Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([NH2:18])[CH:16]=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])[C:23]([Cl:37])=[CH:22][N:21]=1.C(O)(C)C.Cl.O1CCOCC1>>[Cl:37][C:23]1[C:24]([NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])=[N:25][C:20]([NH:18][C:15]2[CH:16]=[CH:17][C:10]3[CH2:9][CH2:8][CH:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH2:13][CH2:12][C:11]=3[CH:14]=2)=[N:21][CH:22]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCC(N1CCOCC1)CC2
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCC(N2CCOCC2)CC3)ncc1Cl
Reaction time: 0.17 h
Yield: 45.4 %

Procedure:
Into a microwave vial was placed 7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (66 mg, 0.00027 mol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (70 mg, 0.0002 mol) in isopropyl alcohol (4 mL, 0.05 mol). To this mixture was added 4N HCl-dioxane (0.03 g, 0.0002 mol) and the contents subjected to microwaves at 120° C. for 10 min. HPLC showed starting materials remaining so the reaction mixture was subjected to an additional 10 min reaction time using the same conditions. A solid had precipitated out of solution and was collected by filtration. The solid was resuspended in methylene chloride and washed with aqueous sat. sodium bicarbonate followed by water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to give 2-[5-Chloro-2-(7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as a pale yellow foam (46 mg, 40% yield). 1HNMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 9.32 (s, 1H), 7.73 (m, 2H), 8.20 (m, 2H), 7.75 (d, 1H, J=7.8 Hz), 7.49 (m, 2H), 7.33 (d, 1H, J=7.8 Hz), 7.15 (t, 1H, J=7.6), 7.01 (d, 1H, J=8.3), 3.55 (s, 4H), 2.81 (d, 3H), 2.76 (m, 1H), 2.60 (m, 3H), 2.47 (s, 4H), 1.98 (m, 2H), 1.32 (m, 3H); MS (m/e) 507 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:45][C:46]1[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(O)c1ccc(Br)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Nc1ccc(O)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 73 %

Procedure:
To a solution of 4-bromobenzoic acid in DMF (0.10 M), 3 eq of NMM, 1.5 eq of Py-BOP and 1.1 eq of 4-aminophenol were added and the mixture was stirred at RT for 20 min. DMF was concentrated in vacuo and the residue diluted with EtOAc and aqueous HCl (1N). The resultant precipitate was filtered off and dried in vacuo to afford the title compound (73%); MS (ES+) m/z 292 (M+H)+, m/z 294 (M+H)+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:8][CH:9]=[C:10]([C:12]([OH:14])=[O:13])[N:11]=1.[Si](Cl)(C)(C)[CH3:16]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:8][CH:9]=[C:10]([C:12]([O:14][CH3:16])=[O:13])[N:11]=1
Reactant: O=C(O)c1csc(-c2ccccn2)n1
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)c1csc(-c2ccccn2)n1
Temperature: 50 °C

Procedure:
To a solution of 2-(pyridin-2-yl)thiazole-4-carboxylic acid 7.4 (500 mg, 2.425 mmol) in commercial anhydrous methanol (10 mL) was added TMS-Cl (0.77 mL, 6.06 mmol) at once. The RM was heated to 50° C. overnight. The RM. was concentrated under reduced pressure and the residue was used crude in next step. Yield: 649 mg (quantitative). LCMS: P=94%, rt=4.07 nm, m/z=221.
Reaction SMILES: C([N:8]([C:15]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][C:41]([F:44])([F:43])[F:42])=[CH:33][CH:32]=1)([C:20]([F:30])([F:29])[C:21](=[O:28])N1CCCCC1)[C:16]([F:19])([F:18])[F:17])[S:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])C1C=CC=CC=1.[C:45]1([CH3:53])[CH:50]=[CH:49][C:48]([Mg]Br)=[CH:47][CH:46]=1>C1COCC1>[CH3:14][C:11]([S:9]([NH:8][C:15]([C:31]1[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH2:39][CH2:40][C:41]([F:44])([F:42])[F:43])=[CH:35][CH:36]=1)([C:20]([F:30])([F:29])[C:21](=[O:28])[C:48]1[CH:49]=[CH:50][C:45]([CH3:53])=[CH:46][CH:47]=1)[C:16]([F:17])([F:18])[F:19])=[O:10])([CH3:12])[CH3:13]
Reactant: CC(C)(C)S(=O)N(Cc1ccccc1)C(c1ccc(OCCCC(F)(F)F)cc1)(C(F)(F)F)C(F)(F)C(=O)N1CCCCC1
Reactant: Cc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)C(F)(F)C(NS(=O)C(C)(C)C)(c2ccc(OCCCC(F)(F)F)cc2)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.4 %

Procedure:
Mg turnings were suspended in 0.1 N aq HCl for a few minutes, rinsed with water, MeOH and dried under vacuum. A flame dried flask equipped with a stir bar was charged with Mg turnings (0.243 g, 10 mmol), anhydrous THF (4.4 mL) and 4-bromotoluene (1.71 g, 10 mmol) in anhydrous THF (4.4 mL) followed by several drops of 1,2-dibromoethane. The reaction initiated in a few minutes and the mixture became warm. The approximate concentration of the Grignard reagent is 1 M. The mixture was diluted with 10 mL anhydrous THF to produce a clear solution of p-tolylmagnesium bromide (˜0.5 M). To a solution of Intermediate 103E (260 mg, 0.396 mmol) in THF (3959 μL) at 0° C. was added the freshly prepared p-tolylmagnesium bromide (3959 μL, 1.980 mmol). The reaction was warmed to rt, concentrated to half of the original volume, and stirred for 3 h. The reaction was cooled to 0° C., quenched with sat'd aq NH4Cl, and then diluted with EtOAc. The layers were separated and the organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography (24 g silica gel, eluted with EtOAc in hexanes) to afford the desired product (60 mg, 24%) as a yellow gum. 1H NMR (500 MHz, CDCl3) δ 7.73 (d, J=8.0 Hz, 2H), 7.55 (d, J=8.5 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 4.19 (s, 1H), 4.01 (br. s., 2H), 2.40 (s, 3H), 2.31 (dd, J=16.2, 10.2 Hz, 2H), 2.10-1.99 (m, 2H), 1.25 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH3:13])[CH:3]=1.[N:14]([O-])=O.[Na+].Cl[Sn]Cl>O.Cl>[CH3:13][O:12][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([NH:1][NH2:14])=[CH:3]2
Reactant: O=N[O-]
Reactant: COc1cccc2cc(N)ccc12
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1cccc2cc(NN)ccc12
Temperature: -6 °C
Reaction time: 0.75 h
Yield: 93 %

Procedure:
To a suspension of 2-amino-5-methoxynaphthalene (3.5 g, 20 mmol) in water (65 ml) and HCl conc. (25 ml) cooled down to −6° C., sodium nitrite (1.55 g, 22 mmol) in water (15 ml) was added dropwise. It was kept at stirring, approximately at the same temperature, during 45 minutes and subsequently a solution of SnCl2 (9.3 g, 40 mmol) in HCl conc. (10 ml) was added. Once the addition was performed, it was allowed that the temperature would slowly increase until achieving room temperature, and it was filtered. The filtered solid was washed with water and ethylic ether and, subsequently, it was suspended in ethylic ether, with stirring, during a few minutes. It was filtered and dried resulting in 3.5 g of a crude brown solid, which was used directly in the following synthesis step.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:20])[C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][CH:11]=1.[C:21](Cl)(=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([CH3:17])([CH3:19])[CH3:18])=[CH:12][CH:11]=2)=[O:30])=[CH:23][CH:24]=1
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2O)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)Oc2ccccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 61 %

Procedure:
Using the procedure described in Example 149, Part B, N-(2-hydroxyphenyl)-4-tert-butylbenzamide (2.00 mmol) was reacted with p-anisoyl chloride to yield 494 mg (61%) of the title compound as a crystalline solid.
Reaction SMILES: [CH3:1][S@:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[NH:4])=[O:3].[CH3:11][Si:12](N(CC)CC)([CH3:14])[CH3:13]>C(#N)C>[CH3:11][Si:12]([CH3:14])([CH3:13])[N:4]=[S@@:2]([CH3:1])(=[O:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C[S@](=N)(=O)c1ccccc1
Reactant: CCN(CC)[Si](C)(C)C
Solvent: CC#N
Product: C[Si](C)(C)N=[S@@](C)(=O)c1ccccc1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To a stirred pre-warmed solution of (S)-(+)-S-methyl-S-phenylsulphoximine (3 g, 18.7 mmol) in acetonitrile (2 mL) at 65° C. was added (trimethylsilyl)diethylamine (4.12 g, 21.1 mmol) dropwise via a syringe. The reaction was maintained at 65° C. and stirred for 3 hours. Additional amount of (trimethylsilyl)diethylamine (2 mL, 10.2 mmol) was added and the reaction mixture was stirred at 65° C. overnight. The reaction was then concentrated under reduced pressure and dried under vacuum to give the title compound. This material was used directly in next step of the synthesis without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[CH:13][C:8]([O:9][CH2:10][C:11]#[N:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([O-])([O-])=O.[K+].[K+].Cl.[NH2:22][OH:23]>O.CCO>[OH:23][NH:22][C:11](=[NH:12])[CH2:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:14][CH:13]=1
Reactant: NO
Reactant: CS(=O)(=O)c1ccc(OCC#N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(OCC(=N)NO)cc1

Procedure:
To a mixture of (4-methanesulfonyl-phenoxy)-acetonitrile (2 g, 9.5 mmol), K2CO3 (1.3 g, 9.5 mmol) in H2O (30 mL) and EtOH (15 mL) was added hydroxylamine hydrogen chloride (1.32 g, 19 mmol). The mixture was heated under reflux overnight, cooled and ethanol was removed in vacuo and the residue was extracted with EtOAc (150 mL). The organic layer was washed successively with H2O and brine. After drying (Na2SO4), the solvent was removed to afford the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>O1CCCC1.C(O)C>[N:1]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=12
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1ccccn1
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1cn2ccccc2n1
Yield: 84.7 %

Procedure:
3 g (31.9 mmol) of 2-aminopyridine were dissolved in 65 ml of tetrahydrofurane with magnetic stirring. The addition of 4.44 ml (31.9 mmol) of ethyl bromopyruvate caused precipitation of a solid. The heterogenous mixture was stirred with reflux for 4 h. After returning to r.t., the solid was isolated by filtration and taken up in 65 ml of ethanol in order to be stirred with reflux in 65 ml of ethanol for 16 h. After returning to r.t., the solid was isolated by filtration. The filtrate was placed in ice in order to facilitate crystallization of the product which was collected by filtration and thus so forth until the liquid phase remained limpid. The solid was rinsed with 30 ml of diisopropyl ether and dried in a vacuum bell jar in order to obtain 5.14 g (yield=84%) of ethyl imidazo[1,2-a]pyridine-2-carboxylate as a white powder. LC-MS: m/z=191 (MH+); UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 8.95 (s, 1H), 8.84 (d, J=6.8 Hz, 1H), 7.98-7.80 (m, 2H), 7.46 (t, J=7.2 Hz, 1H), 4.43 (q, J=7.1 Hz, 2H), 1.35 (d, J=7.1 Hz, 3H).
Reaction SMILES: [CH:1]1([C:5]2[C:6]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:51][C:52]1[O:56][N:55]=[C:54]([C:57]([NH2:64])([CH3:63])[CH2:58][S:59]([CH3:62])(=[O:61])=[O:60])[N:53]=1.Br>CN(C=O)C>[CH:1]1([C:5]2[C:6]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:7][C:8]([C:11]([NH:64][C:57]([CH3:63])([C:54]3[N:53]=[C:52]([CH3:51])[O:56][N:55]=3)[CH2:58][S:59]([CH3:62])(=[O:61])=[O:60])=[O:13])=[N:9][CH:10]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1nc(C(C)(N)CS(C)(=O)=O)no1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CCC2)cn1
Agent: Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)c2cc(OCC(F)(F)F)c(C3CCC3)cn2)no1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 29 %

Procedure:
To a solution of 5-Cyclobutyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example 108f, 40 mg, 145 μmol) in dry DMF (1.00 ml) was added DIEA (76.2 μl, 436 μmol) and TBTU (49.0 mg, 153 μmol) and the reaction mixture was stirred at room temperature for 20 minutes. Addition of 2-(5-methyl-1,2,4-oxadiazol-3-yl)-1-methylsulfonyl-propan-2-amine;hydrobromide (enantiomer B) (example 125b, 45.8 mg, 153 μmol) to the reaction mixture and the latter was stirred at room temperature for 2 hours. The crude was directly purified by preparative HPLC without any work-up to yield the title compound (20 mg, 29%); MS (ESI, m/z): 477.5 (M+H+).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@@:20]1([C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([Cl:49])[CH:43]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:41])[CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[CH2:21]1)(=O)=O.C(#N)C>>[Cl:49][C:44]1[CH:43]=[C:42]([C@@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][CH:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:41])[CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[C:29]([C:37]([F:40])([F:38])[F:39])[CH:28]=3)[CH2:21]2)[CH:47]=[CH:46][C:45]=1[Cl:48]
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: CS(=O)(=O)OCC[C@@]1(c2ccc(Cl)c(Cl)c2)CCN(C(=O)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Solvent: CC#N
Product: O=C(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@](CCN2CCC(N3CCCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
In 30 ml of acetonitrile (R)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-[[3,5-bis(trifluoromethyl)phenyl]acetyl]pyrrolidine (3.17 g), prepared essentially as described, supra, is mixed with an equimolar amount of 4-(piperidin-1-yl)piperidine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum and the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: O[C@@H:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:4]=2[C@H:3]1[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23]O[Si](C(C)(C)C)(C)C)=[CH:18][C:17]1=[O:32].[H-].[Na+].O>O1CCCC1>[C:14]([C:12]1[CH:11]=[CH:10][C:5]2[O:6][C:7]([CH3:8])([CH3:9])[CH:2]=[C:3]([N:16]3[CH:21]=[CH:20][C:19]([CH:22]=[CH2:23])=[CH:18][C:17]3=[O:32])[C:4]=2[CH:13]=1)#[N:15]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](n2ccc(CCO[Si](C)(C)C(C)(C)C)cc2=O)[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1ccn(C2=CC(C)(C)Oc3ccc(C#N)cc32)c(=O)c1
Yield: 94.4 %

Procedure:
In 105 ml of anhydrous tetrahydrofuran, is dissolved 3.18 g of trans-3-hydroxy-6-cyano-3,4-dihydro-2,2-dimethyl-4-{1,2-dihydro-2-oxo-4-(2-t-butyldimethylsilyloxyethyl)-1-pyridinyl}-2H-benzo[b]pyran obtained in Example 23. Then, 0.28 g of 60% oily sodium hydride is added to the solution at room temperature and reacted under reflux for one hour. After stopping the reaction by adding water, the reaction mixture is extracted with ether. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The inorganic matter is filtered off, and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by silica gel column chromatography using 1/4 mixture of ethyl acetate/methylene chloride as a developing solvent to obtain 2.01 g of 6-cyano-2,2-dimethyl-4-(1,2-dihydro-2-oxo-4-vinyl-1-pyridinyl)-2H-benzo[b]pyran.
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1[C:40]([OH:42])=O>>[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1[C:40]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:29])=[O:3])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:42]
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Agent: Cl
Product: CN(C(=O)c1ccc2ccccc2c1)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) according to example 12 with 2-naphthoic acid followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(2-naphthoyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 520 (M+H)+.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=1)(=[O:3])[CH3:2]>C(O)C.O.[Pd]>[C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCNc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CC(=O)NCCNc1ccc(N)cn1
Yield: 43.8 %

Procedure:
A suspension of 2-(2-acetamidoethylamino)-5-nitropyridine (4.0 g, 17.86 mmol) in ethanol-water (3:1, 160 ml) was shaken with 10% palladium on charcoal (400 mg) under an atmosphere of hydrogen for 5 h then filtered through Celite™ and the filtrate concentrated. The residue was subjected to column chromatography (silica, 3-10% methanol-CH2Cl2) to afford the title compound (1.52 g) as an air-sensitive deep mauve gum. MS (ES+) 195 (MH+). δH (d6DMSO) 7.89 (1H, br s), 7.45 (1H, d, J 2.5 Hz), 6.82 (1H, dd, J 2.5, 8.7 Hz), 6.28 (1H, d, J 8.7 Hz), 5.60 (1H, br s), 4.34 (2H, br s), 3.16 (4H, m) and 1.79 (3H, s).
Reaction SMILES: C1(S([CH2:10][C:11]2[N:12]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[NH:14][N:15]=2)(=O)=O)C=CC=CC=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](/[CH:28]=[CH:29]\[C:30]#[N:31])[CH:23]=1>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[N:12]=[C:11]2[CH:10]=[C:28]([C:24]3[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=3)[CH:29]=[C:30]([NH2:31])[N:15]2[N:14]=1
Reactant: N#C/C=C\c1cccnc1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccccn2)n1)c1ccccc1
Product: Nc1cc(-c2cccnc2)cc2nc(-c3ccccn3)nn12

Procedure:
The title compound, MS m/e (%):288 (M+,100), was prepared in accordance with the general method of example 1 from 2-(5-benzenesulfonylmethyl-2H-[1,2,4]triazol-3-yl)-pyridine and (E)/(Z)-3-pyridin-3-yl-acrylonitrile.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([Cl:27])[CH:18]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1.[CH3:29][N:30]([CH3:34])[CH2:31][C:32]#[CH:33].C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1.[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>[Cl:27][C:19]1[CH:18]=[C:17]([C@@H:10]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([NH:8][C:5]2[CH:4]=[N:3][C:2]([C:33]#[C:32][CH2:31][N:30]([CH3:34])[CH3:29])=[CH:7][N:6]=2)=[O:28])[CH:22]=[CH:21][C:20]=1[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: C#CCN(C)C
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CN(C)CC#Cc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.6 %

Procedure:
A solution of N-(5-bromo-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (prepared as in Example 6, 486 mg, 1.0 mmol) and 1-dimethylamino-2-propyne (830 mg, 10.0 mmol) in toluene (6 ml) was treated with N,N-diisopropylethylamine (1.5 ml), copper(I) iodide (19.2 mg, 0.10 mmol), and dichlorobis(triphenylphosphine)palladium(II) (36.0 mg, 0.05 mmol). The resulting reaction mixture was stirred at 25° C. for 24 h. At this time, the reaction mixture was concentrated in vacuo. The residue was extracted into methylene chloride from water. The combined organic layers were dried and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 4/1 ethyl acetate/methanol) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-dimethylamino-prop-1-ynyl)-pyrazin-2-yl]-propionamide (360 mg, 74%) as a pale brown solid: (ES)+-HRMS m/e calcd for C24H29ClN4O3S (M+H)+ 489.1722, found 489.1725.
Reaction SMILES: [CH:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][C:14]3=[O:17])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O-].[Na+].[C:21](=O)([O:24]C)[O:22][CH3:23]>>[CH:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][CH:13]([C:21]([O:22][CH3:23])=[O:24])[C:14]3=[O:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CCCc2ccc(C3CCCCC3)cc21
Reactant: COC(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)C1CCc2ccc(C3CCCCC3)cc2C1=O
Yield: 74 %

Procedure:
A mixture of 7-cyclohexyl-1-tetralone (9.4 g), sodium methoxide (8.9 g) and dimethyl carbonate (65 ml) was refluxed for 30 minutes in a nitrogen gas stream. After the reaction mixture was cooled, the resulting crystals were collected by filtration and suspended in ethyl acetate (250 ml), followed by addition of 6N HCl (50 ml). The organic layer was collected, while the aqueous layer was extracted with ethyl acetate. The extract was combined with the organic layer, successively washed with water and brine, and dried (MgSO4), after which the solvent was evaporated off, to yield methyl 7-cyclohexyl-1-tetralone-2-carboxylate (8.6 g, 74%) as an oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([N:33]1[CH2:34][CH2:35][CH:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[O:23][CH3:22])[CH2:31][CH2:32]1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1C1CCNCC1
Reactant: O=C(O)c1cnc2c(Br)cnn2c1NCc1ccccc1
Product: COc1ccccc1C1CCN(C(=O)c2cnc3c(Br)cnn3c2NCc2ccccc2)CC1
Yield: 85 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-benzylamino-3-bromopyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.150 g, 0.400 mmol) obtained in step 3 and 4-(2-methoxyphenyl)piperidine (0.091 g, 0.480 mmol), the title compound (0.177 g, 80%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][C@H:13]([CH3:17])[CH2:14][O:15][CH3:16])[CH:11]=1)[N:8]=[C:7]([CH3:18])[CH:6]=[CH:5]2.[Se](=O)=[O:20]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][C@H:13]([CH3:17])[CH2:14][O:15][CH3:16])[CH:11]=1)[N:8]=[C:7]([CH:18]=[O:20])[CH:6]=[CH:5]2
Reactant: O=[Se]=O
Reactant: COC[C@@H](C)Oc1cc(F)cc2ccc(C)nc12
Solvent: O
Solvent: C1COCCO1
Product: COC[C@@H](C)Oc1cc(F)cc2ccc(C=O)nc12
Yield: 89.5 %

Procedure:
To a solution of (R)-6-fluoro-8-(1-methoxypropan-2-yloxy)-2-methylquinoline (0.70 g, 2.8 mmol) in dioxane (55 mL) and water (0.55 mL) was added selenium dioxide (0.38 g, 3.4 mmol) and the resultant mixture heated at reflux for 2 hours. The cooled reaction mixture was filtered through a plug of Celite® to remove solids, rinsing with dichloromethane. The filtrate was concentrated under reduced pressure and purified by normal phase chromatography on silica gel (10-30% ethyl acetate/hexanes) to afford the title compound (0.66 g, 89%).