Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:10][C@H:9]([NH:11][C:12](=[O:16])[C@@H:13]([OH:15])[CH3:14])[C:8](=[O:17])[N:7]([CH3:18])[C:6]2[CH:19]=[CH:20][CH:21]=[CH:22][C:5]1=2)(=[O:3])[CH3:2].Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:25]>N1C=CC=CC=1>[N+:33]([C:30]1[CH:29]=[CH:28][C:27]([O:26][C:24](=[O:25])[O:15][C@H:13]([C:12](=[O:16])[NH:11][C@@H:9]2[C:8](=[O:17])[N:7]([CH3:18])[C:6]3[CH:19]=[CH:20][CH:21]=[CH:22][C:5]=3[N:4]([C:1](=[O:3])[CH3:2])[CH2:10]2)[CH3:14])=[CH:32][CH:31]=1)([O-:35])=[O:34]
Reactant: CC(=O)N1C[C@H](NC(=O)[C@H](C)O)C(=O)N(C)c2ccccc21
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Product: CC(=O)N1C[C@H](NC(=O)[C@H](C)OC(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N(C)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.2 %

Procedure:
A solution of 50 mg (0.16 mmol) of (S)—N—((S)-5-acetyl-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-hydroxy-propionamide in 1.5 ml of pyridine was treated with 39 mg (0.18 mmol) of 4-nitrophenyl chloroformate, and the mixture was stirred at room temperature for 18 h. For the working-up, the solvent was evaporated and the residue chromatographed on silica gel using a 3:1-mixture of heptane and ethyl acetate as the eluent. There were obtained 31 mg (40% of theory) of carbonic acid (S)-1-((S)-5-acetyl-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamoyl)-ethyl ester 4-nitro-phenyl ester; MS: m/e=488 (M+NH4)+. The ester was treated with 0.7 ml of 2,2,3,3,3-pentafluoro-propylamine and the mixture was stirred at room temperature for 36 h. For the working-up, 3 ml of ethyl acetate were added and the solution was washed with a saturated solution of sodium carbonate and a saturated solution of sodium chloride. The organic layer was dried over sodium sulphate and evaporated under reduced pressure. For purification, the crude product was chromatographed on silica gel using a gradient of a 98:2- to 95:5-mixture of dichloromethane and methanol as the eluent. There were obtained 12 mg (38% of theory) of the title compound as a white solid; MS: m/e=498 (M+NH4)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[S:3][CH2:4][CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7].[CH3:13]O>>[CH3:13][O:9][C:8](=[O:10])[C@H:6]([CH2:5][CH2:4][S:3][C:2]([F:11])([F:1])[F:12])[NH2:7]
Reactant: CO
Reactant: N[C@@H](CCSC(F)(F)F)C(=O)O
Product: COC(=O)[C@@H](N)CCSC(F)(F)F

Procedure:
The compounds of the present invention can be synthesized from trifluoromethionine, for example. For example, trifluoromethionine amide(WY-200) can be obtained by: reacting trifluoromethionine with methanol to produce trifluoromethionine methyl ester; and reacting ammonia with the trifluoromethionine methyl ester.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[S:13][C:12]([C:14](=[O:18])[CH2:15][C:16]#[N:17])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH4+].[Cl-]>C(O)=O.CCN(CC)CC>[CH:1]1([CH2:7][O:8][C:9]2[S:13][C:12]([C@H:14]([OH:18])[CH2:15][C:16]#[N:17])=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#CCC(=O)c1ccc(OCC2CCCCC2)s1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: O=CO
Product: N#CC[C@@H](O)c1ccc(OCC2CCCCC2)s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(1R,2R)—RuCl(TsDPEN)(p-cymene) (6.3 mg, 0.01 mmol) was added to a degassed solution of 3-(5-(cyclohexylmethoxy)thiophen-2-yl)-3-oxopropanenitrile (4) (0.27 g, 1.03 mmol) in HCOOH:Et3N (1:1, 4.0 M in EtOH) and the reaction mixture was stirred at room temperature for 24 hrs. Aqueous NH4Cl (25%) was added and the mixture was extracted twice with MTBE. Combined organic layers were washed with brine and concentrated under reduced pressure. Purification by flash chromatography gave (R)-3-(5-(cyclohexylmethoxy)thiophen-2-yl)-3-hydroxypropanenitrile as an off-white solid which was used directly in the next step. Yield (0.21 g, 77%); 1H NMR (400 MHz, CD3OD) δ 6.64-6.78 (m, 1H), 6.02-6.10 (m, 1H), 4.99-5.09 (m, 1H), 3.79-3.88 (m, 2H), 2.79-2.91 (m, 2H), 1.62-1.90 (m, 6H), 1.12-1.39 (m, 3H), 0.98-1.12 (m, 2H).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=1)(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:48][C@@H:49]([CH2:63][C:64]1[CH:69]=[C:68]([F:70])[CH:67]=[C:66]([F:71])[CH:65]=1)[C@H:50]([OH:62])[CH2:51][NH:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([CH2:60][CH3:61])[CH:55]=1>C(Cl)Cl>[F:70][C:68]1[CH:69]=[C:64]([CH:65]=[C:66]([F:71])[CH:67]=1)[CH2:63][C@H:49]([NH:48][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:6]([CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])=[N:7][CH:8]=1)[C@H:50]([OH:62])[CH2:51][NH:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([CH2:60][CH3:61])[CH:55]=1
Reactant: CS(=O)(=O)Cc1ccc(C(=O)O)cn1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2ccc(CS(C)(=O)=O)nc2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 36.9 %

Procedure:
To a stirred solution of 6-[(methylsulfonyl)methyl]nicotinic acid (181 mg), diisopropylethylamine (116 mg), and HBTU (341 mg) in methylene chloride (5 mL) was added a mixture of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (326 mg) and N,N-diisopropylethylamine (233 mg) in methylene chloride (5 mL). The mixture was stirred at room temperature for 15 h and concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 mL), washed with saturated sodium bicarbonate, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 5:95 to 10:90 methanol/methylene chloride) provided 165 mg of the title compound: ESI MS m/z 532 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:20]([OH:22])=O)[CH2:10][CH2:11][CH2:12][N:13]=[C:14]([NH:16][N+:17]([O-:19])=[O:18])[NH2:15])=[O:7])([CH3:4])[CH3:3].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:20](=[O:22])[C@@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH2:15])=[N:16][N+:17]([O-:19])=[O:18])[NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CCCN=C(N)N[N+](=O)[O-])C(=O)O
Reactant: NCc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: CC(C)(C)OC(=O)N[C@H](CCCNC(N)=N[N+](=O)[O-])C(=O)NCc1ccc(Cl)cc1
Yield: 87 %

Procedure:
Prepared analogously to Example 5d) from Boc-D-Arg (NO2)-OH, (4-chlorophenyl) methylamine and TBTU in a yield of 87% of theory.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=O>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH:28]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: O=Cc1cccc(-c2ccccn2)c1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-c2ccccn2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 3-(pyridin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.64 min.; [M+H]+: 402.99 g/mol.
Reaction SMILES: BrBr.[C:3]([O-])(=O)[CH3:4].[Na+].[C:8]1([CH2:14][CH2:15][NH:16][C:17]([NH2:19])=[S:18])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])O.[Na+]>CO.CC(C)CC(=O)C>[CH2:9]([C:3]1[N:19]=[C:17]([NH:16][CH2:15][CH2:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:18][CH:4]=1)[CH:8]([CH3:14])[CH3:13]
Reactant: NC(=S)NCCc1ccccc1
Reactant: CC(=O)[O-]
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: CO
Product: CC(C)Cc1csc(NCCc2ccccc2)n1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
To a solution of 4-methyl-2-pentanone (2.00 g) in methanol (10 mL) was added bromine (3.20 g) at −30° C. The mixture was allowed to warm to room temperature and stirred until the red color of bromine disappeared. To the obtained colorless solution were added sodium acetate (3.20 g) and N-(2-phenylethyl)thiourea (1.80 g) and the mixture was stirred with heating under reflux for 4 hr. A saturated aqueous sodium hydrogencarbonate solution (10 mL) was added to the reaction mixture and the mixture was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9-2:1 in volume ratio) to give the title compound (1.15 g, yield 41%) as pale-yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24](O)(=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CCCCCCCC(=O)O
Product: CCCCCCCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and octanoic acid to yield (3aR,4S,7aR)-4-octanoyloxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 296 (ester elimination ion); RT=1.60 min; UPLC Method I
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[OH:23].C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)CCC1>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:2]([O:23][C:17]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=2[F:15])[CH:3]=[CH:4][C:5]=1[N+:12]([O-:14])=[O:13]
Reactant: Oc1ccc(F)cc1F
Reactant: COC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(Oc2ccc(F)cc2F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 63.5 %

Procedure:
Methyl 5-chloro-2-nitrobenzoate (73 g, 0.34 mol), 2,4-difluorophenol (51.1 g, 0.39 mol) and potassium carbonate (73 g, 0.53 mol) in NMP (200 mL) were stirred at 160° C. for 2 h. The reaction mixture was cooled to room temperature poured into water (250 mL) and extracted into EtOAc (2×100 mL). The organic layer was washed several times with water, dried over sodium sulfate, concentrated in vacuo, and the residue was purified by flash chromatography eluting with hexane: EtOAc (95:5) to yield 66.8 g of 5-(2,4-difluoro-phenoxy)-2-nitro-benzoic acid methyl ester (1A).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[C:4]([NH2:6])=[O:5].[C:10]1([C@@H:16]([NH2:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=[N:18][C@H:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:17])[C:4]([NH2:6])=[O:5]
Reactant: C[C@H](N)c1ccccc1
Reactant: CC(C)(C)C(=O)C(N)=O
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H](N=C(C(N)=O)C(C)(C)C)c1ccccc1
Yield: 67.8 %

Procedure:
A solution of 35.0 g (271 mmol) of 3,3-dimethyl-2-oxobutyramide and 75.0 g (619 mmol) of (S)-1-phenylethylamine in 250 ml of toluene was boiled under reflux on a water separator for 92 hours. Subsequently, the solvent and excess amine were removed in a vacuum. The residual oil was crystallized from 300 ml of hexane. 51 g of crude material of melting point 96°-97° C. were obtained. After recrystallization from 400 ml of hexane there were obtained 42.7 g (68%) of analytically-pure (S)-3,3-dimethyl-2-(1-phenylethylimino)-butyramide of melting point 100°-101° C. [α]=-58.5 (c=1.0, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:54])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH2:29][CH2:30]CS(C)(=O)=O)[CH2:25][CH2:24]3)=[O:22])[C:10]([C:36]3[C:37]([O:51][CH2:52][CH3:53])=[CH:38][C:39]([Cl:50])=[C:40]([S:42]([NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])(=[O:44])=[O:43])[CH:41]=3)=[N:9]2)=[CH:4][CH:3]=1.N1(CC[OH:63])CCNCC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:54])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][OH:63])[CH2:27][CH2:28]3)=[O:22])[C:10]([C:36]3[C:37]([O:51][CH2:52][CH3:53])=[CH:38][C:39]([Cl:50])=[C:40]([S:42]([NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])(=[O:43])=[O:44])[CH:41]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1
Reactant: OCCN1CCNCC1
Product: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCO)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(5-tert-butylsulfamoyl-4-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 45) was reacted with 2-piperazin-1-yl-ethanol (Chemical Dynamics) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 25% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C36H45N5O5SCl3 [(M+H)+] 764.2202, observed 764.2198.
Reaction SMILES: [O:1]([C:9]1[CH:14]=[CH:13][C:12]([CH:15](C(OCC2C=CC=CC=2)=O)[CH2:16][CH2:17][CH2:18][NH2:19])=[CH:11][CH:10]=1)[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH3:8]>C(O)C.[Pd]>[O:1]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])=[CH:13][CH:14]=1)[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH3:8]
Reactant: COCCOCCOc1ccc(C(CCCN)C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: COCCOCCOc1ccc(CCCCN)cc1
Reaction time: 5 h
Yield: 99.1 %

Procedure:
Compound 106 (800 mg, 2.0 mmol) in ethanol (20 mL), was subjected to 1 atmosphere of H2 in the presence of 10% Palladium on carbon (100 mg, cat.) with stirring for 5 h. After standing overnight, the reaction was purged with N2 then suction filtered through celite and washed off the celite with methylene chloride. The solvents were evaporated and chromatographed (silica gel, 200:10:1 methylene chloride/methanol/concentrated ammonium hydroxide) to afford 530 mg (>99%) of amine 107. 1H NMR (300 MHz, CDCl3) δ 1.31 (br s, 2H), 1.41–1.52 (m, 2H), 1.55–1.67 (m, 2H), 2.56 (t, J=7.7 Hz, 2H), 2.70 (t, J=7.0 Hz, 2H), 3.39 (s, 3H), 3.58 (m, 2H), 3.72 (m, 2H), 3.84 (t, J=4.9 Hz, 2H), 4.12 (t, J=5.3 Hz, 2H), 6.83 (d, J=8.7 Hz, 2H), 7.07 (d, J=8.7 Hz, 2H). CI MS m/z=268 [C15H25NO3+H]+.
Reaction SMILES: C(N[C:5]1[C:6]([N+:15]([O-:17])=[O:16])=[C:7]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:8]([OH:10])=[O:9])(=O)C.[OH-:18].[K+].Cl>O>[OH:18][C:5]1[C:6]([N+:15]([O-:17])=[O:16])=[C:7]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:8]([OH:10])=[O:9]
Reactant: CC(=O)Nc1c(C)ccc(C(=O)O)c1[N+](=O)[O-]
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: Cc1ccc(C(=O)O)c([N+](=O)[O-])c1O
Yield: 93.1 %

Procedure:
A solution of 3-(acetylamino)-4-methyl-2-nitrobenzoic acid (237.5 g, 0.997 mol) and KOH (451.2 g, 8.04 mol) in water (2830 mL) was refluxed for 48 h. The dark red solution was cooled and acidified to pH 1 with concentrated HCl. The yellow solid was filtered and re-crystallized from water (1800 mL) to give the title compound (183 g, 93.4%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(N(CC)CC)C.C[C@:18]1([OH:24])[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:20]2[CH2:21][CH2:22][CH2:23][C@H:18]([OH:24])[CH2:19]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: C[C@]1(O)CCCNC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O[C@H]1CCCN(Cc2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol), triethylamine (0.84 mL, 6.0 mmol) and (S)-3-methyl-piperidin-3-ol (1.11 g, 8.0 mmol) in THF (20 mL) was stirred at ambient temperature for 16 h. The solvent was evaporated and the resultant residue diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated. The resultant residue was purified by flash chromatography (silica, Biotage 50 g column, 50-100% ethyl acetate in cyclohexane) to afford the title compound (0.8 g, 74%). 1H NMR (CDCl3, 300 MHz): 7.46-7.40 (m, 2H), 7.21-7.14 (m, 2H), 3.85-3.76 (m, 1H), 3.45 (s, 2H), 2.45 (s, 3H), 2.29-2.16 (m, 1H), 1.86-1.70 (m, 1H), 1.67-1.45 (m, 3H) plus 1 exchangeable not observed. LCMS (Method G): RT=1.42 min, M+H+=270.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3]1.[N:25]1([C:30]([O-:32])=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26]1>>[C:7]([O:31][C:30]([N:25]1[CH2:29][CH2:28][C@H:27]([O:14][C:11]2[CH:10]=[CH:9][C:8]([CH:7]3[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[O:16])[CH2:3][CH:2]3[OH:1])=[CH:13][CH:12]=2)[CH2:26]1)=[O:32])([CH3:8])([CH3:2])[CH3:6]
Reactant: O=C([O-])N1CCCC1
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccc(O)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(C3CCN(C(=O)OCc4ccccc4)CC3O)cc2)C1

Procedure:
Analogously to Method I, 0.665 g of benzyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.822 g of tert-butyl 3(R)-toluene-4-sulphonyloxy)pyrrolidine-1-carboxylate are reacted. The title compound is obtained as a white foam. Rf=0.14 (1:1 EtOAc-heptane). Rt=4.91.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([C:6]([N:12]([CH2:22][CH3:23])[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:7][C:8]([Cl:11])=[N:9]2)=[N:4][CH:3]=1.[Cu][C:25]#[N:26]>CN1C(=O)CCC1>[Cl:11][C:8]1[N:7]=[C:6]([N:12]([CH2:22][CH3:23])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:5]2=[N:4][CH:3]=[C:2]([C:25]#[N:26])[N:10]2[N:9]=1
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Cl)nn2c(Br)cnc12
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: CCN(Cc1ccc(OC)cc1)c1nc(Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 101.9 %

Procedure:
(I10B): To an oven dried 500 ml round bottom flask was added 7-bromo-2-chloro-N-ethyl-N-(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (12.5 g, 31.5 mmol) and copper(i) cyanide (9.0 g, 100 mmol). The flask was caped under nitrogen and NMP (250 mL) was added. The mixture stirred 5 min at 25° C. and the flask was evacuated and back-filled with nitrogen 3×. The reaction stirred at 135° C. (oil bath) 21 hr. The reaction cooled to 25° C., diluted with ethyl acetate (500 ml) and filter through edit bed. The bed was washed with EtoAc 3×100 ml and the filtrate washed with water 1×300 ml and brine 3×150 ml. The organics dried with sodium sulphate and remove solvent. The material was crystallized from IPA and filtered to afford 2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (11 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20]>[Pd]>[F:16][C:15]([F:18])([F:17])[O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([CH:19]=[O:20])=[CH:22][CH:23]=3)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)Oc1ccc(-c2cc(Cl)ncn2)cc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: [Pd]
Product: O=Cc1ccc(-c2cc(-c3ccc(OC(F)(F)F)cc3)ncn2)cc1

Procedure:
The compound was prepared by palladium-catalyzed arylation of the product of step 1 with 4-formylphenyl boronic acid: 1H NMR (400 MHz, CDCl3) δ 10.15 (s, 1H), 9.38 (d, J=0.9 Hz, 1H), 8.33 (d, J=8.4 Hz, 2H), 8.23 (d, J=8.5 Hz, 2H), 8.16 (d, J=0.8 Hz, 1H), 8.08 (d, J=8.8 Hz, 2H), 7.40 (d, J=8.1 Hz, 2H); EIMS m/z 344 (M+).
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([OH:5])=O.[NH:32]1[CH:36]=[CH:35][N:34]=[CH:33]1>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([N:32]1[CH:36]=[CH:35][N:34]=[CH:33]1)=[O:5]
Reactant: c1c[nH]cn1
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Product: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)n1ccnc1

Procedure:
Starting materials: 2,6,10,14,18-pentamethyl-22-oxo-2,6,10,14,18-tricosapentaenoic acid and imidazole (imidazole/pyridine solution).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[O:21]([CH2:28][CH2:29][NH2:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OCC)C>[N+:18]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:30][CH2:29][CH2:28][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:10][CH:9]=[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:7]=2)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cnc2cc(-c3ccccc3)ccc2c1Cl
Reactant: NCCOc1ccccc1
Solvent: CCOCC
Product: O=[N+]([O-])c1cnc2cc(-c3ccccc3)ccc2c1NCCOc1ccccc1
Yield: 100.3 %

Procedure:
4-Chloro-3-nitro-7-phenylquinoline (6.0 g, 21 mmol) was treated with 2-phenoxyethylamine (3.18 g, 23.2 mmol) according to the method described in Part A of Examples 125-135. The crude solid was triturated with water (100 mL), isolated by filtration, sonicated with diethyl ether, isolated by filtration, and dried for two hours in a vacuum oven at 40° C. to provide 8.12 g of (3-nitro-7-phenylquinolin-4-yl)-(2-phenoxyethyl)amine as a yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CN(C=O)C>[C:8]1([CH2:7][O:6][C:5]([NH:4][CH2:3][CH2:2][N:15]2[CH2:16][CH2:17][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:19][CH2:20]2)=[O:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(NCCBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCN(CCNC(=O)OCc2ccccc2)CC1
Yield: 93.3 %

Procedure:
A mixture of phenylmethyl (2-bromoethyl)carbamate (12.9 g, 50 mmol) (prepared from phenylmethyl (2-bromoethyl)carbamate and phenylmethyl chloridocarbonate according to the method of A. J. Brouwer and R. M. J. Liskamp, European Journal of Organic Chemistry (2005), (3), 487-495), 1,1-dimethylethyl 4-piperidinylcarbamate (10 g, 50 mmol), potassium carbonate (6.9 g, 50 mmol), acetonitrile (100 ml) and DMF (30 ml) was heated at 40° C. for 2.5 days. The solvents were decanted from inorganic residues and evaporated. The residue was partitioned between ethyl acetate and dilute brine. The organic extract was dried (MgSO4) and evaporated affording a white solid (17.6 g, 93%).