Chlorophenyl)-4-[(S)-N-(2-naphthalene-sulfonyl)prolyl]-3,4-dihydro-2H-1,4-benzothiazine (9.40 g, 0.017 mole) is suspended in ethanol-water (10:1, 188 ml), and thereto is added 86% potassium hydroxide (11.2 g, 0.172 mole), and the mixture is refluxed for 30 minutes. The reaction mixture is poured into ice water and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed with water and saline, dried over sodium sulfate and distilled to remove the solvent. The residue is purified by silica gel column chromatography (CHCl3) and thereafter recrystallized from ethyl acetate-hexane twice to give (R)-(+)-2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazine (2.61 g, 58%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:5]([NH2:6])=[CH:4][C:3]=1[F:12].Cl[Sn]Cl.C(O)C.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.O>[Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([NH2:6])=[C:7]([NH2:9])[CH:8]=1
Reactant: Nc1cc(F)c(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Nc1cc(F)c(Br)cc1N
Temperature: 25 °C

Procedure:
4-Bromo-5-fluoro-1,2-diaminobenzene was prepared using an adaptation of the method of Bellamy et al. (Bellamy, F. D. et al., Tetrahedron Lett. 25:839 (1984)). A mixture of 4-bromo-3-fluoro-6-nitroaniline (320 mg, 1.36 mmol) and SnCl2 ·2H2O (1.53 g, 6.81 mmol) dissolved in 7 mL ethyl acetate and 3 mL absolute ethanol under N2 was heated at 75° C. for 8 h. Some starting material had remained (by TLC) after only 1 h heating. All the starting material had reacted after 8 h as evidenced by TLC (silica gel, 3:1 hexanes:ethyl acetate). The reaction was allowed to cool to room temperature and poured into 50 mL H2O. Sufficient sat'd NaHCO3 solution was added (foaming!) to bring the pH to 5. The resulting mixture was extracted with 3×25 mL ethyl acetate and the combined organic extracts washed with 20 mL sat'd NaCl solution. The organic phase was dried (MgSO4), vacuum filtered and the solvent rotary evaporated to yield a white powder 277 mg (99%). 1H NMR (CDCl3) δ3.22 (br s, 2H, NH2); 3.60 (br s, 2H, NH2); 6.50 (d, 1H, JHF =9.6 Hz, H-6); 6.83 (d, 1H, JHF =6.6 Hz, H-3).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:38])=[N:18][C:19]=3[NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:11]([OH:39])[C@@H:10]1[OH:40].C(N(C(C)C)CC)(C)C.[C:50](Cl)(=[O:53])[CH2:51][CH3:52]>C1COCC1>[Cl:38][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@@H:12]2[CH2:13][C@H:9]([NH:8][C:50](=[O:53])[CH2:51][CH3:52])[C@@H:10]([OH:40])[C@H:11]2[OH:39])=[C:19]([NH:23][CH2:24][CH:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:18]=1
Reactant: CCC(=O)Cl
Reactant: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1S,2R,3S,5R)-3-Amino-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopentane-1,2-diol trifluoroacetate (9.50 g, 16.42 mmol) and diisopropylethylamine (6.36 g, 49.27 mmol) are placed in a flask with dry THF (150 ml). Propionyl chloride (1.52 g, 16.42 mmol) is added dropwise and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 1 hour. The solvent is removed in vacuo and the residue is partitioned between dichloromethane (250 ml) and water (250 ml). The organic layer is washed with water (200 ml) and brine (200 ml), dried over MgSO4, filtered and the solvent is removed in vacuo. The solid is recrystallised from 1,2-dichloroethane to give the title compound. 1H nmr (MeOD, 400 MHz); 8.00(s, 1H), 7.40-7.15(m, 10H), 4.75(m, 1H), 4.60(m, 1H), 4.50(m, 1H), 4.20(m, 3H), 3.95(m, 1H), 2.85(m, 1H), 2.40(q, 2H), 2.10(m, 1H), 1.20(t, 3H), MS (ES+) m/e 521 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][N:5]=[C:4](S(C)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:26][S:27]([N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1)(=[O:29])=[O:28].C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:6][N:5]=[C:4]([NH:36][CH:33]2[CH2:34][CH2:35][N:30]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:31][CH2:32]2)[N:3]=1
Reactant: CS(=O)c1ncc(C(=O)c2ccccc2)c(N)n1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3ccccc3)c(N)n2)CC1

Procedure:
Treatment of the material prepared in Example 282 with material prepared in Example 162 in ethanol containing triethylamine at reflux for one hour, gave, after chilling and filtering, [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-phenyl-methanone, as a colorless solid, MP 249-250° C. MS(ES) MH+376
Reaction SMILES: FC1CCCN(C([O-])=O)C1.O=P(Cl)(Cl)[Cl:13].[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C@@H:29]([O:32][C:33]2[CH:34]=[CH:35][CH:36]=[C:37]3[C:42]=2[N+:41]([O-])=[CH:40][CH:39]=[CH:38]3)[C@H:28]([F:44])[CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)(=O)C.C1(C)C=CC=CC=1.CN(C=O)C>[Cl:13][C:40]1[CH:39]=[CH:38][C:37]2[C:42](=[C:33]([O:32][C@@H:29]3[CH2:30][CH2:31][N:26]([C:24]([O:23][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:25])[CH2:27][C@H:28]3[F:44])[CH:34]=[CH:35][CH:36]=2)[N:41]=1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](Oc2cccc3ccc[n+]([O-])c23)[C@H](F)C1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])N1CCCC(F)C1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CC[C@@H](Oc2cccc3ccc(Cl)nc23)[C@H](F)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.9 %

Procedure:
Preparation of (trans)-benzyl 4-f2-chloroquinolin-8-yloxy)-3-fluoropiperidine-1-carboxylate: To a 0° C. solution of 4 mL 1:1 DMF:toluene was added neat POCl3 (0.360 ml, 3.94 mmol). The reaction mixture was warmed to ambient temperature, stirred 10 minutes, and then cooled to 0° C. A solution of 8-((trans)-1-(benzyloxycarbonyl)-3-fluoropiperidin-4-yloxy)quinoline 1-oxide (1.04 g, 2.62 mmol) in 1.2 mL 1:1 DMF:toluene was added dropwise by syringe to the reaction mixture, and the reaction mixture was heated in a 110° C. sand bath and stirred for 1 hours. The reaction mixture was cooled to ambient temperature and added dropwise to a stirring ice/saturated NaHCO3 mixture. The mixture was stirred 20 minutes, then extracted with DCM, and the combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was purified on silica gel (Biotage 40S, loaded with 12:1hexanes:ethyl acetate, flushed 300 mL, then gradient to 5:1 hexanes:ethyl acetate) to give (trans)-benzyl 4-(2-chloroquinolin-8-yloxy)-3-fluoropiperidine-l-carboxylate (0.563 g, 1.36 mmol, 51.7% yield) as a syrup. MS APCI (+) m/z 415 (M+1) detected.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][CH3:17])(=O)=O.[Cl:18]C1C=C2C(=CC=1)NC=C2CC(N)(C)C.[NH:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([CH2:42][CH2:43][CH2:44][NH2:45])=[CH:34]1>>[ClH:18].[NH:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([CH2:42][CH2:43][CH2:44][NH:45][CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH3:17])=[CH:34]1
Reactant: NCCCc1c[nH]c2ccccc12
Reactant: CCOc1ccccc1OCCOS(C)(=O)=O
Reactant: CC(C)(N)Cc1c[nH]c2ccc(Cl)cc12
Product: CCOc1ccccc1OCCNCCCc1c[nH]c2ccccc12
Product: Cl

Procedure:
Proceeding as in Example 3, but replacing 2-[2-(cyclopropylmethyloxy)phenoxy]ethyl methanesulfonate with 2-(2-ethyloxyphenoxy)ethyl methanesulfonate and [2-(5-chloro-1H-indol-3-yl)-1,1-dimethylethyl]amine with [3-(1H-indol-3-yl)-prop-1-yl]amine, gave [3-(1H-indol-3-yl)prop-1-yl][2-(2-ethyloxyphenoxy)ethyl]amine hydrochloride, m.p. 147°-148° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][N:7]2[CH2:11][CH:10]([CH2:12][CH2:13][CH3:14])[CH2:9][C:8]2=[O:15])[N:3]=[CH:2]1.[Cl:16]N1C(=O)CCC1=O>CC#N.C1COCC1>[Cl:16][C:5]1[N:1]=[CH:2][NH:3][C:4]=1[CH2:6][N:7]1[CH2:11][CH:10]([CH2:12][CH2:13][CH3:14])[CH2:9][C:8]1=[O:15]
Reactant: CCCC1CC(=O)N(Cc2c[nH]cn2)C1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Solvent: C1CCOC1
Product: CCCC1CC(=O)N(Cc2[nH]cnc2Cl)C1
Temperature: 0 °C
Reaction time: 18 h
Yield: 75.8 %

Procedure:
In a 100 ml, three-necked flask fitted with a magnetic stirrer and under inert atmosphere, 1-(1H-imidazol-4-ylmethyl)-4-propylpyrrolidin-2-one 110 (500 mg, 2.4 mmol) is dissolved in a 1/1 mixture of CH3CN/THF (40 ml) and the solution is cooled to 0° C. N-chlorosuccinimide (410 mg, 3.1 mmol) is added by portions while the temperature is maintained at 0° C. The mixture is stirred for 18 h at this temperature. Most of the solvents are removed under vacuum and the residue is dissolved in 1N HCl and diluted with CH2Cl2. The first organic phase is removed and pH of the aqueous phase is adjusted to 9 by addition of solid Na2CO3. Then CH2Cl2 is added and the second organic phase is separated, dried over MgSO4 and concentrated to dryness. Purification by preparative chromatography on silicagel (eluent: CH2Cl2/MeOH/NH4OH: 95/05/0.5 (v/v/v)) affords 440 mg of 1-[(4-chloro-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one 126.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].Cl[C:9]1[C:10]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:15][C:11]=2[N:12]=[CH:13][N:14]=1.ClCCl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([C:17]2[C:10]3[C:9]([O:4][CH2:3][C:2]([CH3:7])([CH3:1])[CH2:5][OH:6])=[N:14][CH:13]=[N:12][C:11]=3[O:15][C:16]=2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(CO)CO
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC(C)(C)CO)c23)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Put 1.546 g (14.85 mmol) 2,2-dimethylpropane-1,3-diol in 30 ml THF. Add 833 mg (7.42 mmol) potassium tert.-butylate and stir for a further 15 min at RT. Then cool to 0° C. and add a solution of 1.00 g (2.97 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine in 15 ml THF dropwise over a time of 30 min. Leave to return to RT and stir for a further 30 min at RT. Then add dichloromethane and water, acidify with 10% citric acid solution and separate the phases. Extract the aqueous phase once with dichloromethane. Combine the organic phases and wash once with satd. sodium chloride solution, dry over magnesium sulphate and concentrate by evaporation. 1.20 g (99.9% of theor.) of the target compound is obtained.
Reaction SMILES: [CH2:1]1[CH:6]([NH2:7])[C:4](=[O:5])[S:3][CH2:2]1.Cl.C[C:10]1([CH3:21])[C:14]2(C)[C:15]([O:17][C:18](=O)[CH:11]1[CH2:12][CH2:13]2)=[O:16].C([O-])(O)=[O:23].[Na+]>C(Cl)Cl.O>[O:5]=[C:4]1[CH:6]([NH:7][C:21]([C:10]2[CH:18]=[CH:11][CH:12]=[CH:13][C:14]=2[C:15]([OH:17])=[O:16])=[O:23])[CH2:1][CH2:2][S:3]1
Reactant: NC1CCSC1=O
Reactant: O=C([O-])O
Reactant: CC12CCC(C(=O)OC1=O)C2(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1ccccc1C(=O)NC1CCSC1=O

Procedure:
According to the same procedure, 10 g (65 mmol) of DL-homocysteine thiolactone hydrochloride, 11.52 g (63 mmol) of DL-camphoric anhydride and 5.46 g (65 mmol) of NaHCO3 in 42 ml of CH2Cl2 and 1 ml of H2O were reacted.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]2[C:6]([CH2:9][N:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH:19]1([CH2:22][NH:23][C:24](=[O:40])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:26]=2)[CH2:21]C1.[C:41](=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C.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>[CH:22]1([NH:23][C:24](=[O:40])[C:25]2[CH:26]=[CH:27][C:28]([CH3:41])=[C:29]([C:2]3[CH:18]=[CH:17][C:5]4[C:6]([CH2:9][N:10]5[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]5)=[N:7][O:8][C:4]=4[CH:3]=3)[CH:30]=2)[CH2:19][CH2:21]1
Reactant: O=C([O-])[O-]
Reactant: CN1CCN(Cc2noc3cc(Br)ccc23)CC1
Reactant: CC1(C)OB(c2cccc(C(=O)NCC3CC3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(CN3CCN(C)CC3)noc2c1

Procedure:
A mixture of 6-bromo-3-[(4-methyl-1-piperazinyl)methyl]-1,2-benzisoxazole (Intermediate 46) (0.02 g) N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate 5) (0.02 g) 2N aqueous sodium carbonate and tetrakis(triphenylphosphine)palladium(0) (1 mg) in isopropanol (0.3 ml) was heated in a Reactivial™ at 65° for 18 h. the reaction mixture was partitioned between water and ethyl acetate, the phases were separated and the aqueous layer was re-extracted with ethyl acetate. The combined organic extracts were washed with water (×2) and brine, dried using a hydrophobic filter tube and concentrated under a stream of nitrogen. The residue was purified by reverse phase preparative Hplc to give the title compound as a white foam (0.006 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10]C)[C:3]=1C#N.C[Mg]I.[CH2:15]([O:17][CH2:18][CH3:19])C.Cl>>[F:1][C:2]1[CH:9]=[CH:8][CH:19]=[C:18]([O:17][CH3:15])[C:3]=1[C:6](=[O:10])[CH3:7]
Reactant: CCOCC
Reactant: COc1cccc(F)c1C#N
Agent: C[Mg]I
Agent: Cl
Product: COc1cccc(F)c1C(C)=O
Temperature: 25 °C
Yield: 663.4 %

Procedure:
A mixture of 2-fluoro-6-methoxybenzonitrile (15.94 g, 105.5 mmol) and a solution of methyl magnesium iodide in diethyl ether (3 M, 46.0 cm3, 137 mmol) was heated to 100° C. for 18 h. Upon cooling to room temperature, aqueous hydrochloric acid (3 M, 94 cm3) was added and the mixture was heated to reflux to for 4 h. When the reaction had cooled to room temperature the organic layer was separated and the aqueous phase was extracted with ethyl acetate (100 cm3). The combined organic extracts were washed with brine (100 cm3) before being dried (Na2SO4). The solvent was removed in vacuo to afford the title compound as an oil (117.7 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:1][C:2]1[CH:3]=[C:4]([CH2:12][Br:13])[C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc(Br)cc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ncc(Br)cc1CBr
Temperature: 80 °C
Reaction time: 5 h
Yield: 48.7 %

Procedure:
To a solution of methyl 5-bromo-3-methylpyridine-2-carboxylate (1.01 g, 4.39 mmol) in carbon tetrachloride (30.0 mL) was added N-bromosuccinimide (8.60E2 mg, 4.83 mmol) and 2,2′-azo-bis-isobutyronitrile (14.4 mg, 0.0877 mmol). The reaction mixture was stirred at 80° C. for 5 h. The reaction mixture was filtered and the filtrate was concentrated to afford 0.66 g (49% yield) of the desired product.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5ccc(Cl)cc5s4)cc3CC[C@@H]12
Yield: 52.8 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2,6-dichlorobenzothiazole (155 mg, 0.76 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 86 mg (53%) of the title compound as an amorphous solid mp 156°-162°. FDMS: m/e=429. α[D]589 =+63.53 (c=0.66, chloroform).
Reaction SMILES: [N:1]1[C:6]2[O:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:17]([C:22]([NH:24][C:25]2[N:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=2)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1.C(N(CC)C(C)C)(C)C>ClCCl>[N:1]1[C:6]2[O:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][N:11]([C:31]([C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:22]([C:17]4[C:16]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:23])=[N:30][CH:29]=3)=[O:32])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CNc1cccnc1O2
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)nc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Oc3ncccc32)cn1)c1ccccc1-c1ccccc1

Procedure:
As described for Example 66, the reaction of 5,6-dihydropyrido[2,3-b][1,4]benzoxazepine (0.198 g) with 6-[([1,1'-biphenyl]-2-carbonyl)amino]pyridine-3-carbonyl chloride (0.404 g) in dichloromethane in the presence of N,N-diisopropylethylamine (0.155 g) gives the product as a solid.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](Br)=[N:7][CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:19]([Si:21]([CH3:24])([CH3:23])[CH3:22])#[CH:20]>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([C:20]#[C:19][Si:21]([CH3:24])([CH3:23])[CH3:22])=[N:7][CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CC(=O)Oc1cccnc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Oc1cccnc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.1 %

Procedure:
2-Bromopyridin-3-yl acetate (10 g, 46 mmol) was dissolved in THF (80 mL) and triethylamine (32 ml, 231 mmol), ethynyltrimethylsilane (19.5 ml, 139 mmol), and CuI (0.44 g, 23 mmol) were added. The mixture was degassed with argon for 15 minutes, then PdCl2(PPh3)2 (1.6 g, 2.3 mmol) was added and the mixture was stirred under argon at ambient temperature for 18 hours. The reaction was concentrated in vacuo, dissolved in 25% EtOAc in hexanes, filtered and purified over silica gel (25% ethyl acetate/hexanes) to afford 2-((trimethylsilyl)ethynyl)pyridin-3-yl acetate (9.7 g, 41 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH2:11][CH:12](OC)[C:13]([O:15]C)=O)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].O.[NH2:21][NH2:22].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:15])[NH:21][N:22]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: COC(=O)C(CC(=O)c1cc(Cl)c(C)c(Cl)c1)OC
Reactant: NN
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1c(Cl)cc(-c2ccc(=O)[nH]n2)cc1Cl
Yield: 70.6 %

Procedure:
A mixture of 3.05 g (0.01 mole) of methyl 4-(3,5-dichloro-4-methylphenyl)-2-methoxy-4-oxobutyrate, 0.6 g (0.012 mole) of hydrazine monohydrate and 30 ml of methanol was heated under reflux for 3.5 hours. 1.1 ml of concentrated hydrochloric acid was then added to the mixture, after which it was again heated under reflux for a further 6 hours. At the end of this time, the solvent was distilled off and the residue was washed, in turn, with water and with a small amount of diethyl ether, after which it was dried to give 1.80 g of the desired product. The washings were extracted with ethyl acetate and the extract was dried over anhydrous sodium sulphate, after which the organic solvent was distilled off. The residue was washed in turn with benzene and with diethyl ether, to give a further 0.11 g of the desired product. The total yield of 6-(3,5-dichloro-4-methylphenyl)-3(2H)pyridazinone was 1.91 g (74.9%) and the properties of the product were identical with those of the products of Examples 1(d), 2 and 3.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21]C2CCSS2)=[CH:12][CH:11]=1)=[NH:8].C1[C@@H](CC(O)=O)[S:31][S:30]C1.S1CCC(CC(O)=O)S1.C1[C@@H](CCCCC(O)=O)SSC1>>[NH2:8][C:7](=[N:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:27])[CH2:18][CH:19]2[CH2:20][CH2:21][S:31][S:30]2)=[CH:14][CH:15]=1)[C:3]1[S:2][CH:6]=[CH:5][CH:4]=1
Reactant: N=C(Nc1ccc(NC(=O)CCCCC2CCSS2)cc1)c1cccs1
Reactant: O=C(O)C[C@@H]1CCSS1
Agent: Cl
Agent: O=C(O)CC1CCSS1
Agent: O=C(O)CCCC[C@@H]1CCSS1
Product: NC(=Nc1ccc(NC(=O)CC2CCSS2)cc1)c1cccs1

Procedure:
The experimental protocol used is the same as that described for compound 1, with trisnorlipoic acid [or 2-(1,2-dithiolan-3-yl)acetic acid] (prepared according to Tetrahedron Letters, (1997), 38, 33, 5785) replacing lipoic acid. Yellow foam.