Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([C:27]([CH3:32])([CH3:31])[CH:28]([CH3:30])[CH3:29])[O:23][SiH:24]([CH3:26])[CH3:25])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:33]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([C:27]([CH3:31])([CH3:32])[CH:28]([CH3:29])[CH3:30])[O:23][SiH:24]([CH3:26])[CH3:25])=[C:14]([Br:33])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C(C)(C)C(O[SiH](C)C)c1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)C(C)(C)C(O[SiH](C)C)c1nc2c(cc1Br)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Yield: 100 %

Procedure:
To a solution of 22.78 g (4R,9aR)-6-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 200 ml tetrahydrofuran was added at 0° C. 8.78 g (0.049 mol) N-bromosuccinimide and the mixture was stirred at 0° C. for 30 minutes. The reaction mixture was diluted with 500 ml ethyl acetate and extracted sequentially with a 10% aqueous solution of sodium thiosulfate, a 10% aqueous solution of citric acid, water and brine dried over sodium sulfate, evaporated under aspirator vacuum and dried to constant weight under high vacuum to yield 26.5 g of the title compound as colorless oil. (MS: 541 (M+H+)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[NH2:6].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][S:14]([CH3:13])(=[O:16])=[O:15])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(N)cc([N+](=O)[O-])c1
Product: COc1cc(NS(C)(=O)=O)cc([N+](=O)[O-])c1
Yield: 102.5 %

Procedure:
3-Methoxy-5-nitroaniline (2 g, 11.89 mmol) was treated with methanesulfonyl chloride (1.01 ml, 13.08 mmol) according to the method described in Preparation 15b to give 3 g (100% yield) of the title compound. Purity 97%.
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:3]1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](Cl)=[O:29])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][N:2]2[C:11](=[O:12])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]([CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:3]2)=[O:29])=[CH:23][CH:22]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)c1nn(N)c(=O)c2ccccc12
Product: CCOC(=O)C(C)c1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12

Procedure:
The product of Example 109B and 2-(4-chlorophenyl)acetyl chloride were processed using a method similar to that described in Example 4C to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 11.60 (s, 1H), 8.34 (d, J=7.8, 1H), 8.05-7.96 (m, 2H), 7.92 (ddd, J=8.1, 6.1, 2.3, 1H), 7.45-7.35 (m, 4H), 4.52 (q, J=7.1, 1H), 4.12-3.99 (m, 2H), 3.68 (s, 2H), 1.46 (d, 3H), 1.06 (t, 3H); MS (ESI+) M/Z 414 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:7][CH2:6][N:5]([C:8](=[O:18])[C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:4]1.NN>CO.[Ni]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]([N:5]2[CH2:6][CH2:7][CH:3]([N:2]([CH3:1])[CH3:19])[CH2:4]2)=[O:18])=[CH:10][CH:11]=1
Reactant: CN(C)C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)C1
Agent: [Ni]
Agent: NN
Solvent: CO
Product: CN(C)C1CCN(C(=O)c2ccc(N)cc2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The 3-dimethylamino-1-(4-nitrobenzoyl)pyrrolidine (2.4 g, crude), obtained in Step 1, is dissolved in methanol, treated sequentially with hydrazine (5 mL) and Raney-Nickel (suspension in water, approximately 1 g), stirred at room temperature for 4 h and filtered through celite. The filtercake is washed with methanol. The filtrates are combined and concentrated to give 1-(4-aminobenzoyl)-3-dimethylamino-pyrrolidine as a pale brown oil, identified by HPLC and MS [234.5 m/e (M+H)].
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@@H:9]([OH:27])[CH2:10][C@H:11]([C:17](=[O:26])[NH:18][CH:19]1[CH2:24][CH:23]2[CH2:25][CH:20]1[CH2:21][CH2:22]2)[CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])(C)(C)C.C12CC(CC1)CC2NC(=O)[C@H](C)C[C@H](O)[C@@H](N)CC1C=CC=CC=1>>[CH:20]12[CH2:25][CH:23]([CH2:22][CH2:21]1)[CH2:24][CH:19]2[NH:18][C:17](=[O:26])[C@H:11]([CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[CH2:10][C@H:9]([OH:27])[C@@H:8]([NH2:7])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)CC[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NC1CC2CCC1C2
Agent: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Product: CC(C)CC[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2

Procedure:
D8 was prepared from D7 by the method described in D4, as a white foam (100%).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([NH:18][CH2:19][CH2:20][OH:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)(=O)C>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[N:18]([CH2:19][CH2:20][OH:21])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1nc2ccccc2s1
Reactant: OCCNCc1ccccc1
Solvent: CCOC(C)=O
Product: OCCN(Cc1ccccc1)c1nc2ccccc2s1

Procedure:
2-Chlorobenzothiazole (13 g) and 2-(benzylamino)ethanol (29 g) were heated together in a sealed vessel at 120° C. for 20 h. After cooling, the reaction mixture was dissolved in ethyl acetate (200 ml) and the solution was washed with saturated aqueous sodium hydrogen carbonate (3×100 ml), water (3×100 ml) and brine (100 ml), dried over anhydrous magnesium sulphate and evaporated to give the title compound (m.p. 95°-96° C.; dichloromethane/hexane).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C@@H:10]([NH2:24])[CH2:11][CH2:12][CH:13]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14]([F:17])([F:16])[F:15].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[NH2:24][C@@H:10]([CH2:11][CH2:12][CH:13]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14]([F:15])([F:16])[F:17])[CH2:9][OH:8]
Reactant: COC(=O)[C@@H](N)CCC(c1ccccc1)C(F)(F)F
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: N[C@H](CO)CCC(c1ccccc1)C(F)(F)F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a suspension of lithium aluminum hydride (0.267 g) in tetrahydrofuran (30 ml) was added a solution of (S)-2-amino-6,6,6-trifluoro-5-phenyl-hexanoic acid methyl ester (0.97 g) in tetrahydrofuran (3 ml) and the mixture was stirred for 2 hours at 50° C. Sodium sulphate solution (2M, 0.3 ml) was added and the mixture was filtered through Celite. The solvent was evaporated and the residue was purified by chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: ethyl acetate/MeOH=98:2) to yield a light yellow liquid, (0.50 g, 57%); MS (ISP): 248.1 ((M+H)+).
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH2:21].[CH3:22][C:23]1[O:27][C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:25]([C:34](Cl)=[O:35])[CH:24]=1>ClCCl>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH:21][C:34]([C:25]1[CH:24]=[C:23]([CH3:22])[O:27][C:26]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:35]
Reactant: Cc1cc(C(=O)Cl)c(-c2ccccc2)o1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.5 %

Procedure:
Triethylamine (0.128 mL; 0.886 mmol) was added to a mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.082 g; 0.354 mmol) and 5-methyl-2-phenylfuran-3-carbonyl chloride (0.082 g; 0.372 mmol) in dichloromethane (7 mL) at room temperature. The reaction mixture was stirred at room temperature for 20 minutes and washed with water. The organic layer was concentrated under reduced pressure and the crude material was purified by flash chromatography on silica gel (eluent 2 to 10% ethyl acetate in dichloromethane) to afford 0.116 g (86%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-methyl-2-phenylfuran-3-carboxamide as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[N:13][C:12](Cl)=[CH:11][C:10]=2[CH3:16])[CH:6]=[CH:7][CH:8]=1)#[N:2].[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[NH:18][NH2:19]>C(O)CCC>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[N:13][C:12]([NH:19][NH:18][C:17]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][C:10]=2[CH3:16])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1cc(Cl)nnc1-c1cccc(C#N)c1
Reactant: CCOC(=O)NN
Solvent: CCCCO
Product: CCOC(=O)NNc1cc(C)c(-c2cccc(C#N)c2)nn1

Procedure:
A 3.15 g. portion of 6-(m-cyanophenyl)-5-methyl-3-chloropyridazine and 2.85 g. of ethyl carbazate in 50 ml. of butanol is stirred at reflux temperature for 4 hours. The mixture is concentrated free of solvent and the oily concentrate is triturated with water and a little ether. The resulting solid is recovered by filtration, air dried and recrystallized several times from ethanol giving a white solid, m.p. 189°-190° C.
Reaction SMILES: [C:1]([CH2:8][N:9]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][N:16]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:31]I>C(Cl)(Cl)Cl>[C:24]([CH2:23][N:16]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][N:9]([CH2:8][C:1]([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2])[CH2:22][CH2:21][CH2:20][N:19]([CH3:31])[CH2:18][CH2:17]1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: CI
Reactant: CC(C)(C)OC(=O)CN1CCCNCCN(CC(=O)OC(C)(C)C)CCCNCC1
Solvent: ClC(Cl)Cl
Product: CN1CCCN(CC(=O)OC(C)(C)C)CCNCCCN(CC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.3 %

Procedure:
To a solution of compound (5) (2.33 g, 5.43 mmol) in dry chloroform (50 ml) was added methyl iodide (6.78 ml, 15.43 g, 108.72 mmol). After stirring at an ambient temperature for 24 hours, the solvent was removed from the reaction mixture under reduced pressure. The residue was purified via column chromatography on silica using chloroform/isopropyl amine (20:2) as an eluent, to obtain compound (31) as a clear oil (2.41 g, 84% yield). 1H NMR (500 MHz, CDCl3): δ 3.27-3.25 (dd, 4H), 2.84-2.43 (m, 16H), 2.16 (s, 3H), 1.73-1.59 (m, 4H), 1.45 (s, 18H); 13C NMR (125 MHz, CDCl3): δ 170.94, 170.68, 80.57, 55.99, 55.93, 54.80, 53.77, 53.40, 52.26, 50.11, 48.34, 47.41, 47.17, 41.88, 28.18, 25.59, 25.00; HRMS (FAB) calculated for C23H47N4O4: 443.3597 [(M+H)+], measured value: 443.3600 [(M+H)+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](Br)([CH3:7])[CH3:6])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C@H:16]12[CH2:22][C@H:19]([NH:20][CH2:21]1)[CH2:18][N:17]2[CH2:23][C:24]1[N:25]([CH3:50])[C:26]2[C:31]([N:32]=1)=[C:30]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[N:29]=[C:28]([N:39]1[C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[N:41]=[C:40]1[CH2:48][CH3:49])[N:27]=2>C(#N)C>[CH2:48]([C:40]1[N:39]([C:28]2[N:27]=[C:26]3[C:31]([N:32]=[C:24]([CH2:23][N:17]4[CH2:18][C@@H:19]5[CH2:22][C@H:16]4[CH2:21][N:20]5[C:5]([CH3:7])([CH3:6])[C:4]([O:3][CH2:1][CH3:2])=[O:9])[N:25]3[CH3:50])=[C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[N:29]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=1)[CH3:49]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3C[C@@H]4C[C@H]3CN4)n(C)c2n1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)N1C[C@@H]2C[C@H]1CN2Cc1nc2c(N3CCOCC3)nc(-n3c(CC)nc4ccccc43)nc2n1C
Temperature: 80 °C
Yield: 56.7 %

Procedure:
2-Bromo-2-methylpropionic acid ethyl ester (90 μL, 0.61 mmol) was added to a solution of potassium carbonate (84 mg, 0.61 mmol) and 8-[(1S,4S)-1-(2,5-diazabicyclo[2.2.1]hept-2-yl)methyl]-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (140 mg, 0.30 mmol) in anhydrous acetonitrile. The resulting mixture was heated at 80° C. for 48 h, then cooled to ambient temperature and partitioned between EtOAc and water. The organic layer was separated, washed with brine, then dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; gradient from 100:0 to 85:15) to afford 417 as a cream solid (100 mg, 58%). LCMS (Method I): RT=2.92 min, M+H+=588. 1H NMR (CDCl3, 400 MHz) δ 8.01 (m, 1 H); 7.75 (m, 1 H); 7.29-7.23 (m, 2 H); 4.34 (m, 4 H); 4.15 (m, 2 H); 3.93-3.82 (m, 9 H); 3.64 (m, 1 H); 3.35 (q, J=7.5 Hz, 2 H); 3.19 (m, 1 H); 2.81-2.63 (m, 3 H); 1.58 (m, 4 H); 1.45 (t, J=7.5 Hz, 3 H); 1.36 (m, 2 H) and 1.32-1.23 (m, 6 H)
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20](=[O:27])[NH:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:28]C(=O)OC(C)(C)C)[CH2:6][C@@H:5]1[CH3:36])(=[O:3])[CH3:2].F[P-](F)(F)(F)(F)F.Cl>O1CCOCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([NH:21][CH2:22][CH2:23][N:24]([CH3:25])[CH3:26])=[O:27])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:28])[CH2:6][C@@H:5]1[CH3:36])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCN(C)C)cc3)cc2[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCN(C)C)cc3)cc2[C@H](N)C[C@@H]1C
Yield: 84 %

Procedure:
A suspension of crushed tert-butyl ((2S,4R)-1-acetyl-6-(4-((2-(dimethylamino)ethyl)carbamoyl)phenyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate (for a preparation see Intermediate 41) (8 g, possibly as the PF6 salt) was treated with 1,4-dioxane (30 mL) followed by hydrogen chloride in 1,4-dioxane (4N, 40 mL, 160 mmol). After −30 min most of the dioxane was removed and the residue dissolved in warm MeOH (100 mL) at 70° C. for 1.5 h. The residual insoluble material which was filtered off and discarded. The filtrate was concentrated in vacuo and purified using a SCX column (70 G, pre-conditioned with MeOH.) The cartridge was washed with MeOH (200 ml) and eluted with ammonia in MeOH (2M, 200 ml). The methanolic ammonia fractions were combined and concentrated in vacuo to give 4-((2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(2-(dimethylamino)ethyl)benzamide (3.65 g, 9.25 mmol, 84% yield) as a yellow foam. LCMS (HpH, 2 min), Rt=0.71 min, MH+=395.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([C@@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[CH3:11])=[O:9])=[N:6][CH:7]=1.[OH:26][CH2:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([C:36](O)=[O:37])[CH2:32][CH2:31]1)=[O:29]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([C@@H:12]2[CH2:17][CH2:16][N:15]([C:36]([CH:33]3[CH2:34][CH2:35][N:30]([C:28](=[O:29])[CH2:27][OH:26])[CH2:31][CH2:32]3)=[O:37])[CH2:14][C@H:13]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: CN(C(=O)c1ccc(Br)cn1)[C@@H]1CCNC[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)C1CCN(C(=O)CO)CC1
Product: CN(C(=O)c1ccc(Br)cn1)[C@@H]1CCN(C(=O)C2CCN(C(=O)CO)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
Using the compound obtained in step 1 and 1-(hydroxyacetyl)piperidine-4-carboxylic acid, and by the reaction and purification in the same manner as in Example 265, the title compound was obtained.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8].[C:16]([O:20][C:21]([NH:23][CH:24]([C:28]([F:31])([F:30])[F:29])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>ClCCl>[F:29][C:28]([F:30])([F:31])[CH:24]([NH:23][C:21](=[O:22])[O:20][C:16]([CH3:17])([CH3:19])[CH3:18])[C:25](=[O:26])[NH:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:8])[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C(F)(F)F
Reactant: Nn1cccc1C(=O)Nc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C(=O)Nn1cccc1C(=O)Nc1ccccc1)C(F)(F)F
Reaction time: 8 h
Yield: 47 %

Procedure:
1-Amino-N-phenyl-1H-pyrrole-2-carboxamide (570 mg, 2.83 mmol), 2-(tert-butoxycarbonylamino)-3,3,3-trifluoropropanoic acid (826 mg, 3.40 mmol), HATU (1.29 g, 3.40 mmol) and N-methylmorpholine (685 μl, 6.23 mmol) were suspended in 20 mL of dichloromethane and stirred overnight. The reaction mixture was diluted with more dichloromethane and the solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed in vacuum. The product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to obtain the title compound in a 47% yield (562 mg) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:26]=[CH:25][C:9]2[N:10]=[C:11]([NH:14][C@H:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:2][C:3]([NH:5][C:6]2[CH:26]=[CH:25][C:9]3[N:10]=[C:11]([NH:14][C@H:15]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH2:18][CH2:17][CH2:16]4)[O:12][CH2:13][C:8]=3[CH:7]=2)=[O:4])[CH2:30][CH2:29]1
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(N[C@@H]1CCCc3ccccc31)=N2
Reactant: CN1CCNCC1
Product: CN1CCN(CC(=O)Nc2ccc3c(c2)COC(N[C@@H]2CCCc4ccccc42)=N3)CC1
Yield: 100 %

Procedure:
Prepared from the above described 2-chloro-N-{2-[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)amino]-4H-benzo[d][1,3]oxazin-6-yl}-acetamide (150 mg, 0.406 mmol, HPLC 1.185 min) and N-methylpiperazine (901 ul, 8.1 mmol) according to the procedure described for Example 3 step B. Obtained the title compound as a white foam (176 mg, 100%, HPLC 0.503 min), MS (ISP) m/e=434.4 [(M+H)+].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:20])=[C:16]([CH:19]=1)[CH:17]=O>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:20])=[C:16]([CH2:17][C:5]2[S:1][C:2]([N:6]3[CH:10]=[CH:9][CH:8]=[N:7]3)=[CH:3][CH:4]=2)[CH:19]=1
Reactant: O=Cc1cc(Br)ccc1Cl
Reactant: c1csc(-n2cccn2)c1
Product: Clc1ccc(Br)cc1Cc1ccc(-n2cccn2)s1

Procedure:
1-(2-thienyl)pyrazole (see: Chemica Scripta (1979) 13, 157-161) and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were used and treated in a manner similar to Reference Example 7 to give the title compound as colorless solid. APCI-Mass m/z 353/355 (M+H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1/[CH:14]=[CH:15]\[CH3:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>C(O)C.[Pd]>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][CH3:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C/C=C\C1CCCCN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCCC1CCCCN1C(=O)OC(C)(C)C
Yield: 94.4 %

Procedure:
A solution of the 1.5 g (6.66 mmol) of N-Boc-2-(cis-1-propenyl)piperdine in 2 mL of ethanol was shaken under 58 psi H2 pressure over 0.3 g Pd/C catalyst overnight, and then the mixture was filtered through Celite and concentrated to give 1.43 g (94%) of the product as a clear colorless oil. No further purification was necessary. 1H NMR (250 MHz) δ4.21-4.17 (br s, 1 H), 3.98-3.92 (br d, I H), 2.79-2.68 (dt, 1 H), 1.67-1.23 (m, 19 H), 0.93-0.88 (t, 3 H); 13C NMR (62.7 MHz) 155.1 (s), 78.9 (s), 50.0 (s), 38.6 (s), 31.8 (s), 28.4 (s), 25.6 (s), 19.1 (s), 18.9 (s), 14.0 (s) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](#[N:11])[CH:9]=[CH2:10].Cl.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl.CCCCCCC>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:9]([CH3:10])[C:8]#[N:11])=[CH:4][CH:3]=1
Reactant: C=CC#N
Reactant: Nc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCCCCCC
Product: CC(C#N)c1ccc(N)cc1
Reaction time: 8 h
Yield: 30.8 %

Procedure:
To 4.95 g aniline (53.128 mmol) are added 2.82 g acrylonitrile (53.128 mmol) and 3.89 ml heptane. A dry HCl gasflow is lead through the solution. Aluminiumchloride (4.10 g; 30.726 mmol) is added portionwise in 2.5 hours. The HCl flow is stopped and the reaction mixture is stored overnight at 0° C. After reflux for 1 hour, the reaction mixture is poured on ice, and dichloromethane is added. The organic phase is washed with 10% aqueous KCl-solution (4×) and, after drying, evaporated. The oil obtained is purified by column chromatography, yielding 2,39 g 4-aminophenylpropionitrile.
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[CH2:57][CH2:56][CH2:55][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:24]([NH:26][C@H:27]([C@H:32]([CH2:34][C:35]([NH:37][C@H:38]([C:40]([NH:42][C@H:43]([C@H:48]([CH2:50][C:51]([O:53][CH3:54])=[O:52])[OH:49])[CH2:44][CH:45]([CH3:47])[CH3:46])=[O:41])[CH3:39])=[O:36])[OH:33])[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:25])[CH2:18][C:19]1[N:23]=[CH:22][NH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].C(=O)=O>CO.[Pd]>[NH:1]1[CH2:57][CH2:56][CH2:55][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:24]([NH:26][C@H:27]([C@H:32]([CH2:34][C:35]([NH:37][C@H:38]([C:40]([NH:42][C@H:43]([C@H:48]([CH2:50][C:51]([O:53][CH3:54])=[O:52])[OH:49])[CH2:44][CH:45]([CH3:46])[CH3:47])=[O:41])[CH3:39])=[O:36])[OH:33])[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:25])[CH2:18][C:19]1[N:23]=[CH:22][NH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: COC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C=O
Solvent: CO
Product: COC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1

Procedure:
125 mg of Z-Pro-Phe-His-Sta-Ala-Sta-OMe (from Example 13), dissolved in 10 ml of 90% strength methanol, are hydrogenated in the presence of 30 mg of palladium-on-carbon catalyst (10% Pd) at 25° under normal pressure with CO2 -absorption (CO2 from the removal of the Z-protecting group) until saturation. The catalyst is then filtered off, the filtrate is concentrated by evaporation and the residue is dried in a high vacuum. H-Pro-Phe-His-Sta-Ala-Sta-OMe (cf. Example 9) is obtained in the form of a colourless foam; Rf (G)=0.12.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C@H:3]([N:26]1[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10]/[N:11]=[CH:12]/[C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][C:17]([O:24][CH3:25])=[C:18]([CH3:23])[CH:19]=3)[N:14]=2)=[CH:8][CH:9]=1.C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O>C(Cl)Cl>[F:40][C:2]([F:39])([F:1])[C@H:3]([N:26]1[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:37])[CH3:35])[CH2:27]1)[C:4]1[CH:9]=[CH:8][C:7]2[N:6]([C:12]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:24][CH3:25])=[C:18]([CH3:23])[CH:19]=4)[N:14]=3)=[N:11][N:10]=2)[CH:5]=1
Reactant: COc1cc2nc(/C=N/Nc3ccc([C@@H](N4CC[C@H](NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)ccc2cc1C
Agent: O=Ic1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc2nc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)ccc2cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.9 %

Procedure:
To tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-((E)-2-((7-methoxy-6-methylquinolin-2-yl)methylene)hydrazinyl)pyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (278 mg, 0.498 mmol) in DCM was added iodosobenzene diacetate (208 mg, 0.647 mmol) and the reaction was stirred at ambient temperature for 2 hours. After concentration, the residue was purified by reverse phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 25 column volumes) to yield tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(7-methoxy-6-methylquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (130 mg, 46.9% yield) as a beige solid