Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Sn]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)(CCCC)CCCC)CCC.Br[C:21]1[O:22][CH:23]=[CH:24][C:25]=1[Br:26]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Br:26][C:25]1[CH:24]=[CH:23][O:22][C:21]=1[C:18]1[CH:19]=[CH:14][N:15]=[CH:16][CH:17]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Brc1ccoc1Br
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Brc1ccoc1-c1ccncc1
Temperature: 100 °C
Yield: 24.7 %

Procedure:
A solution of tributylstannylpyridine (8.0 g, 21.7 mmol) and 2,3-dibromofuran (5.9 g, 26.1 mmol) in dry toluene (200 ml) was treated with bis(triphenylphosphine)palladium (II) chloride (1.5 g, 2.2 mmol) and heated at 100° C. overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate to afford the title compound (1.2 g, 25%); 1H NMR (CDCl3) 8.66 (2H, d, J 11 Hz), 7.84 (2H, d, J 11 Hz), 7.50 (1H, d, J 3 Hz), 6.60 (1H, d, J 3 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(OCC)(=O)CC(O)=O.[CH2:23]([NH2:25])[CH3:24].BrC1C=CC([C@H](N)C)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:25][CH2:23][CH3:24])=[O:11])=[CH:6][CH:7]=1
Reactant: CCN
Reactant: CC(C)(C(=O)O)c1ccc(Br)cc1
Agent: CCOC(=O)CC(=O)O
Agent: C[C@@H](N)c1ccc(Br)cc1
Product: CCNC(=O)C(C)(C)c1ccc(Br)cc1
Yield: 82 %

Procedure:
The title compound was prepared as described in Step 1 of Example A(39), where 2-(4-bromophenyl)-2-methyl propionic acid was substituted for ethyl hydrogen malonate and ethyl amine was substituted for (R)-(+)-1-(4-bromophenyl)ethylamine on that example. Yield 82%.
Reaction SMILES: [CH3:1][N:2]([CH2:23][CH2:24][Cl:25])[C:3]([C:5]1[C:14]2[O:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([CH3:21])[C:10](=[O:22])[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[ClH:25].[CH3:1][N:2]([CH2:23][CH2:24][N:37]1[CH2:36][CH2:35][N:34]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[O:27][CH3:26])[CH2:39][CH2:38]1)[C:3]([C:5]1[C:14]2[O:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([CH3:21])[C:10](=[O:22])[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COc1ccccc1N1CCNCC1
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)N(C)CCCl)cccc2c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCN(C)C(=O)c2cccc3c(=O)c(C)c(-c4ccccc4)oc23)CC1
Product: Cl
Temperature: 100 °C
Reaction time: 6 h
Yield: 78.4 %

Procedure:
A mixture of 3.56 g of Intermediate XV, 2.35 g of 1-(2-methoxyphenyl)-piperazine, 2.76 g of anhydrous potassium carbonate and 1.66 g of potassium iodide in 25 ml of dimethylformamide was stirred at 100° C. for 6 hours. After cooling, the solvent was removed in vacuo and the residue was taken up in 50 ml of water, stirred for 1 hour at room temperature, collected by filtration, washed with water and crystallized from 95% ethanol in the presence of a small amount of activated charcoal (for decoloring). The base was dissolved in 105 ml of boiling 0.086N aqueous hydrochloric acid solution. After cooling, the crystallized salt was collected by filtration, giving 4.3 g of the title compound (m.p. 201°-203° C.).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[O:11])(=[O:3])[CH3:2].[Cl-].[CH3:13][NH2+]C.C=O>>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](=[CH2:13])[CH:10]=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCCC=O
Reactant: C[NH2+]C
Agent: C=O
Agent: [Cl-]
Product: C=C(C=O)CCCCOC(C)=O

Procedure:
16 g (101.1 mmol) of 6-acetoxyhexanal, 9.2 g (113 mmol) of dimethylammonium chloride and 9.2 ml (118.3 mmol) of a 37% solution of formaldehyde are stirred for 1 hour at a bath temperature of 110° C. The mixture is allowed to cool and extracted three times with CH2Cl2. The combined organic phases are dried over Na2SO4, filtered, and concentrated by evaporation giving 6-acetoxy-2-methylene-hexanal as a slightly yellowish oil which is further reacted without purification.
Reaction SMILES: Br[CH:2]1[CH2:5][CH2:4][CH2:3]1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16]2[N:21]=[C:20]([O:22][C@@H:23]([C@H:25]3[CH2:29][NH:28][C:27](=[O:30])[CH2:26]3)[CH3:24])[C:19]3[NH:31][CH:32]=[N:33][C:18]=3[CH:17]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH:2]1([N:31]2[C:19]3[C:20]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[N:21][C:16]([C:10]4[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([O:7][CH3:6])[CH:9]=4)=[CH:17][C:18]=3[N:33]=[CH:32]2)[CH2:5][CH2:4][CH2:3]1
Reactant: BrC1CCC1
Reactant: COc1ccc(-c2cc3nc[nH]c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc3ncn(C4CCC4)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)cc1OC
Temperature: 80 °C

Procedure:
Bromocyclobutane (18 mg, 0.137 mmol) was added to a mixture of (R)-4-((R)-1-(6-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.09 (50 mg, 0.131 mmol) and cesium carbonate (127 mg, 0.392 mmol) in 5 mL of DMF at room temperature. Reaction mixture was heated at 80° C. in a microwave reactor for one hour. Reaction mixture was taken up in ethyl acetate and washed with saturated NaHCO3 (aq) and brine. The separated organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. Residues were purified via reverse phase chromatography to yield (R)-4-((R)-1-(3-cyclobutyl-6-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.27.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7](B(O)O)[C:8]2[O:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]=2[CH:15]=1)[CH:2]([CH3:4])[CH3:3].[F:19][C:20]1[C:27](I)=[C:26]([O:29][CH3:30])[C:25]([F:31])=[CH:24][C:21]=1[CH:22]=[O:23]>>[F:19][C:20]1[C:27]([C:7]2[C:8]3[O:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]=3[CH:15]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH:6]=2)=[C:26]([O:29][CH3:30])[C:25]([F:31])=[CH:24][C:21]=1[CH:22]=[O:23]
Reactant: CC(C)Cc1cc(B(O)O)c2c(c1)C(C)(C)CO2
Reactant: COc1c(F)cc(C=O)c(F)c1I
Product: COc1c(F)cc(C=O)c(F)c1-c1cc(CC(C)C)cc2c1OCC2(C)C

Procedure:
The intermediate 2,5-Difluoro-3-(5-isobutyl-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-4-methoxy-benzaldehyde was prepared in a similar manner as in example 1 a using 5-isobutyl-3,3-dimethyl-2,3-dihydro-benzofuran-7-boronic acid (example 1b) and 2,5-difluoro-3-iodo-4-methoxy-benzaldehyde
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[O:10])=[C:4]([Cl:19])[CH:3]=1.I[CH3:21]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:21])[C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[O:10])=[C:4]([Cl:19])[CH:3]=1
Reactant: COc1ccc(C(=O)Cc2ccc(Br)cc2Cl)cn1
Reactant: CI
Product: COc1ccc(C(=O)C(C)c2ccc(Br)cc2Cl)cn1

Procedure:
In analogy to Example 165, steps 2 and 3, 2-(4-bromo-2-chloro-phenyl)-1-(6-methoxy-pyridin-3-yl)-ethanone was alkylated with iodomethane to give 2-(4-bromo-2-chloro-phenyl)-1-(6-methoxy-pyridin-3-yl)-propan-1-one which was further converted to the title compound. Colorless Oil. MS (m/e)=424.0 [M+H+].
Reaction SMILES: [C:1]1([C:7]2[N:11]3[N:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]3=[N:9][C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([C:24]3([NH:28]C(=O)OC(C)(C)C)[CH2:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O1CCOCC1.[OH-].[Na+]>C(Cl)Cl.CO>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]2[N:11]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:18]3[CH:19]=[CH:20][C:21]([C:24]4([NH2:28])[CH2:25][CH2:26][CH2:27]4)=[CH:22][CH:23]=3)[N:9]=2)[N:12]=1
Reactant: COc1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
To a mixture of tert-butyl (1-{4-[3-phenyl-6-methoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-5 (550 mg, 1.17 mmol) in DCM (7.5 mL) and MeOH (0.8 mL) was added a 4 M hydrogen chloride solution in dioxane (5.8 mL, 23.4 mmol, 20.0 eq), and the resulting mixture was stirred at room temperature for 12 h. The resulting mixture was added to ice water, made alkaline with aqueous sodium hydroxide (2 N), and extracted with EtOAc (3×25 mL). The combined organic phases were washed, dried (Na2SO4 anh.) and concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage Isolera; 100 g SNAP cartridge: 100% DCM 3.5 min., gradient to 95% DCM/5% MeOH 1 min., 95% DCM/5% MeOH 3.5 min., gradient to 90% DCM/10% MeOH 1 min., 90% DCM/10% MeOH 4.5 min.) to give 1-[4-(6-methyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine (379 mg, 83% yield):
Reaction SMILES: CN1CC[O:5]CC1.C([C:11]1[N:12]=[C:13]([F:35])[N:14]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=1)C=C.[CH3:36][C:37]([CH3:39])=[O:38]>[Os](=O)(=O)(=O)=O>[OH:38][CH:37]([CH2:39][OH:5])[CH2:36][C:11]1[N:12]=[C:13]([F:35])[N:14]([C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:15]=1
Reactant: C=CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: CN1CCOCC1
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Product: OCC(O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of osmium tetroxide in acetone was treated with N-methylmorpholine in aqueous acetone. 4-Allyl-2-fluoro-1-triphenylmethylimidazole was added, and the mixture stirred at ambient temperature overnight. Reductive work-up with sodium metabisulphite and magnesium trisilicate, followed by extraction into ether, gave 4-(2,3-dihydroxypropyl)-2-fluoro-1-triphenylmethylimidazole, having the following n.m.r. in CDCl3 : 2.6 (d, 2H); 3.6 (m, 2H); 3.9 (m, 1H); 6.3 (s, 1H); 7.0-7.5 (m, 15H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH2:18])[CH3:17]>O>[CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:18][CH2:16][CH3:17])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(SCc2ccccc2)n1
Reactant: CCN
Solvent: O
Product: CCNc1cccc(SCc2ccccc2)n1

Procedure:
A mixture of 10 g of 2-benzylthio-6-bromopyridine, 70 ml of a 40% ethylamine aqueous solution, and a catalytic amount of cuprous chloride was allowed to react in an autoclave at 180° for 4 hours. After completion of the reaction, the reaction mixture was poured into water and extracted with methylene chloride. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/hexane=1/19 by volume) to obtain 5.9 g of 2-benzylthio-6-ethylaminopyridine as an oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21](O)=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([NH:33][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:22])=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: NCc1ccccc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(CCC(=O)O)cc2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2ccc(CCC(=O)NCc3ccccc3)cc2)=C(C)C1=O
Yield: 13.8 %

Procedure:
3-[(4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (200 mg, 0.58 mmol) obtained in Example 1 and benzylamine (80 mg, 0.75 mmol) were used, and a method similar to that described in Example 3 was employed to obtain the title compound (33 mg, 0.08 mmol, yield 13%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][CH2:14][OH:15])[CH2:8][CH2:7][C:6]=2[C:16]=1[O:17][CH3:18].Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([N:36]2[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37]2)(=[O:35])=[O:34])[C:23]([Cl:42])=[CH:22][N:21]=1>>[Cl:42][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([N:36]2[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37]2)(=[O:34])=[O:35])=[N:25][C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][CH2:14][OH:15])[CH2:8][CH2:7][C:6]=3[C:16]=2[O:17][CH3:18])=[N:21][CH:22]=1
Reactant: COc1c(N)ccc2c1CCC(NCCO)CC2
Reactant: O=S(=O)(c1ccccc1Nc1nc(Cl)ncc1Cl)N1CCC(O)C1
Product: COc1c(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CCC(O)C3)n2)ccc2c1CCC(NCCO)CC2
Yield: 26 %

Procedure:
In an analogous manner to Experimental 691, part c, 2-(2-Amino-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ylamino)-ethanol and 1-[2-(2,5-Dichloro-pyrimidin-4-ylamino)-benzenesulfonyl]-pyrrolidin-3-ol were combined to yield 1-(2-{5-Chloro-2-[7-(2-hydroxy-ethylamino)-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-benzenesulfonyl)-pyrrolidin-3-ol (45.15 mg, 26% yield) as an off white foam. 1H-NMR (CDCl3) δ 9.37 (s, 1H), 8.50 (d, J=8.2 Hz, 1H), 8.15 (s, 1H), 7.95 (m, 2H), 7.70-7.57 (m, 2H), 7.47 (s, 1H), 6.81-6.73 (m, 2H), 5.02 (br s, 1H), 4.35 (br s, 1H), 3.72 (s, 3H), 3.63 (s, 2H), 3.41 (m, 4H), 3.27 (m, 2H), 2.83 (m, 4H), 2.68 (m, 1H), 2.47 (m, 1H), 2.13 (m, 2H), 1.95 (m, 2H), 1.26 (m, 2H). LC/MS (ESI+)=603 (M+H).
Reaction SMILES: [CH2:1]([C:5]1[CH:14]=[C:13](Cl)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].O1[CH2:20][CH2:19][CH2:18][CH2:17]1>[Zn].BrCC1C=CC(C#N)=CC=1>[CH2:1]([C:5]1[CH:14]=[C:13]([CH2:17][C:18]2[CH:3]=[CH:2][C:1]([C:5]#[N:6])=[CH:20][CH:19]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(Cl)c2ccccc2n1
Reactant: C1CCOC1
Agent: N#Cc1ccc(CBr)cc1
Agent: [Zn]
Product: CCCCc1cc(Cc2ccc(C#N)cc2)c2ccccc2n1

Procedure:
Using the procedure of Step G of Example 1, 0.614 g of 4-chloro-2-butyl quinoline of Step D, 0.8 ml of tetrahydrofuran, 0.323 g of tetrakis triphenylphosphine palladium and 10 ml of a 0.5M 4-bromomethyl benzonitrile zinc solution in tetrahydrofuran were reacted to obtain after chromatography on silica (eluant: hexane--ethyl acetate (8-2)) 0.781 g of the desired product.
Reaction SMILES: [OH-:1].[Na+].N[C@@:4]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([C:6]#C)C.CC[O:16][C:17]([CH3:19])=[O:18].O>C(Cl)(Cl)Cl>[C:8]1([CH2:19][C:17]([O:16][C:6](=[O:1])[CH2:4][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:18])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(C)=O
Reactant: C#C[C@@](C)(N)C1CCCCC1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(Cc1ccccc1)OC(=O)Cc1ccccc1

Procedure:
A 1.50 M sodium hydroxide solution was added to the hydrochloride salt of (S)-2-amino-2-cyclohexyl-3-butyne 30 (1 equiv). A solution of anhydride (0.17 M, 1 equiv) in chloroform was added to the above solution and heated at reflux for 24 h. The reaction mixture was transferred to a separatory funnel, and EtOAc (150 mL) and water (15 mL) were added. The organic layer was washed with brine (25 mL), 10 M aqueous sodium hydroxide solution (25 mL×4), brine (25 mL×4), and water (25 mL×2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by flash chromatography (1:1 hexanes:EtOAc) to afford the desired product.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:22])[CH2:5][S:6][C:7]=1[CH:8]1[CH:13]=[CH:12][N:11](C(OCC(Cl)(Cl)Cl)=O)[CH:10]=[CH:9]1.C(Cl)(Cl)Cl.CO>C(O)=O.[Zn]>[CH3:1][C:2]1[NH:3][C:4](=[O:22])[CH2:5][S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1
Reactant: CC1=C(C2C=CN(C(=O)OCC(Cl)(Cl)Cl)C=C2)SCC(=O)N1
Agent: [Zn]
Solvent: CO
Solvent: O=CO
Solvent: ClC(Cl)Cl
Product: CC1=C(c2ccncc2)SCC(=O)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.1 %

Procedure:
Zinc powder (1.7 g) was added to a solution of 5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one (1g) in formic acid (14 ml) and the mixture was stirred at ambient temperature for 3 hours. The mixture was filtered and the filtrate was evaporated to dryness. The residue was dissolved in water (30 ml), was adjusted to pH 7.0 by 1N aqueous sodium hydroxide, was extracted with chloroform and was dried over magnesium sulfate. Chloroform was removed and the residue was purified by the preparative thin layer chromatography [Merck TLC plate, silica gel 60F254 (supplied by Merck & Co. Inc., U.S.A.), 20×20 cm, thickness=1 mm, developing solvent; chloroform/methanol=20:1] to give the titled compound (0.2 g, yield 37.1%) as pale yellow plates. The physiocochemical properties were as described above.
Reaction SMILES: Cl.C(OC(N[C@H](C(N[C@@H](CC1C=CC=CC=1)[C@H](O)C(N1C[C@@H](Cl)C[C@H]1C(NC(C)(C)C)=O)=O)=O)CC(=O)N)=O)C1C=CC=CC=1.Cl.[NH2:47][C@H:48]([C:53]([NH:55][C@@H:56]([CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[C@H:57]([OH:73])[C:58]([N:60]1[CH2:71][C@@H:70]([Cl:72])[CH2:69][C@H:61]1[C:62]([NH:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])=[O:59])=[O:54])[CH2:49][C:50](=[O:52])[NH2:51].[N:81]1[C:90]2[C:85](=[CH:86][CH:87]=[CH:88][CH:89]=2)[N:84]=[CH:83][C:82]=1[C:91](O)=[O:92].P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>CO.CN(C)C=O>[N:81]1[C:90]2[C:85](=[CH:86][CH:87]=[CH:88][CH:89]=2)[N:84]=[CH:83][C:82]=1[C:91]([NH:47][C@H:48]([C:53]([NH:55][C@@H:56]([CH2:74][C:75]1[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=1)[C@H:57]([OH:73])[C:58]([N:60]1[CH2:71][C@@H:70]([Cl:72])[CH2:69][C@H:61]1[C:62]([NH:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])=[O:59])=[O:54])[CH2:49][C:50](=[O:52])[NH2:51])=[O:92]
Reactant: O=C(O)c1cnc2ccccc2n1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Agent: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1cnc2ccccc2n1
Reaction time: 3 h

Procedure:
0.6 ml of 1N aqueous hydrochloric acid was added to a solution of 300 mg (0.48 mmol) of (4S)-1-[(2S,3S)-3-(N2 -benzyloxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyryl]-N-t-butyl-4-chloro-L-prolinamide (prepared as described in Example 1) in methanol, and a stream of hydrogen was bubbled through the mixture at atmospheric pressure for 3 hours in the presence of 60 mg of 10% w/w palladium-on-charcoal, to remove the benzyloxycarbonyl group. The whole of the resulting (4S)-1-[(2S,3S)-3--asparaginylamino-2-hydroxy-4-phenylbutyryl]-N-t-butyl-4-chloroprolinamide hydrochloride and 99 mg (0.57 mmol) of 2-quinoxalinecarboxylic acid were dissolved in 5 ml of dimethylformamide, and 93 mg (0.57 mmol) of diethyl cyanophosphate and 144 mg (1.44 mmol) of triethylamine under ice-cooling were added to this solution. The resulting mixture was stirred for 3 hours, after which it was concentrated by evaporation under reduced pressure. The residue was mixed with a 10% w/v aqueous solution of sodium hydrogencarbonate and then extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by preparative thin layer chromatography, using a 10:1 by volume mixture of methylene chloride and methanol as the developing solvent, to give 140 mg of the title compound as a colorless powder, melting at 132°-134° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH:23]([C:25]([F:28])([F:27])[F:26])[NH:22][CH2:21][CH2:20]2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:22]3[CH2:21][CH2:20][C:19]4[C:24](=[C:15]([F:14])[CH:16]=[CH:17][CH:18]=4)[CH:23]3[C:25]([F:26])([F:28])[F:27])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Fc1cccc2c1C(C(F)(F)F)NCC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2cccc(F)c2C1C(F)(F)F

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-fluoro-1-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([S:29][Si](C(C)C)(C(C)C)C(C)C)[C:12]2[O:21][CH:20]3[CH:15]([CH2:16][N:17]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:19]3)[C:13]=2[CH:14]=1.I[CH2:41][CH2:42][CH3:43].[F-].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([S:29][CH2:41][CH2:42][CH3:43])[C:12]2[O:21][CH:20]3[CH:15]([CH2:16][N:17]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:18][CH2:19]3)[C:13]=2[CH:14]=1
Reactant: CC(C)[Si](Sc1cc(-c2ccc(Cl)cc2Cl)cc2c1OC1CCN(C(=O)OC(C)(C)C)CC21)(C(C)C)C(C)C
Reactant: CCCI
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: CCCSc1cc(-c2ccc(Cl)cc2Cl)cc2c1OC1CCN(C(=O)OC(C)(C)C)CC21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
tert-Butyl 8-(2,4-dichlorophenyl)-6-[(triisopropylsilyl)thio]-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate (0.111 g, 0.182 mmol) was dissolved in DMF (3 mL). 1-Iodopropane (0.2 mL) and cesium fluoride (0.060 g) were added to the reaction mixture. The reaction mixture was stirred at rt under N2 for 2.5 h. The reaction mixture was partitioned between EtOAc (30 mL) and 2:3 water:brine (25 mL). The aqueous layer was back extracted with EtOAc (30 mL). The combined organic layers were washed with water (20 mL), with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. tert-Butyl 8-(2,4-dichlorophenyl)-6-(propylthio)-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate was obtained in quantitative yield (0.090 g). MS (ESI+) for C25H29Cl2NO3S m/z 517.0 (M+23)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([Mg]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1COCC1.O>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Reactant: Br[Mg]c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OC1(c2ccccc2)CCCN(Cc2ccccc2)C1
Temperature: 0 °C
Yield: 80 %

Procedure:
To a solution of 1-benzyl-3-piperidinone (0.193 g, 1.02 mmol) in toluene dry (10 mL) cooled at 0° C. was added a solution of phenyl magnesium bromide 3.1M in THF (0.48 mL, 1.4 mmol). The resulting solution was maintained at 0° C. for 2 h, then was allowed to warm at 25° C. for 1 h. Water (50 mL) was added and the mixture was extracted with EtOAc (2×50 mL). The collected organic phase was dried and concentrated under reduced pressure. The crude compound was purified by flash chromatography on silica gel using EtOAc/cyclohexane as eluant to afford the title compound as a white solid (0.235 g, 80%). 1H NMR (CDCl3): 1.65-1.85 (m, 3H), 1.9-2.15 (m, 1H), 2.067 (bd, J=8.1 Hz, 1H), 2.34 (d, J=11.1 Hz, 1H), 2.77 (d, J=11.1 Hz, 1H), 2.95 (bd, J=8.1 Hz, 1H), 3.60 (s, 2H), 4.005 (bs, 1H), 7.2-7.4 (m, 8H), 7.50 (s, 1H), 7.525 (s, 1H).