Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O-:7])=[O:6].[Na+].[C:12]([C:16]([CH2:18][N:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:22][C@@H:21]([NH:36][C:37](OC2C=CC=CC=2)=[O:38])[C:20]1=[O:46])=[O:17])([CH3:15])([CH3:14])[CH3:13]>CN(C)C1C=CN=CC=1.CS(C)=O>[C:12]([C:16]([CH2:18][N:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:22][C@@H:21]([NH:36][C:37](=[O:38])[NH:1][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([OH:7])=[O:6])[C:20]1=[O:46])=[O:17])([CH3:15])([CH3:13])[CH3:14]
Reactant: Nc1cccc(C(=O)[O-])c1
Reactant: CC(C)(C)C(=O)CN1C(=O)[C@H](NC(=O)Oc2ccccc2)CN(C2CCCCC2)c2ccccc21
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)CN1C(=O)[C@H](NC(=O)Nc2cccc(C(=O)O)c2)CN(C2CCCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.9 %

Procedure:
Under an argon atmosphere, 2.0 g of sodium 3-aminobenzoate, 77 mg of 4-dimethylaminopyridine and 3.0 g of Molecular Sieves 3A were added to a solution of 3.0 g of (R)-(−)-1-tert-butylcarbonylmethyl-2-oxo-3-phenoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine in 30 ml of anhydrous dimethylsulfoxide. The mixture was stirred at room temperature for 15 hours. After filtration of the reaction mixture, ice water and a 1N aqueous solution of sodium hydroxide were added to the filtrate. The mixture was extracted with ethyl acetate. The organic layer was washed successively with a 1N aqueous solution of sodium hydroxide, 1N hydrochloric acid and brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. To the residue was added a mixed solvent of ethanol and water (2:1). Crystals so precipitated were collected by filtration, whereby 2.32 g of the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16](I)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1.[F:31][C:32]([F:40])([F:39])[CH:33]1[O:38][CH2:37][CH2:36][NH:35][CH2:34]1.C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([N:35]3[CH2:36][CH2:37][O:38][CH:33]([C:32]([F:40])([F:39])[F:31])[CH2:34]3)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1
Reactant: FC(F)(F)C1CNCCO1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N3CCOC(C(F)(F)F)C3)c21
Temperature: 150 °C

Procedure:
Under argon atmosphere, 200 mg (purity 62%, 0.24 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was put in 4 ml of absolute NMP, and 924 mg (4.82 mmol) of 2-(trifluoromethyl)morpholine and 623 mg (4.82 mmol) of N,N-diisopropyl ethylamine were added. The mixture was heated in the microwave at 150° C. for 5 h. The reaction solution was filtered and purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→100:0). 60 mg (46% of theor.) of the target compound was obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.Cl.[NH:15]1[CH2:19][CH2:18][C:17]2([CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[O:20]2)[CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:15]3[CH2:19][CH2:18][C:17]4([CH2:23][C:22]5[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=5[O:20]4)[CH2:16]3)=[CH:7][CH:6]=2)[O:12][N:11]=1
Reactant: Cc1noc(-c2ccc(Cl)nn2)n1
Reactant: c1ccc2c(c1)CC1(CCNC1)O2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(-c2ccc(N3CCC4(Cc5ccccc5O4)C3)nn2)n1
Temperature: 25 °C
Yield: 52.6 %

Procedure:
A mixture of 3-chloro-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridazine (39 mg) obtained in Example 43(2), 3H-spiro[1-benzofuran-2,3′-pyrrolidine] hydrochloride (42 mg) and potassium carbonate (55 mg) was stirred in DMF (5 mL) at 120° C. overnight. After cooling to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The desiccant was filtered off, and the filtrate was concentrated. The residue was washed with a small amount of acetic acid to give the object product (35 mg, 52%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([C:12]2[CH:13]=[C:14]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[O:29])=[CH:24][N:23]=3)[C:15]3[N:16]([N:18]=[CH:19][N:20]=3)[CH:17]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:36]1[N:45]=[CH:44][C:43]2[C:38](=[C:39]([F:50])[CH:40]=[C:41]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:42]=2)[C:37]1=[O:51])(=O)C.[OH-].[Na+]>C1COCC1.C([O-])(O)=O.[Na+].C(Cl)Cl>[C:46]([C:41]1[CH:42]=[C:43]2[C:38](=[C:39]([F:50])[CH:40]=1)[C:37](=[O:51])[N:36]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]3[CH:13]=[C:14]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([C:28]([N:30]5[CH2:31][CH2:32][O:33][CH2:34][CH2:35]5)=[O:29])=[CH:24][N:23]=4)[C:15]4[N:16]([N:18]=[CH:19][N:20]=4)[CH:17]=3)[C:6]=1[CH2:5][OH:4])[N:45]=[CH:44]2)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c3ncnn3c2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-c4cc(Nc5ccc(C(=O)N6CCOCC6)cn5)c5ncnn5c4)c3CO)ncc2c1
Temperature: 60 °C
Yield: 22.5 %

Procedure:
To a solution of 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(8-(5-(morpholine-4-carbonyl)pyridin-2-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)benzyl acetate (289 mg, 418 μmol, Eq: 1.00) in THF (5.0 ml) was added NaOH (1.0 N, 5.0 ml, 5.00 mmol, Eq: 12.0). The solution was heated to 60° C. for 18 h. The reaction was cooled to room temperature. The reaction was diluted with sat NaHCO3 (aq) and DCM. The layers were separated. The aqueous layer was extracted three times with DCM, and then dried over MgSO4. The solid was removed by filtration. The filtrate was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 10% MeOH/DCM gradient) to give a residue. The residue was triturated with Et2O to give 6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{8-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-[1,2,4]triazolo[1,5-a]pyridin-6-yl}-phenyl)-2H-phthalazin-1-one (61 mg, 23%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.36-1.49 (m, 9H) 3.51-3.95 (m, 8H) 4.40 (s, 2H) 7.20 (dd, J=18.13, 7.18 Hz, 1H) 7.41-7.67 (m, 6H) 7.76 (dd, J=8.31, 2.27 Hz, 1H) 8.31 (d, J=2.64 Hz, 1H) 8.36-8.48 (m, 2H) 8.66 (s, 1H) 8.95 (s, 1H) LC/MS-ESI observed [M+H]+ 649.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-])=O.[ClH:19]>CCOC(C)=O.CCOCC.O1CCOCC1.[Pd]>[ClH:19].[C:13]1([N:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:4]([NH2:1])[C:5]=3[CH:6]=[N:7]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1cccc2c1cnn2-c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1COCCO1
Product: Nc1cccc2c1cnn2-c1ccccc1
Reaction time: 2 h

Procedure:
4-Nitro-1-phenyl-1H-indazole (Intermediate 7) was dissolved in EtOAc (200 mL) then 10% Pd/C (500 mg) was added and the mixture was stirred under a hydrogen atmosphere for 2 hours. Filtration through Celite and concentration of the filtrate gave a yellow oil which was dissolved in ether (100 mL). A solution of 4N HCl in dioxan (10 mL) was added slowly resulting in a yellow precipitate which was filtered off to give the title compound as a yellow solid (2.5 g).
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[C:27]1([C:33]2[N:34]3[CH:40]=[N:39][CH:38]=[C:35]3[S:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:39]3[CH:38]=[C:35]4[S:36][CH:37]=[C:33]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N+:34]4=[CH:40]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: c1ccc(-c2csc3cncn23)cc1
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4scc(-c5ccccc5)[n+]4c3)[C@H](C)[C@H]12
Yield: 13.4 %

Procedure:
The same procedure as in Example 1 was repeated except that 104 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 86 mg of 3-phenylimidazo[5,1-b]thiazole were used, thereby obtaining 16.2 mg of the title compound.
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[CH3:13][O:14][C:15](=[O:18])[CH2:16][NH2:17].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[CH3:13][O:14][C:15](=[O:18])[CH2:16][NH:17][C:1](=[O:11])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: COC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)CNC(=O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cinnamic acid (38.0 g) was coupled to glycine methyl ester hydrochloride in dimethylformamide by treatment with dicyclohexylcarbodiimide (52.84 g) and 1-hydroxybenzotriazole (39.24 g), followed by N-methylmorpholine (37.56 ml). The reaction mixture was stirred overnight at room temperature and then worked up in the usual manner to give the desired product.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:28][CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.[CH3:36][C:37]1([CH3:65])[CH2:63][C:41]2[C:42]([C:51]3[CH:52]=[C:53]([NH:57][C:58](=[O:62])[C:59](O)=[O:60])[CH:54]=[CH:55][CH:56]=3)=[C:43]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)[S:44][C:40]=2[C:39](=[O:64])[CH2:38]1>C(Cl)Cl>[CH3:36][C:37]1([CH3:65])[CH2:63][C:41]2[C:42]([C:51]3[CH:52]=[C:53]([NH:57][C:58](=[O:62])[C:59]([NH:28][CH2:29][CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:60])[CH:54]=[CH:55][CH:56]=3)=[C:43]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)[S:44][C:40]=2[C:39](=[O:64])[CH2:38]1
Reactant: CC1(C)CC(=O)c2sc(N3CCOCC3)c(-c3cccc(NC(=O)C(=O)O)c3)c2C1
Reactant: NCCN1CCCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC1(C)CC(=O)c2sc(N3CCOCC3)c(-c3cccc(NC(=O)C(=O)NCCN4CCCC4)c3)c2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 19.1 %

Procedure:
Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (145 mg, 0.33 mmol) and 1-(2-aminoethyl)pyrrolidine (60 μL, 0.49 mmol) were added to a solution of Example 292 (70 mg, 0.16 mmol) in DCM (10 mL) and the reaction mixture was stirred at room temperature for 18 h. A further portion of 1-(2-aminoethyl)-pyrrolidine (60 μL, 0.49 mmol) was added and stirring was continued for 72 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC (pH 2.5) to give the title compound (16 mg, 19%) as an off-white solid. δH (CDCl3) 9.26 (1H, s), 8.43 (1H, br s), 7.74-7.69 (1H, m), 7.65-7.59 (1H, m), 7.45 (1H, t, J 7.7 Hz), 7.23-7.16 (1H, m), 3.78-3.64 (6H, m), 3.11-2.92 (10H, m), 2.49 (2H, s), 2.45 (2H, s), 2.07-1.96 (4H, m), 1.05 (6H, s). LCMS (ES+) 525.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17])([CH3:4])([CH3:3])[CH3:2].CN([CH:22]=[O:23])C>>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][N:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:22]1=[O:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NCCNc1ccccc1N
Product: CC(C)(C)OC(=O)NCCn1c(=O)[nH]c2ccccc21
Yield: 56 %

Procedure:
A mixture of [2-(2-aminophenylamino)ethyl]carbamic acid t-butyl ester (3.85 g, 15.3 mmol) and 1,1-carbonyldiimidazole (CDI) (2.73 g, 16.8 mmol) in DMF are heated at 110°-120° C. until reaction is complete by TLC, cooled and extracted with EtOAc. The combined extracts are washed with water, dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (silica gel, 1:1 CH2Cl2: EtOAc as eluent) to give the title compound as a brown solid, 2.4 g (56% yield), identified by HPLC and mass spectral analyses.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][CH3:21])[CH2:34][CH2:33]2)=[O:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: COc1nc(C)c(C)nc1NC(=O)Oc1ccccc1
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(C(=O)Nc2nc(C)c(C)nc2OC)CC1
Yield: 82 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li]CCCC.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.[C:43]([O:47][C:48](=[O:50])[CH3:49])([CH3:46])([CH3:45])[CH3:44].Cl[C:52]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:55]=[C:54]([Cl:62])[N:53]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:43]([O:47][C:48](=[O:50])[CH2:49][C:52]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:55]=[C:54]([Cl:62])[N:53]=1)([CH3:46])([CH3:45])[CH3:44]
Reactant: Clc1cc2ccccc2c(Cl)n1
Reactant: CC(=O)OC(C)(C)C
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Cc1nc(Cl)cc2ccccc12
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
1,1,1,3,3,3-Hexamethyl-disilazane (27.4 ml, 20.37 g, 126.2 mmol) are dissolved in dry toluene (150 ml). After cooling to −78° C., n-BuLi (79 ml of a 1.6 M solution in hexanes, 126.2 mmol) is slowly added during 20 minutes. The white suspension is stirred at −78° C. for 15 minutes and at RT for 15 minutes, after which time a clear bright yellow solution is obtained. This solution is canulated into a second two-necked flask, containing Pd2(dba)3 (1.39 g, 1.51 mmol) and (2′-Dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (1.25 g, 3.18 mmol). After stirring at RT for 10 minutes, the clear dark red solution is cooled to −10° C. Acetic acid tert-butyl ester (15.7 ml, 13.5 g, 116.1 mmol) is added during 5 min. After 10 minutes at −10° C. 1,3-Dichloro-isoquinoline (10.0 g, 50.49 mmol) is added in one portion. The dark red solution is allowed to warm to RT. After 30 minutes at RT, TLC analysis indicates complete conversion of the starting material. The reaction mixture is filtered through a 2-cm pad of silica, which is rinsed with EtOAc/MeOH 98:2. After concentration, the residue is purified by FCC (toluene/CH2Cl2 2:1 to toluene/EtOAc 100:0 to 99:1 to 98:2 to 97:3 to 96:4 to 94:6 to 90:10) to afford (3-Chloro-isoquinolin-1-yl)-acetic acid tert.-butyl ester. This compound is dissolved in a saturated ethanolic solution of HCl (200 ml) and refluxed for 15 minutes. Concentration affords the title compound in quantitative yield. 1H NMR (DMSO, 400 MHz) δ 1.17 (t, J=8.8, 3H), 4.11 (q, J=8.8, 2H), 4.28 (s, 2H), 7.51-7.57 (m, 1H), 7.61 (s, 1H), 7.61-7.66 (m, 1H), 7.72 (d, J=8.8, 1H), 7.98 (d, J=8.8, 1H); ES-MS: 250 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=[CH:3][C:2]=1[C:11](OCC)=[O:12].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>O1CCCC1>[N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=[CH:3][C:2]=1[CH2:11][OH:12]
Reactant: CCOC(=O)c1cnc2c(n1)CCCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: OCc1cnc2c(n1)CCCC2
Reaction time: 0.75 h
Yield: 78.5 %

Procedure:
To a solution of 0.16 g of ethyl 5,6,7,8-tetrahydroquinoxaline-2-carboxylate in 1.5 mL of tetrahydrofuran, 29 mg of lithium aluminum hydride was added under cooling with ice, the mixture was stirred for 45 minutes, 29 mg of lithium aluminum hydride was further added thereto, and the mixture was stirred for 30 minutes. Thereto were added ethyl acetate and water, the insoluble substance was filtered off, sodium chloride was added to a filtrate, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.10 g of (5,6,7,8-tetrahydroquinoxalin-2-yl)methanol as a brown solid.
Reaction SMILES: [CH3:1][P:2]([O-:8])[O:3][CH2:4][CH:5]([CH3:7])[CH3:6].[C:9](#[N:12])[CH:10]=[CH2:11].[Na].C(O)(=O)C>C(O)C>[C:9]([CH2:10][CH2:11][P:2]([CH3:1])(=[O:8])[O:3][CH2:4][CH:5]([CH3:7])[CH3:6])#[N:12]
Reactant: C=CC#N
Reactant: CC(C)COP(C)[O-]
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)COP(C)(=O)CCC#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 15.0 g of isobutyl P-methylphosphonite and 5.3 g of acrylonitrile in 50 ml of dry ethanol is added to a stirred mixture of 0.5 g of sodium (50% dispersion in oil) in 25 ml of ethanol, at 0° C. , under an atmosphere of nitrogen. The reaction mixture is allowed to warm to room temperature, and stirred for 4 hours. 1 ml of glacial acetic acid is added and the mixture is concentrated under reduced pressure. The resulting crude product is dissolved in 50 ml of ethyl acetate, washed twice with 20 ml of water, and the organic extract is dried over magnesium sulphate, and then concentrated under reduced pressure. The crude product is distilled to give isobutyl P-(2-cyanoethyl)-P-methyl-phosphinate, b.p. 140°/0.2 mbar, 31P-NMR spectrum: δ=+50.5 ppm (CDCl3).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH3:19])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C([O-])(O)=O.[Na+].[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(OC(C)C)(C)C>C(Cl)(Cl)Cl.C1COCC1.O>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([CH:4]([C:5]2[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=2)[CH:3]([NH:2][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:19])=[CH:13][CH:14]=1
Reactant: CC(N)C(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)OC(C)C
Product: CC(NC(=O)c1ccccc1)C(c1ccc(O)cc1)c1ccc(O)cc1
Reaction time: 120 h
Yield: 80.9 %

Procedure:
The product from Example 12 (5.00 g, 17.0 mmol) was dissolved in chloroform (70 mL), THF (30 mL), and 50 mL saturated aqueous NaHCO3 solution. The reaction mixture was treated with benzoyl chloride (2.5 mL, 21.5 mmol) and the water (25 mL). The reaction mixture was stirred for 5 days. The organic phase was collected, dried (MgSO4), and filtered. The filtrate was concentrated. The residue obtained was dissolved in hot THF and diisopropylether was added until a slight cloudiness developed. The solid which formed on cooling was collected by filtration, washed with additional diisopropylether, and dried under vacuum to give the title compound (4.78 g, 77%) as a white solid.
Reaction SMILES: C(=O)([O-])O.[Na+].[N+]([C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1)([O-])=O.O.C(OCC)(=O)C.[NH:24]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:25]([C:38]([OH:40])=[O:39])[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([CH:36]=[O:37])[CH:28]=1>>[NH:24]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:25]([C:38]([O:40][CH2:13][C:12]1[CH:15]=[CH:16][CH:9]=[CH:10][CH:11]=1)=[O:39])[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([CH:36]=[O:37])[CH:28]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cn(C=O)c2ccccc12)C(=O)O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cn(C=O)c2ccccc12)C(=O)OCc1ccccc1
Reaction time: 24 h
Yield: 47.7 %

Procedure:
In 5 mg of DMP was dissolved 0.33 g of t-Boc-Trp(CHO)-OH, 0.17 g of sodium hydrogen carbonate was added. The solution was then stirred. To the mixture was added 1.08 g (5 mmol) of p-nitrobenzyl bromide, and stirring was effected at room temperature for 24 hours. Water and ethyl acetate were added to the reaction solution. The mixture was shaken, and the organic layer was recovered and the solvent was evaporated. The residue was purified with a silica gel column (manufactured by Merck Co., Kieselgel 60, 50 g, elution with hexane:ethyl acetate=6:4), to obtain 0.2 g of t-Boc-Trp(CHO)-OBzl (NO2). The peptide was dissolved in 5 ml of DMF, 0.5 ml of piperidine was added thereto, and the mixture was stirred at 0° C. for 1.5 hours. The solvent was evaporated under reduced pressure, 0.5 ml of 98% formic acid was added thereto, and the mixture was stirred at room temperature for 4 hours. About 30 ml of ether was added to obtain a precipitate. The precipitate was filtered and dried to obtain 0.16 g of H-Trp-OBzl (NO2).
Reaction SMILES: [Al].[CH2:2](Br)[C:3]#[CH:4].[O:6]1[CH2:11][CH2:10][CH2:9][O:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([CH3:27])([CH3:26])[CH2:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22].C1(C2OCCCO2)C=CC=CC=1.C([Al])C#C>C1COCC1>[CH3:26][C:18]1([CH3:27])[CH2:19][C:20]([CH2:4][C:3]#[CH:2])([C:21]([F:23])([F:24])[F:22])[O:25][CH:7]([O:8][CH2:9][CH2:10][CH2:11][OH:6])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=2
Reactant: CC(C)(CC(=O)C(F)(F)F)c1ccccc1C1OCCCO1
Reactant: C#CCBr
Agent: C#CC[Al]
Agent: [Al]
Agent: c1ccc(C2OCCCO2)cc1
Solvent: C1CCOC1
Product: C#CCC1(C(F)(F)F)CC(C)(C)c2ccccc2C(OCCCO)O1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
A flask was charged with aluminum (4.1 g of aluminum foil cut into 50 mg pieces, 152 mmol) and mercuric chloride (0.27 g, 1 mmol). The flask was sealed with a septum, flushed with argon, and anhydrous THF (300 mL) was added. Propargyl bromide (80% in toluene, 16.9 mL, 152 mmol) was added via syringe slowly and the resulting mixture was stirred for 30 minutes at 23° C. then warmed to 55° C.-60° C. and stirred an additional 2 hours. A second flask was charged with a 1:2 inseparable mixture of the 4-(2-[1,3]dioxan-2-ylphenyl)-1,1,1-trifluoro-4-methylpentan-2-one and 2-phenyl [1,3]dioxane (15.5 g). Anhydrous THF (150 mL) was added and the solution was cooled to −78° C. The solution of the propargyl aluminum solution was transferred to the ketone solution via cannula. The resulting solution was allowed to warm to 23° C. over a period of 75 minutes then stirred overnight. The reaction was quenched by carefully pouring into an aqueous saturated solution of ammonium chloride (500 mL). The mixture was diluted with diethyl ether (500 mL) and the layers were separated. The aqueous layer was washed with diethyl ether (250 mL) and the organics were combined, dried over sodium sulfate, filtered, and concentrated in vacuo to yield 3-(5,5-dimethyl-3-prop-2-ynyl-3-trifluoromethyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yloxy)propan-1-ol as an orange oil (15.0 g) that was used without purification.
Reaction SMILES: FC(F)(O[C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1)C(F)F.[S-:15][C:16]#[N:17].[K+].BrBr>C(O)(=O)C>[S:15]1[C:9]2[CH:8]=[CH:7][CH:13]=[CH:12][C:10]=2[N:11]=[C:16]1[NH2:17]
Reactant: N#C[S-]
Reactant: Nc1ccc(OC(F)(F)C(F)F)cc1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccccc2s1
Yield: 27.8 %

Procedure:
The procedure is as in Example 1, starting with 4-(1,1,2,2-tetrafluoroethoxy)aniline (10 g), potassium thiocyanate 18.5 g), bromine (2.4 cc) and acetic acid (80 cc). After purification on a column of silica (1 kg; particle size: 0.063-0.200 mm), eluting with a mixture of cyclohexane and ethyl acetate (50:50 by volume), and recrystallization in toluene (22 cc), 6- 1,1,2,2-tetrafluoroethoxy)-2-benzothiazolamine (2 g), m.p. 161° C., is obtained.