Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1/[C:9](/[CH3:16])=[CH:10]\[C:11]([O:13][CH2:14][CH3:15])=[O:12].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C.[CH2:68]([SH:75])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1>O1CCOCC1.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].O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:75][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)=[CH:4][C:3]=1/[C:9](/[CH3:16])=[CH:10]\[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)/C=C(/C)c1cc(Br)ccc1N
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)/C=C(/C)c1cc(SCc2ccccc2)ccc1N
Temperature: 90 °C
Reaction time: 36 h
Yield: 58 %

Procedure:
A solution of (Z)-ethyl 3-(2-amino-5-bromophenyl)but-2-enoate (3.3817 g, 11.90 mmol), xantphos (1.033 g, 1.785 mmol), pd2(dba)3 (0.545 g, 0.595 mmol), and n,n-diisopropylethylamine (6.24 ml, 35.7 mmol) in 24 mL dioxane was heated to 80° C. then was treated with benzyl mercaptan (2.252 ml, 19.04 mmol). After stirring for 36 hours, an additional portion of xantphos (1.033 g, 1.785 mmol), pd2(dba)3 (0.545 g, 0.595 mmol), and n,n-diisopropylethylamine (6.24 ml, 35.7 mmol) was added, and the reaction mixture was heated to 90° C. overnight. The reaction mixture was then poured into water and was extracted with DCM. The organics were dried over MgSO4 and concentrated. Purification of the crude residue by silica gel column chromatography (0-100% EtOAc/heptane) gave (Z)-ethyl 3-(2-amino-5-(benzylthio)phenyl)but-2-enoate (2.26 g, 6.90 mmol, 58.0% yield). m/z (ESI) 328.2 (M+H)+.
Reaction SMILES: C(N[C@H](C([NH:14][C@H:15]([C:19]([N:21]([C:39](=[O:48])[CH2:40][CH2:41][CH:42]([NH2:47])[CH2:43][CH:44]([CH3:46])[CH3:45])[C@H:22]([C:25]([CH:27]([CH:31]([OH:38])[CH:32]([NH2:37])[CH2:33][CH:34]([CH3:36])[CH3:35])[C:28]([OH:30])=[O:29])=[O:26])[CH2:23][OH:24])=[O:20])[CH:16]([CH3:18])[CH3:17])=O)C(C)C)(=O)CC(C)C.P([O-])([O-])([O-])=O>>[NH2:14][C@H:15]([C:19]([N:21]([C:39](=[O:48])[CH2:40][CH2:41][CH:42]([NH2:47])[CH2:43][CH:44]([CH3:46])[CH3:45])[C@H:22]([C:25]([CH:27]([CH:31]([OH:38])[CH:32]([NH2:37])[CH2:33][CH:34]([CH3:35])[CH3:36])[C:28]([OH:30])=[O:29])=[O:26])[CH2:23][OH:24])=[O:20])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)CC(=O)N[C@H](C(=O)N[C@H](C(=O)N(C(=O)CCC(N)CC(C)C)[C@@H](CO)C(=O)C(C(=O)O)C(O)C(N)CC(C)C)C(C)C)C(C)C
Agent: O=P([O-])([O-])[O-]
Product: CC(C)CC(N)CCC(=O)N(C(=O)[C@@H](N)C(C)C)[C@@H](CO)C(=O)C(C(=O)O)C(O)C(N)CC(C)C
Reaction time: 20 h
Yield: 84.3 %

Procedure:
A reaction mixture containing 100 mg of isovaleryl-L-valyl-L-valyl-4-amino-3-hydroxy-6-methylheptanoyl-L-alanyl-4-amino-3-hydroxy-6-methylheptanoic acid, 250 units of purified enzyme prepared by the procedure described in Experiment 17 and 0.05M phosphate buffer, pH 7.2, in a total volume of 100 ml was incubated at 37° C for 20 hours. By a procedure similar to that described in Example 1, 61.8 mg of crystalline Val-X-Ala-X was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[C:17]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH:30]4[CH2:32][CH2:31]4)[CH2:22][CH2:21]3)=[O:19])=[CH:16][N:15]=[C:14]([CH3:33])[CH:13]=2)[C:8]([Cl:34])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH3:36][O:37][C:38](=[O:41])[CH2:39][NH2:40]>>[CH3:36][O:37][C:38](=[O:41])[CH2:39][NH:40][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Cl:34])[C:9]([O:11][C:12]2[C:17]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH:30]4[CH2:32][CH2:31]4)[CH2:22][CH2:21]3)=[O:19])=[CH:16][N:15]=[C:14]([CH3:33])[CH:13]=2)=[CH:10][C:2]=1[Cl:1]
Reactant: COC(=O)CN
Reactant: Cc1cc(Oc2cc(Cl)c(C(=O)O)cc2Cl)c(C(=O)N2CCN(C3CC3)c3ccccc32)cn1
Agent: Cl
Product: COC(=O)CNC(=O)c1cc(Cl)c(Oc2cc(C)ncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Yield: 39 %

Procedure:
The title compound was prepared in analogy to Example 29, from 2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoic acid and glycine methyl ester hydrochloride (commercially available, CAS RN 5680-79-5). The compound was purified on a preparative HPLC system (Phenomenex Gemini column) with a gradient of acetonitrile:water (containing 0.05% formic acid) (50:50 to 95:5), to give 44 mg (39%) of the title compound as a light yellow solid. MS (ESI): m/z=569.136 [M+H]+.
Reaction SMILES: [C:1]1(/[CH:11]=[CH:12]\[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.P([O-])([O-])(O)=[O:15].[Na+].[Na+]>C(Cl)Cl>[C:1]1([C@H:11]2[O:15][C@H:12]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: O=P([O-])([O-])O
Reactant: C/C=C\c1cccc2ccccc12
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1O[C@@H]1c1cccc2ccccc12
Temperature: 6 °C
Reaction time: 6 h

Procedure:
(ref. E. Jacobsen, el al; JACS 1991, 7064.) The (Z)-1-(1-naphthyl)-propene (2.06 g, 0.012 mol) was dissolved in methylene chloride, and (R, R)-Jacobsen's catalyst (0.168 g) was added, then cooled to 6° C., and a bleach solution (10 mL, buffered to pH=11.3 with disodium hydrogen phosphate) was added. After 6 h at 6° C., the layers were separated, and the aqueous layer washed with ether. The combined organic layers were washed with water, then brine, dried over magnesium sulfate, filtered and rotovapped. The crude product was chromatographed on silica using 5% ether/pentane, to give the desired (1R, 2S)-1-(1-naphthyl)-1-propene oxide (0.421 g). NMR (CDCl3) 8.1-7.7 (3H, m), 7.6-7.3 (4H, m), 4.6-4.5 (1H, m), 3.7-3.5 (1H, m), 1.0 (3H, d, J=5.3 Hz).
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[O:12][CH2:13][C:14]3[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:22]1([S:25](Cl)(=[O:27])=[O:26])[CH2:24][CH2:23]1>>[C@H:1]1([NH:10][C:11]2[O:12][CH2:13][C:14]3[C:20]([NH:21][S:25]([CH:22]4[CH2:24][CH2:23]4)(=[O:27])=[O:26])=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Nc1cccc2c1COC(N[C@@H]1CCc3ccccc31)=N2
Product: O=S(=O)(Nc1cccc2c1COC(N[C@@H]1CCc3ccccc31)=N2)C1CC1

Procedure:
The title compound, MS (ISP) m/e=384.1 [(M+H)+], was prepared from (R)—N2-indan-1-yl-4H-benzo[d][1,3]oxazine-2,5-diamine (example 2) and cyclopropylsulfonyl chloride according to the procedure described for example 5.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[C:12]([N:17]2[CH2:22][CH2:21][CH:20]([C:23](O)=[O:24])[CH2:19][CH2:18]2)[CH:13]=[CH:14][C:15]=1[Cl:16].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]1[CH:11]=[C:12]([N:17]2[CH2:18][CH2:19][CH:20]([C:23]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)=[O:24])[CH2:21][CH2:22]2)[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: CN1CCNCC1
Reactant: O=C(O)C1CCN(c2ccc(Cl)c(-c3nc4ccccc4[nH]3)c2)CC1
Product: CN1CCN(C(=O)C2CCN(c3ccc(Cl)c(-c4nc5ccccc5[nH]4)c3)CC2)CC1

Procedure:
Synthesized as described in Method X-Step c starting from 1-[3-(1H-Benzoimidazol-2-yl)-4-chloro-phenyl]-piperidine-4-carboxylic acid (0.1 g, 0.28 mmol) and 1-methyl-piperazine (37 μL, 0.34 mmol). Obtained 30 mg (24%).
Reaction SMILES: [CH2:1]1[CH2:10][O:9][CH:8]2[CH:3]([C@:4]3([CH2:22][CH2:21][C@H:20]4[C:11](=[CH:12][CH2:13][C:14]5[CH2:15][C:16]([O:23]C)=[CH:17][CH2:18][C:19]=54)[C@@H:6]3[CH2:7]2)[CH3:5])[O:2]1.O.O.O.C(O)(=O)C(O)=O>ClCCl.C1COCC1.CO>[CH2:1]1[CH2:10][O:9][CH:8]2[CH:3]([C@:4]3([CH2:22][CH2:21][C@H:20]4[C:11](=[CH:12][CH2:13][C:14]5[CH2:15][C:16](=[O:23])[CH2:17][CH2:18][C:19]=54)[C@@H:6]3[CH2:7]2)[CH3:5])[O:2]1
Reactant: COC1=CCC2=C(CC=C3[C@@H]2CC[C@]2(C)C4OCCOC4C[C@@H]32)C1
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@H]3C(=CCC4=C3CCC(=O)C4)[C@@H]1CC1OCCOC12
Reaction time: 8.5 h
Yield: 98.3 %

Procedure:
To a solution of the enol ether 2 (0.5 g, 1.52 mmol) in dichloromethane (30 mL), THF (20 mL) and methanol (20 mL) was added water (30 mL) followed by oxalic acid dihydrate (1.2 g, 9.5 mmol) and the resulting biphasic mixture was vigorously stirred for 8.5 h. The layers were separated and the aqueous layer washed with dichloromethane (2×20 mL). The organic layers were combined, dried over anhydrous potassium carbonate and concentrated to give the ketone 3 as a glassy solid (0.47 g, 98%).
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH2:12][CH2:13][Cl:14])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1)[NH2:19]>C(O)(C)C>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:2]2[C:3]3[N:10]([CH2:11][CH2:12][CH2:13][Cl:14])[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1
Reactant: ClCCCn1ccc2ncnc(Cl)c21
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Solvent: CC(C)O
Product: Fc1cccc(COc2ccc(Nc3ncnc4ccn(CCCCl)c34)cc2Cl)c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 73.3 %

Procedure:
A mixture of 4-chloro-5-(3-chloropropyl)-5H-pyrrolo[3,2-d]pyrimidine (839 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (1.10 g) and isopropyl alcohol (5 mL) was stirred at 80° C. for 1.5 hrs. The mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate (30 mL) was added to the residue, and the mixture was extracted with ethyl acetate (30 mL×3). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=90:10→20:80) to give the title compound (1.19 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1.[CH2:17]([C:19]1[C:27]2[C:22](=[N:23][CH:24]=[C:25]([F:28])[CH:26]=2)[N:21]([NH2:29])[CH:20]=1)[CH3:18].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>[CH2:17]([C:19]1[C:27]2[C:22](=[N:23][CH:24]=[C:25]([F:28])[CH:26]=2)[N:21]([NH:29][C:8]([C:7]2[C:2]([CH3:1])=[N:3][C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:5][CH:6]=2)=[O:10])[CH:20]=1)[CH3:18]
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Reactant: CCc1cn(N)c2ncc(F)cc12
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCc1cn(NC(=O)c2cnc(-c3ccccn3)nc2C)c2ncc(F)cc12
Temperature: 40 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
A solution of 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (490 mg, 2.28 mmol) and 3-ethyl-5-fluoropyrrolo[2,3-b]pyridin-1-ylamine (340 mg, 1.9 mmol) in DMF (6 mL) is stirred at 40° C. for 1 h. The mixture is treated with DMTMM (524 mg, 1.9 mmol) and stirred at 40° C. for 1 h. The mixture is diluted with saturated aqueous Na2CO3 (5 mL) and stirred for 5 min. The precipitate is collected by filtration and dried in vacuo to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (3-ethyl-5-fluoro-pyrrolo[2,3-b]pyridin-1-yl)-amide (427 mg, 60%). MS: 377 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 11.94 (s, NH, 1H), 9.14 (s, 1H), 8.81 (d, 1H), 8.47 (d, 1H), 8.30 (s, 1H), 8.03 (m, 2H), 7.61 (m, 2H), 2.81 (s, 3H), 2.75 (q, 2H), 1.29 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=2)=[CH:20][CH:19]=1>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)=[CH:31][CH:30]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(-c2ccncc2)cc1
Reactant: CC(C)(C)OC(=O)COc1cccc(CN)c1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3ccncc3)cc2)c1

Procedure:
The compound of Step A was prepared from (3-aminomethyl-phenoxy)-acetic acid tert-butyl ester, of Preparation 20, and 4-pyridin-4-yl-benzaldehyde, of Preparation 24, using the method described in Example 3, Step A, except no triethylamine was used. 1H NMR (400 MHz, CDCl3) δ 8.63 (dd, 2H), 7.60 (dd, 2H), 7.47 (m, 4H), 7.24 (m, 1H), 6.96 (m, 2H), 6.78 (dd, 1H), 4.52 (s, 2H), 3.85 (s, 2H), 3.80 (s, 2H), 1.47 (s, 9H); MS 405 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH:4]=[C:3]1[CH:12]=O.Cl.[NH2:15]O.Cl>C(O)C>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH:4]=[C:3]1[C:12]#[N:15]
Reactant: O=Cc1coc2ccccc2c1=O
Reactant: NO
Agent: Cl
Solvent: CCO
Product: N#Cc1coc2ccccc2c1=O

Procedure:
2.52 Parts of 4-oxo-4H-1-benzopyran-3-carboxaldehyde are admixed well with 2.10 parts of hydroxylamine hydrochloride, followed by the addition of 30 volume parts of 95 weight % ethyl alcohol and 0.5 volume part of concentrated hydrochloric acid. The whole mixture is refluxed for 6 hours and cooled. The resulting precipitate is recovered by filtration, treated with activated carbon and recrystallized from ethanol. This procedure yields 4-oxo-4H-1-benzopyran-3-carbonitrile as colorless crystals. Melting point: 177°-178° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[C:6]([N:8]([CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=[O:7].[CH:25]12[O:31][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30]2>>[OH:31][C@@H:26]1[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]1[N:19]1[CH2:18][CH2:17][CH:16]([N:8]([C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[C:6](=[O:7])[C:5]2[CH:22]=[CH:23][CH:24]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:21][CH2:20]1
Reactant: COc1cccc(C(=O)N(c2ccc(C)cc2)C2CCNCC2)c1
Reactant: C1CCC2OC2C1
Product: COc1cccc(C(=O)N(c2ccc(C)cc2)C2CCN([C@@H]3CCCC[C@H]3O)CC2)c1

Procedure:
The title compound, MS (ISP): m/e=499.0 (M+H+), was prepared as for example 141, steps (A) to (F). Step (B) was performed using 3-methoxybenzoyl chloride, and yielded 4-[(3-methoxy-benzoyl)-p-tolyl-amino]-piperidine-1-carboxylic acid tert-butyl ester. This was then deprotected to 3-methoxy-N-piperidin-4-yl-N-p-tolyl-benzamide (step C), and reacted with cyclohexene oxide to give (+/−)-N-[trans-1-(2-hydroxy-cyclohexyl)-piperidin-4-yl]-3-methoxy-N-p-tolyl-benzamide [step (D)]. Oxidation to (+/−)-3-methoxy-N-[1-(2-oxo-cyclohexyl)-piperidin-4-yl]-N-p-tolyl-benzamidein step (E) and reaction with phenyl lithium [step (F)] led to the title compound of the example.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH:5]([C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH2:25][NH:26][CH2:27][CH3:28])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:6])[CH3:2].[CH2:30]([N:37]=[C:38]=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4](=[O:29])[CH:5]([C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH2:25][N:26]([CH2:27][CH3:28])[C:38]([NH:37][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:39])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:6])[CH3:2]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(C(C)C(=O)OCC)ccc1OC
Reactant: O=C=NCc1ccccc1
Product: CCOC(=O)C(C)c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)NCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 95, Step 1, using the following starting materials: 2-(2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-propionic acid ethyl ester and benzyl isocyanate.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=1)[C:6]#[N:7])=[CH2:2].[CH3:11][N:12]([CH3:30])[C:13]([C:15]1[O:16][C:17]2[C:23]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:22][CH:21]=[CH:20][C:18]=2[CH:19]=1)=[O:14].C(O)(=O)C>C(O)C>[C:6]([C:5]1[CH:8]=[CH:9][N:10]=[C:3]([CH2:1][CH2:2][N:27]2[CH2:28][CH2:29][N:24]([C:23]3[C:17]4[O:16][C:15]([C:13]([N:12]([CH3:30])[CH3:11])=[O:14])=[CH:19][C:18]=4[CH:20]=[CH:21][CH:22]=3)[CH2:25][CH2:26]2)[CH:4]=1)#[N:7]
Reactant: CN(C)C(=O)c1cc2cccc(N3CCNCC3)c2o1
Reactant: C=Cc1cc(C#N)ccn1
Solvent: CC(=O)O
Solvent: CCO
Product: CN(C)C(=O)c1cc2cccc(N3CCN(CCc4cc(C#N)ccn4)CC3)c2o1
Temperature: 90 °C

Procedure:
The compound was prepared according to the procedure disclosed in Example 39 starting from of 2-vinylisonicotinonitrile (0.076 g, 0.59 mmol), N,N-dimethyl-7-(piperazin-1-yl)benzofuran-2-carboxamide (0.080 g, 0.29 mmol) (Example 39d), and acetic acid (0.013 mL, 0.23 mmol). Ethanol was used as solvent and the reaction heated at 90° C. for two days. The crude product was purified by preparative HPLC to give the title compound. Yield: 0.061 g (52%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[F:31][C:32]([F:85])([F:84])[C:33]1[CH:34]=[C:35]([CH:77]=[C:78]([C:80]([F:83])([F:82])[F:81])[CH:79]=1)[C:36]([N:38]1[CH2:42][C@@:41]([CH2:50][CH2:51][N:52]2[CH2:57][CH2:56][C:55]3([C:65]4[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=4)[CH2:59][C@@H:58]3[O:66][CH2:67][C:68]([N:70]([CH3:76])[CH2:71][CH2:72][CH2:73][NH:74][CH3:75])=[O:69])[CH2:54][CH2:53]2)([C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)[O:40][CH2:39]1)=[O:37]>C(Cl)Cl>[F:83][C:80]([F:81])([F:82])[C:78]1[CH:77]=[C:35]([CH:34]=[C:33]([C:32]([F:31])([F:85])[F:84])[CH:79]=1)[C:36]([N:38]1[CH2:42][C@@:41]([CH2:50][CH2:51][N:52]2[CH2:53][CH2:54][C:55]3([C:65]4[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=4)[CH2:59][C@@H:58]3[O:66][CH2:67][C:68]([N:70]([CH3:76])[CH2:71][CH2:72][CH2:73][N:74]([CH3:75])[C:14]([C:12]3[S:13][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:10][CH:11]=3)=[O:16])=[O:69])[CH2:56][CH2:57]2)([C:43]2[CH:44]=[CH:45][C:46]([F:49])=[CH:47][CH:48]=2)[O:40][CH2:39]1)=[O:37]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)s1
Reactant: CNCCCN(C)C(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCCN(C)C(=O)c1ccc(NC(=O)OC(C)(C)C)s1)C(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
The compound (94 mg, 0.385 mmol) obtained in Example 4c was dissolved in methylene chloride (4 mL), triethylamine (80 μL, 0.578 mmol) and pivaloyl chloride (52 μL, 0.424 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 15 minutes. The compound (300 mg, 0.385 mmol) obtained in Example 1k was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:2→0:100, v/v) to give the title compound (366 mg; yield, 94%) as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:15][C:14](=O)[C:6]2=[CH:7][C:8]3[C:13]([N:5]2[N:4]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.P(Cl)(Cl)([Cl:19])=O.C(N(CC)C1C=CC=CC=1)C>>[Cl:19][C:14]1[C:6]2=[CH:7][C:8]3[C:13]([N:5]2[N:4]=[C:3]([S:2][CH3:1])[N:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: CSc1nn2c(cc3ccccc32)c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: CSc1nc(Cl)c2cc3ccccc3n2n1
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
A mixture of 2-methylsulfanyl-3H-[1,2,4]triazino[1,6-a]indol-4-one (3.00 g, 13.0 mmol), phosphoryl chloride (6.04 mL, 64.8 mmol), and N,N-diethylaniline (4.0 mL, 25.0 mmol) was allowed to sit for 30 min at room temperature and then refluxed for 1 hour. The mixture was then concentrated and the residue was azeotroped with toluene, cooled, and poured over ice. The resulting mixture was transferred to a separation funnel and the product was extracted in ether with 10-20% dichloromethane. The combined organic extracts were washed with dilute and cold aqueous HCl. then with dilute cold NaHCO3, and finally with cold water, dried over magnesium sulfate and concentrated. The product was purified by flash chromatography (ISCO, Silicagel, EtOAc/Hexanes 10-15%) to provide 4-chloro-2-methylsulfanyl-[1,2,4]triazino[1,6-a]indole (2.30 g, 71%). 1H-NMR (CDCl3) δ 8.11 (d, J=8.5 Hz, 1H), 7.86 (d, J=8.2 Hz, 1H), 7.49 (m, 1H), 7.41 (m, 1H), 7.14 (s, 1H), 2.68 (s, 3H); LC/MS (ESI+): 250.5 (M+H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[C:13](F)[CH:12]=[C:11](Br)[C:10]=1[Cl:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1[CH2:22][CH2:21][CH2:20][C:19]1=[O:23]>>[CH2:1]([S:8][C:9]1[C:10]([Cl:17])=[C:11]([N:18]2[CH2:22][CH2:21][CH2:20][C:19]2=[O:23])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCN1
Reactant: Fc1cc(Br)c(Cl)c(SCc2ccccc2)c1
Product: O=C1CCCN1c1cccc(SCc2ccccc2)c1Cl

Procedure:
Intermediate 35 (35 g, 313.6 mmol) was coupled with pyrrolidin-2-one (11.396 g, 133.91 mmol) in close analogy to the procedure described in step 1.6). After workup the crude product was used without further purification.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:42])[C@H:33]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[NH2:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:42])[C@H:33]([CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[NH2:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: N[C@@H](Cc1ccccc1)C(=O)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
115 mg (0.200 mmol) of diastereomer B of (2R*,4S*)-2-benzyl-1-((S)-phenylalanyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted with 30 mg (0.801 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR54## is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.20, FD-MS: M+ =478.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:37]#[N:38])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][C:34]#[CH:35])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:36])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:37]#[N:38])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][C:34]#[CH:35])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:36])[CH:9]=2)[CH:7]=1
Reactant: C#CCC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: C#CCC(C(=O)Nc1ccc(C(=O)O)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
91 mg (0.17 mmol) of tert-butyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]pent-4-ynoyl}amino)benzoate (racemate) (Example 23.1C) were hydrolysed with TFA according to General Method 2. Yield: 55 mg (67% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)[S:5][CH:6]=1.C(N(CC)CC)C.ClC(OCC)=O.[N-:25]=[N+:26]=[N-:27].[Na+]>CC(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4](/[CH:7]=[CH:8]/[C:9]([N:25]=[N+:26]=[N-:27])=[O:11])[S:5][CH:6]=1
Reactant: O=C(O)/C=C/c1cc(Br)cs1
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NC(=O)/C=C/c1cc(Br)cs1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of (E)-3-(4-bromo-thiophen-2-yl)-acrylic acid (3.0 g, 12.9 mmol) in anhydrous acetone (20 ml) was cooled in an ice-bath to 0° C. and treated with triethylamine (2.15 ml, 15.4 mmol) and ethyl chloroformate (1.24 ml, 15.4 mmol). The reaction was left to stir for 0.5 h before being treated with a solution of sodium azide (1.0 g, 15.4 mmol) in distilled water (4 ml). After stirring for 1 h at 0° C., the reaction was further diluted with distilled water (40 ml) and extracted with DCM (3×25 ml). The organic layer was dried (MgSO4) and filtered for direct use in the next reaction.