Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:36]5[NH:37][C:38]([CH:41]6[CH2:45][CH2:44][CH2:43][N:42]6[C:46]([O:48][CH2:49][C:50]6[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=6)=[O:47])=[N:39][CH:40]=5)[CH:32]=4)[CH:27]=3)=[CH:22][CH:21]=2)=[CH:18][N:19]=1)=O)(C)(C)C.Cl.[CH3:57][O:58][C:59]([NH:61][CH:62]([CH:66]1[CH2:71][CH2:70][O:69][CH2:68][CH2:67]1)[C:63]([OH:65])=O)=[O:60].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[CH2:49]([O:48][C:46]([N:42]1[CH2:43][CH2:44][CH2:45][CH:41]1[C:38]1[NH:37][C:36]([C:31]2[CH:30]=[CH:29][C:28]3[C:33](=[CH:34][CH:35]=[C:26]([C:23]4[CH:24]=[CH:25][C:20]([C:17]5[NH:16][C:15]([CH:9]6[CH2:10][C:11]([F:14])([F:13])[CH2:12][N:8]6[C:63](=[O:65])[CH:62]([NH:61][C:59]([O:58][CH3:57])=[O:60])[CH:66]6[CH2:71][CH2:70][O:69][CH2:68][CH2:67]6)=[N:19][CH:18]=5)=[CH:21][CH:22]=4)[CH:27]=3)[CH:32]=2)=[CH:40][N:39]=1)=[O:47])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)OCc6ccccc6)[nH]5)ccc4c3)cc2)[nH]1
Reactant: COC(=O)NC(C(=O)O)C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: COC(=O)NC(C(=O)N1CC(F)(F)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)OCc6ccccc6)[nH]5)ccc4c3)cc2)[nH]1)C1CCOCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 45.3 %

Procedure:
To a solution of 2-[5-(4-{6-[2-(1-Benzyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-1H-imidazol-2-yl]-4,4-difluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (0.25 g, 0.34 mmol) in CH2Cl2 (3.5 mL) and MeOH (0.25 mL) was added HCl (in dioxanes, 4 M, 1.7 mL, 7.8 mmol). The solution was stirred at room temperature for 2.5 h and concentrated to dryness. The resulting solid was slurried in CH2Cl2 (3 mL) and DMF (1 mL). Methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (0.11 g, 0.50 mmol), HATU (0.15 g, 0.40 mmol), and DIPEA (0.3 mL, 1.7 mmol) were added. The resulting solution was stirred at room temperature for 18 h. The solution was diluted with CH2Cl2 and washed with saturated sodium bicarbonate. The organic layer was dried over Na2SO4 and concentrated. The crude oil was purified by column chromatography (SiO2, 2→20% MeOH in CH2Cl2), followed by preparative HPLC (Gemini, 15→50% MeCN in H2O (0.1% TFA)) to provide 2-(5-{6-[4-(2-{4,4-Difluoro-1-[2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid benzyl ester (0.13 g, 46%). LCMS-ESI+: calc'd for C47H47F2N7O6: 843.36 (M+); Found: 844.78 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([N+:15]([O-])=O)[CH:3]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:15][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)/C=C/c1ccc(C)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(C)cc1N
Yield: 95.6 %

Procedure:
Ethyl (2E)-3-(4-methyl-2-nitrophenyl)-2-propenoate D141 (0.500 g, 2.126 mmol), iron (0.593 g, 10.63 mmol) and ammonium chloride (0.057 g, 1.063 mmol) in ethanol (11 mL) and water (2 mL) was heated at reflux for 2 hours. The mixture was cooled and filtered through a pad of kieselguhr. The filtrate was concentrated and the residue diluted with ethyl acetate, washed with water and dried (MgSO4). Filtration and evaporation of solvent afforded a bright yellow solid (0.417 g, 96%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:32])[CH3:2].[C:34]([C:36]1[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][CH:37]=1)#[CH:35].C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:17]=[C:16]([C:35]#[C:34][C:36]3[CH:37]=[CH:38][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:40][CH:41]=3)[CH:15]=2)=[CH:9][C:8]=1[CH3:32])[CH3:2]
Reactant: C#Cc1ccc(S(C)(=O)=O)cc1
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(Oc3ncccc3C(F)(F)F)c2)cc1C
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(S(C)(=O)=O)cc3)cc(Oc3ncccc3C(F)(F)F)c2)cc1C

Procedure:
The title product was prepared from {4-[3-Bromo-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (250 mg; 0.46 mmol) and 1-Ethynyl-4-methanesulfonyl-benzene (249.2 mg; 1.38 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 197 mg (67%). HPLC-MS: m/z: 642.4 (M+H)+; Rt: 2.73 min
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][NH:7][N:6]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][N:7]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:6]=1)=[O:4]
Reactant: BrCCc1ccccc1
Reactant: COC(=O)c1n[nH]cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1nn(CCc2ccccc2)cc1[N+](=O)[O-]
Yield: 65.5 %

Procedure:
430 mg (2.5 mM) of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester was dissolved in 4 ml of N,N-dimethylformamide, to which 0.41 ml (3 mM) of (2-bromoethyl)benzene and 1.6 g (5.0 mM) of cesium carbonate were added dropwise, and the mixture was stirred under a nitrogen atmosphere for a day. The solvent was distilled off under reduced pressure, and the resultant was extracted with ethyl acetate and brine. The organic solvent layer was dried over anhydrous sodium sulfate, filtered, and then distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane:ethyl acetate=5:1), to obtain 506 mg (65.5%) of the title compound and 218 mg (31.2%) of the compound of Preparative Example 10.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[NH2:13][C:14]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26](=[O:39])[C@@H:27]([CH2:29][CH2:30][CH2:31][NH:32][C:33]([NH2:38])=[N:34][N+:35]([O-:37])=[O:36])[NH2:28])=[CH:20][CH:19]=1)=[O:15].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:13][C:14]([NH:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][NH:25][C:26](=[O:39])[C@@H:27]([CH2:29][CH2:30][CH2:31][NH:32][C:33]([NH2:38])=[N:34][N+:35]([O-:37])=[O:36])[NH:28][C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)=[CH:22][CH:23]=1)=[O:15]
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: NC(=O)NCc1ccc(CNC(=O)[C@H](N)CCCNC(N)=N[N+](=O)[O-])cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Product: NC(=O)NCc1ccc(CNC(=O)[C@@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)Cc2ccc(O)cc2)cc1
Yield: 90 %

Procedure:
Prepared analogously to Example 14c) from 4-hydroxybenzene acetic acid, (R)-N-[[4-(aminocarbonylaminomethyl)phenyl]methyl]-N5 -[amino(nitroimino)methyl]-ornithinamidehydrochloride and TBTU in a yield of 90% of theory. Colourless crystals, Mp. 168-170° C.
Reaction SMILES: [CH3:1][C:2]1([CH2:16][CH2:17][CH2:18][C:19]([Cl:34])([CH3:33])[CH2:20][CH2:21][CH2:22][C:23]([Cl:32])([CH3:31])[CH2:24][CH2:25][CH2:26][C:27]([Cl:30])([CH3:29])[CH3:28])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([CH3:14])=[C:7]([OH:13])[C:8]=2[CH3:12])[O:3]1.CN(C1C=CC=CN=1)C.[C:44](OC(=O)C)(=[O:46])[CH3:45].C(=O)([O-])[O-].[Na+].[Na+].C(=O)=O>CCCCCC.O.C(N(CC)CC)C>[C:44]([O:13][C:7]1[C:8]([CH3:12])=[C:9]2[C:4](=[C:5]([CH3:15])[C:6]=1[CH3:14])[O:3][C:2]([CH3:1])([CH2:16][CH2:17][CH2:18][C:19]([Cl:34])([CH3:33])[CH2:20][CH2:21][CH2:22][C:23]([Cl:32])([CH3:31])[CH2:24][CH2:25][CH2:26][C:27]([Cl:30])([CH3:28])[CH3:29])[CH2:11][CH2:10]2)(=[O:46])[CH3:45]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCCC(C)(Cl)CCCC(C)(Cl)CCCC(C)(C)Cl)O2
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCCCCC
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(CCCC(C)(Cl)CCCC(C)(Cl)CCCC(C)(C)Cl)O2
Temperature: 25 °C
Yield: 93 %

Procedure:
The product obtained in Example 3 (2.1 g), dimethylaminopyridine (150 mg) and triethylamine (10 cc) are introduced, under an argon atmosphere, into a three-neck flask and acetic anhydride (6 cc) is then added rapidly, with stirring, at a temperature of 25° C. After 1 hour's stirring, water (20 cc) is added and the reaction mixture is thereafter neutralised by gradual addition of sodium carbonate until the evolution of carbon dioxide gas ceases. The reaction mixture is extracted with ethyl acetate (twice 50 cc). The organic phase is washed with a 0.1N aqueous hydrochloric acid solution (3 times 50 cc). The organic phases are dried over magnesium sulphate. After filtration and evaporation of the solvent, the residue obtained is taken up in hexane. The precipitate which forms is filtered off. This gives a 93% yield of 2,5,7,8-tetramethyl-2-(4',8',12'-trichloro-4',8',12'-trimethyl-tridecyl)-chroman-6-ol acetate, melting at 95°-105° C.
Reaction SMILES: [S:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)(=[O:4])(=[O:3])[NH2:2].Cl[C:19]1[CH:24]=[C:23]([O:25][C@@H:26]([C@@H:28]2[CH2:32][O:31][C:30]([CH3:34])([CH3:33])[O:29]2)[CH3:27])[N:22]=[C:21]([S:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:38]=2[F:44])[N:20]=1>>[F:44][C:38]1[C:39]([F:43])=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][S:35][C:21]1[N:20]=[C:19]([NH:2][S:1]([N:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]2)(=[O:3])=[O:4])[CH:24]=[C:23]([O:25][C@@H:26]([C@@H:28]2[CH2:32][O:31][C:30]([CH3:33])([CH3:34])[O:29]2)[CH3:27])[N:22]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(N)(=O)=O)CC1
Reactant: C[C@@H](Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1)[C@@H]1COC(C)(C)O1
Product: C[C@@H](Oc1cc(NS(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)nc(SCc2cccc(F)c2F)n1)[C@@H]1COC(C)(C)O1

Procedure:
The subtitle compound was prepared from 1,1-dimethylethyl 4-sulfamoylpiperazine-1-carboxylate (the product of example 15, step i), 0.26 g) and 4-chloro-2-[(2,3-difluorobenzyl)thio]-6-{(1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethoxy}pyrimidine (the product of Example 47, step i) (0.21 g) according to the procedure outlined in Example 1, step iv). Yield: 0.28 g
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[BH4-].[Na+].B(F)(F)F.CCOCC>O1CCCC1>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([S:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[CH2:14][OH:15])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(OC)cc(Sc2ccccc2C(=O)O)c1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(OC)cc(Sc2ccccc2CO)c1
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
To a stirred solution of 12.3 g of the 2-(3,5-dimethoxyphenylthio)benzoic acid, prepared in Example 1, in 50 ml of anhydrous tetrahydrofuran was added 1.8 g of sodium borohydride portionwise at 0° C. After 30 minutes, the resulting solution was treated with 6.3 ml of BF3. Et2O at the same temperature and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and dilute hydrochloric acid, and the ethyl acetate layer was successively washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The concentrate was purified by silica gel column chromatography (eluting solvent; hexane:ethyl acetate=3:1) to give 8.3 g (71%) of a compound of the indicated formula (11).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:23][CH2:22][N:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18]([C:19]([OH:21])=O)=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.[Cl-].[NH4+]>[C:1]([O:5][C:6]([N:8]1[CH2:23][CH2:22][N:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18]([C:19]([N:35]3[CH2:36][CH2:37][CH:32]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[O:25][CH3:24])[CH2:33][CH2:34]3)=[O:21])=[C:10]2[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccccc1C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCn2c(c(C(=O)O)c3ccccc32)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1ccccc1C1CCN(C(=O)c2c3n(c4ccccc24)CCN(C(=O)OC(C)(C)C)C3)CC1
Reaction time: 3 h
Yield: 55.5 %

Procedure:
To a solution of 0.10 g (0.32 mmol) 3,4-dihydro-1H-pyrazino[1,2-a]indole-2,10-dicarboxylic acid 2-tert-butyl ester, 0.067 g (0.35 mmol) 4-(2-methoxyphenyl)-piperidine and 0.051 g (0.38 mmol) 1-hydroxybenzotriazole in 3.5 ml N,N-dimethylformamide were added 0.073 g (0.38 mmol) N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride at room temperature. After stirring for 3 h the reaction mixture was diluted with saturated aqueous ammonium chloride solution and extracted with tert-butyl methyl ether (2×50 ml). The combined organic layers were washed with 1 M sodium hydroxide solution (1×30 ml) and water (1×30 ml), dried over sodium sulfate, concentrated in vacuo and purified by flash-chromatography (aminopropyl-modified silica gel, n-heptane/ethyl acetate) to give the title compound (0.087 g, 56%) as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CO[CH2:12][CH2:13][O:14][CH3:15]>C([O-])(O)=O.[Na+].CCOCC>[CH3:6][C:3]1[CH:4]=[CH:12][C:13]2[O:14][C:15]([C:2]3[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=3[C:4]#[N:5])=[CH:8][C:9]=2[CH:2]=1
Reactant: N#Cc1ccccc1Br
Reactant: COCCOC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ccc2oc(-c3ccccc3C#N)cc2c1
Temperature: 25 °C

Procedure:
Intermediate 1 (20 g) was added to a stirred solution of 2-bromobenzonitrile (10.34 g) and tetrakistriphenylphosphine palladium (0) (1.5 g) in DME (200 ml) and 8% NaHCO3 (50 ml) at reflux under nitrogen. Further catalyst (1.5 g) was added and the reaction continued overnight. The reaction was cooled to room temperature and diluted with ether (200 ml). The organic layer was separated, washed with water (3×100 ml) and dried. Filtration and evaporation gave a white solid which was purified by chromatography eluting with system A (1:9) to give the title compound (10.58 g) as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(OCC)(=O)C>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[C:19]2[C:14]=1[N:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][CH:2]([NH:1][CH2:34][C:32]2[CH:31]=[CH:30][C:27]3[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=3[N:33]=2)[CH2:7][CH2:6]1
Reactant: NC1CCN(CCn2c(=O)cnc3c(F)cc(F)cc32)CC1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1COc2ccc(CNC3CCN(CCn4c(=O)cnc5c(F)cc(F)cc54)CC3)nc2N1
Temperature: 0 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
To a solution of 1-[2-(4-aminopiperidin-1-yl)ethyl]-5,7-difluoroquinoxalin-2(1H)-one (Intermediate 192, 0.158 g) in methanol (10 mL) were added 3 Å molecular sieve power (0.15 g) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (92 mg). After 2 hours at reflux, the reaction was cooled to 0° C. and NaBH(OAc)3 (0.19 g) was added. The reaction was allowed to warm to room temperature and was stirred overnight. It was diluted with ethyl acetate, filtered, washed with saturated solutions of Na2CO3 and brine, dried over sodium sulfate and concentrated. Chromatography on silica gel with 0-20% methanol in dichloromethane. Fractions containing product were collected, concentrated, dissolved in a minimum of CH2Cl2, precipitated with diethyl ether, and filtered to yield 104 mg of product.
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]([NH:16][C:17]([C:19]1[S:23][C:22]([NH2:24])=[N:21][C:20]=1[CH3:25])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([NH:16][C:17]([C:19]1[S:23][C:22]([NH:24][C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:7])=[N:21][C:20]=1[CH3:25])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)C2CCCC2)sc1C(=O)NCc1ccccc1
Yield: 38 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use cyclopentanecarbonyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 38% yield; 1H NMR (CDCl3, 300 MHz) δ 9.56 (s, br, 1H), 7.35-7.24 (m, 5H), 5.92 (s, br, 1H), 4.56 (d, J=5.7 Hz, 2H), 2.81-2.69 (m, 1H), 2.62 (s, 3H), 1.97-1.72 (m, 8H); MS (ES+) m/z 344.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.CON(C)[C:17](=[O:27])[CH2:18][O:19][CH:20]([CH:25]=[CH2:26])[C:21]([F:24])([F:23])[F:22]>C1COCC1>[F:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:17](=[O:27])[CH2:18][O:19][CH:20]([CH:25]=[CH2:26])[C:21]([F:23])([F:22])[F:24]
Reactant: C=CC(OCC(=O)N(C)OC)C(F)(F)F
Reactant: Fc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CC(OCC(=O)c1ccccc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.9 %

Procedure:
To a solution 1-bromo-2-fluorobenzene (0.967 kg, 5.527 mol) in THF (6.2 L) at −75° C., was added n-butyllithium (2.50 M in hexane, 2.09 L, 5.22 mol) while maintaining temperature below −65° C. (ca. 100 min.). After 15 mins, a solution of N-methoxy-N-methyl-2-(1,1,1-trifluorobut-3-en-2-yloxy)acetamide (0.949 kg, 4.178 mol) in THF (1.6 L) was added while maintaining temperature below −65° C. (ca. 70 min.). After 2.5 h at −78° C., the reaction was quenched by addition of sat. aq. NH4Cl (3.0 L) and methyl tert-butyl ether (9.0 L). The reaction mixture was warmed to rt, the aq. phase was extracted again with methyl tert-butyl ether (2.5 L). The organic phases were combined, washed with sat. aq. NaCl (2×0.3 L) and concentrated under vacuum to afford the title compound as an oil (1.007 kg, 80.0%). 1H NMR (500 MHz, CDCl3) δ ppm 7.96 (td, J=7.6, 1.8 Hz, 1H), 7.62-7.54 (m, 1H), 7.33-7.25 (m, 1H), 7.20-7.12 (m, 1H), 5.86 (ddd, J=17.5, 10.4, 7.3 Hz, 1H), 5.60 (dd, J=20.5, 13.8 Hz, 2H), 4.91-4.76 (m, 2H), 4.39 (dq, J=12.8, 6.4 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ ppm 193.55, 162.14 (d, JCF=254.1 Hz), 135.36 (d, JCF=9.2 Hz), 130.62 (d, JCF=3.2 Hz), 128.49, 124.85 (d, JCF=3.3 Hz), 123.89, 122.93, 122.72 (d, JCF=24.5 Hz), 116.50 (d, JCF=23.7 Hz), 78.97 (q, JCF=31.4 Hz), 74.56 (d, JCF=12.4 Hz). HRMS Calculated for C12H10F4O2 [M+H]+ 263.0695. found 263.0709.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[N:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[C:27](O)=[O:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][N:21]=3)=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnccn1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1cnccn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 2-pyrazinecarboxylic acid as starting materials, MS (LC/MS): 409.6 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[C:16]3[CH2:19][CH2:20][CH2:21][C:15]=3[N:14]([CH3:22])[C:13]2=[O:23])=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[Na+].[CH3:25][O:26][CH2:27]Cl>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[C:16]3[CH2:19][CH2:20][CH2:21][C:15]=3[N:14]([CH3:22])[C:13]2=[O:23])=[CH:7][C:3]=1[C:4]([O:6][CH2:25][O:26][CH3:27])=[O:5]
Reactant: COCCl
Reactant: Cn1c2c(c(=O)n(-c3cc(C(=O)[O-])c(Cl)cc3F)c1=O)CCC2
Agent: [Na+]
Product: COCOC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)c(F)cc1Cl

Procedure:
using sodium 2-chloro-4-fluoro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate and chlorodimethyl ether there is obtained methoxymethyl 2-chloro-4-fluoro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, 1H-NMR (CDCl3, 400 MHz) 7.93 ppm (d, 1H), 7.36 ppm (d, 1H), 5.45 ppm (s, 2H), 3.54 ppm (s, 3H), 3.41 ppm (s, 3H), 2.95 ppm (m, 2H), 2.81 ppm (m, 2H), 2.17 ppm (m, 2H),
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([CH3:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].B(F)(F)F.CC[O:23]CC.[OH-].[Na+].OO.Cl>C1COCC1.O>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([CH3:14])[CH:12]([OH:23])[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1=CCN(Cc2ccccc2)CC1
Reactant: CCOCC
Agent: Cl
Agent: FB(F)F
Agent: OO
Solvent: O
Solvent: C1CCOC1
Product: CC1CCN(Cc2ccccc2)CC1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of the product from Method B (72.45 grams/0.387 mol) dissolved in 240 mL of THF was added 21.4 grams of NaBH4 and the mixture cooled to 0° C. A solution of borontrifluoride etherate (109.4 mL dissolved in 200 mL of THF) was then added dropwise over 1.5 hours. Once added, the reaction mixture was brought to room temperature and stirred for 2 hours. The reaction was again cooled to 0° C. and 29.3 mL of water were added dropwise over 15 minutes followed by dropwise addition of 2N sodium hydroxide (97.5 mL) over 20 minutes. The resulting mixture stirred at 0° C. for 40 minutes and was then brought to room temperature. Hydrogen peroxide (30%) (97.5 mL) was added dropwise at a rate so as not to exceed 50° C. in the reaction mixture (approximately 30 minutes). When the addition was complete, the reaction mixture stirred for 10 minutes, then was cooled to 0° C. Concentrated hydrochloric acid (97.5 mL) was added over 5 minutes, the reaction mixture was reduced to one third its volume in vacuo, and the pH adjusted to 9-10 with 6N sodium hydroxide (aq). The resulting mixture was extracted three times with ether, the combined ether layers dried over MgSO4 and evaporated to dryness in vacuo affording 65.32 grams (79%) of the title compound as yellow oil. LRMS: 206.1 (M+1).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@H:10]1[CH2:14][CH2:13][C@@H:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[N:11]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[H][H]>CO.[Pd]>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][C@@H:12]2[CH2:13][CH2:14][C@H:10]([C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:11]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:21][CH:20]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc([N+](=O)[O-])cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(N)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1

Procedure:
A 500 mL parr shaker flask was charged with 10% Pd/c (4.75 g) and to this was added 100 mL of methanol to cover the catalyst. A solution of the nitro intermediate from Step I (8.5 g, 18.5 mmol) in methanol (80 mL) was then added to the suspension, followed by 15.4 mL of 1.0 M hydrogen chloride in methanol solution. The reaction vessel was set under 50 PSI hydrogen gas and the mixture aggitated overnight. An aliquot was taken and analyzed through the LC-MS which showed complete reaction.