Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:41][CH2:40][C:17]3([N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][N:19]([CH2:28][C:29]4[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=4)[C:32]([O:34]C)=[O:33])[C:18]3=[O:39])[CH2:16][CH2:15]2)[C:3]1=[O:42].[OH-].[Li+].CO>O>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][C:17]3([N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][N:19]([CH2:28][C:29]4[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=4)[C:32]([OH:34])=[O:33])[C:18]3=[O:39])[CH2:40][CH2:41]2)[C:3]1=[O:42]
Reactant: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)n(C)c5ccccc54)CC3)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1c(=O)n(CCCN2CCC3(CC2)C(=O)N(Cc2cccc(C(=O)O)c2)CN3c2ccccc2)c2ccccc21
Temperature: 35 °C
Reaction time: 24 h
Yield: 17.6 %

Procedure:
A solution of methyl 3-((8-(3-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (326 mg, 0.575 mmol, 1 equiv) and lithium hydroxide (48.3 mg, 1.15 mmol, 2.0 equiv) in a 4:1 mixture of methanol and water (5 ml t/v) was stirred at 35° C. for 24 hrs. The reaction was concentrated in vacuo and purified using preparatory high performance liquid chromatography. The combined pure fractions were lyophilized to afford the acetate salt of the title compound as a white solid (56 mg, 17%); 1H NMR (400 MHz, DMSO-d6): δ 1.61 (d, 2H, J=13.6 Hz), 1.84 (t, 2H, J=6.8 Hz); 2.37 (t, 2H, J=7.2 Hz, J=6.4 Hz); 2.54-2.59 (m, 2H); 2.66-2.73 (m, 4H); 3.32 (s, 3H); 3.91 (t, 2H, J=6.8 Hz); 4.58 (s, 2H); 4.60 (s, 2H); 6.76 (t, 1H, J=7.2 Hz); 6.85 (d, 2H, J=8 Hz); 7-7.07 (m, 2H); 7.12-7.15 (m, 1H); 7.2-7.26 (m, 3H); 7.47-7.53 (m, 2H); 7.86-7.88 (m, 2H); 12.9 (bs, 1H); MS for C32H35N5O4 m/z 554.05 (M+H)+.
Reaction SMILES: [CH:1]([O:5][C:6]1[CH:7]=[C:8]([CH:26]=[CH:27][CH:28]=1)[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24]Cl)=[CH:12][N:11]=1)([CH2:3][CH3:4])[CH3:2].[N-:29]=[N+:30]=[N-:31].[Na+]>CS(C)=O.C(OCC)(=O)C>[N:29]([CH2:24][C:13]1[C:14]2[C:19](=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[C:10]([CH2:9][C:8]2[CH:26]=[CH:27][CH:28]=[C:6]([O:5][CH:1]([CH2:3][CH3:4])[CH3:2])[CH:7]=2)=[N:11][CH:12]=1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: CCC(C)Oc1cccc(Cc2ncc(CCl)c3cc(OC)c(OC)cc23)c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCC(C)Oc1cccc(Cc2ncc(CN=[N+]=[N-])c3cc(OC)c(OC)cc23)c1
Temperature: 65 °C
Yield: 54.1 %

Procedure:
A solution of 1-(3-sec-butoxy-benzyl)-4-chloromethyl-6,7-dimethoxy-isoquinoline (1.0 g, 2.5 mmol) in dimethylsulfoxide (2 mL) was added to a solution of sodium azide (813 mg, 12.5 mmol) in dimethylsulfoxide (10 mL) prewarmed to 65° C. The solution was stirred at 65° C. for 1½ hrs. The reaction mixture was cooled and dissolved in ethyl acetate (100 mL). This ethyl acetate solution was washed with saturated aqueous sodium bicarbonate solution (2×20 mL), saturated aqueous sodium chloride solution (20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford 4-azidomethyl-1-(3-sec-butoxy-benzyl)-6,7-dimethoxy-isoquinoline (550 mg, 54%) as a light yellow solid which was used without further purification: APCI-MS m/e calcd for C23H26N4O3 (M+H+) 407.5, found 406.9; 1H NMR (300 MHz) compatible.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH2:11])=[N:6]2.Br[C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[O:30][CH3:31].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC([O-])(C)C.[Na+]>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]>[F:29][C:27]1[CH:26]=[CH:25][C:24]([O:30][CH3:31])=[C:23]([NH:11][C:7]2[N:8]=[CH:9][C:10]3=[C:2]([CH3:1])[N:3]=[C:4]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=4)[N:5]3[N:6]=2)[CH:28]=1
Reactant: COc1ccc(F)cc1Br
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)n2nc(N)ncc12
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: COc1ccc(F)cc1Nc1ncc2c(C)nc(-c3cccc(C(F)(F)F)c3)n2n1
Yield: 29.3 %

Procedure:
In a similar manner as described for Example 41, 5-methyl-7-[3-(trifluoromethyl)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (Intermediate 45) (0.025 g, 0.09 mmol), 2-bromo-4-fluoro-1-methoxybenzene (0.017 g, 0.09 mmol), Pd2(dba)3 (0.008 g, 0.01 mmol), 2-(Di-t-butylphosphino)biphenyl (0.008 g, 0.03 mmol), and NaOtBu (0.011 g, 0.11 mmol) in 1,4-dioxane (1 mL) gave N-(5-fluoro-2-methoxyphenyl)-5-methyl-7-[3-(trifluoromethyl)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (0.011 g) as a yellow solid. 1H NMR (Acetone-d6): δ9.17 (s, 1H), 8.83-8.79 (m, 1H), 8.76 (s, 1H), 8.16 (dd, J=10.9, 3.0 Hz, 1H), 7.87-7.74 (m, 3H), 7.09-7.04 (m, 1H), 6.83-6.76 (m, 1H), 3.98 (s, 3H), 2.59 (s, 3H). MS m/z 418 (M+1).
Reaction SMILES: C([O:3][P:4]([C:9]1[C:10](=[O:26])[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:14]([Cl:25])[CH:13]=2)(=[O:8])[O:5]CC)C.Br[Si](C)(C)C>C(#N)C>[Cl:25][C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[C:9]([P:4](=[O:3])([OH:5])[OH:8])[C:10](=[O:26])[NH:11]2)=[CH:16][C:15]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOP(=O)(OCC)c1cc2cc(-c3ccccc3)c(Cl)cc2[nH]c1=O
Agent: C[Si](C)(C)Br
Solvent: CC#N
Product: O=c1[nH]c2cc(Cl)c(-c3ccccc3)cc2cc1P(=O)(O)O

Procedure:
The compound obtained in Example 1 (130 mg, 0.33 mmol) is suspended in 10 ml of anhydrous acetonitrile, 0.435 ml (3.3 mmol) of bromotrimethylsilane are added and the mixture is stirred at reflux for 1 hour. Evaporation to dryness is carried out. The residue is dried in vacuo and dissolved in methanol. The solution is stirred for 20 minutes, evaporated to dryness, taken up in acetonitrile, and triturated to obtain a homogeneous precipitate. The white precipitate is filtered off and rinsed with a small amount of acetonitrile and then ether to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([CH3:16])[CH:10]=2)[N:4]=1.[C:17]([CH2:20][C:21](=O)[CH3:22])(=[O:19])[CH3:18]>C(O)(=O)C>[CH3:1][O:2][C:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:21](=[CH:20][C:17](=[O:19])[CH3:18])[CH3:22])=[C:11]([CH3:16])[CH:10]=2)[N:4]=1
Reactant: COc1nn(-c2ccc(N)c(C)c2)c(=O)o1
Reactant: CC(=O)CC(C)=O
Solvent: CC(=O)O
Product: COc1nn(-c2ccc(NC(C)=CC(C)=O)c(C)c2)c(=O)o1

Procedure:
The latter compound was obtained by reacting 5-methoxy-3-(4-amino-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one with equimolar amounts of acetylacetone in glacial acetic acid at 80° C. and was isolated by precipitation by adding water and filtration.
Reaction SMILES: CN1CCOCC1.S(Cl)(Cl)=O.[CH3:12][C:13]1([CH3:25])[S:17][C@@H:16]2[C@H:18](N)[C:19](=[O:20])[N:15]2[C@H:14]1[C:22]([OH:24])=[O:23]>CN(C)C=O.O>[CH3:12][C:13]1([CH3:25])[S:17][C@@H:16]2[CH2:18][C:19](=[O:20])[N:15]2[C@H:14]1[C:22]([OH:24])=[O:23]
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Solvent: O
Solvent: CN1CCOCC1
Solvent: O=S(Cl)Cl
Product: CC1(C)S[C@@H]2CC(=O)N2[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 6.5 %

Procedure:
To a slurry of 3.12 g. of 4-pyridylformimidoylglycyl-d-phenylglycine in 40 ml. of dimethylformamide cooled to -20° C. is added 1.0 g. of N-methylmorpholine followed by 1.2 g. of thionyl chloride. The resulting clear solution is stirred for 45 min. at -15° to -20° C., and is subsequently treated with 2.16 g. of 6-aminopenicillanic acid in 20 ml. of water, 10 ml. of dimethylformamide at pH 7.8. After allowing the reaction mixture to stir for 10 min. at -10° C., it is allowed to warm to room temperature. High-pressure-liquid-chromatography of the solution indicates a yield of 335 mg. of 6- D-2-phenyl-2-(4-pyridylformimidoylaminoacetamido)acetamido!penicillanic acid (6.5% yield).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][C:13]3=[O:18])[CH:7]=[CH:6][C:5]=12.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH2:30][CH:31]=O>>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH2:31][CH2:30][C:22]4[CH:23]=[CH:24][C:25]([N+:27]([O-:29])=[O:28])=[CH:26][C:21]=4[O:20][CH3:19])[CH2:14][C:13]3=[O:18])[CH:7]=[CH:6][C:5]=12
Reactant: O=C1CNCCN1CCc1ccc2nonc2c1
Reactant: COc1cc([N+](=O)[O-])ccc1CC=O
Product: COc1cc([N+](=O)[O-])ccc1CCN1CCN(CCc2ccc3nonc3c2)C(=O)C1

Procedure:
The title compound was prepared from 1-[2-(2,1,3-Benzoxadiazol-5-yl)ethyl]piperazin-2-one and (2-Methoxy-4-nitrophenyl)acetaldehyde following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 426 [M+1]+.
Reaction SMILES: [O:1]=[C:2]([C:4]1[N:11]2[C:7](=[N:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=32)[S:6][N:5]=1)[CH3:3].[BH4-].[Na+].O>CO>[OH:1][CH:2]([C:4]1[N:11]2[C:7](=[N:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=32)[S:6][N:5]=1)[CH3:3]
Reactant: CC(=O)c1nsc2nc3ccccc3n12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(O)c1nsc2nc3ccccc3n12
Reaction time: 0.5 h

Procedure:
To a suspension of 3-(1-oxoethyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole (729 mg, 3.36 mmol) in 200 mL methanol, was added sodium borohydride (140 mg, 3.69 mmol). The mixture was stirred for 30 min and 0.1 mL of water was added. The methanol was evaporated and the residue was partitioned between ethyl acetate and 0.1 M hydrochloric acid. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed twice with brine, dried and evaporated. The crude residue was purified by chromatography using chloroform/methanol to give 3-(1-hydroxyethyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole. mp 174-175° C.; 1H NMR (CDCl3) δ 8.05 (d, 1H), 7.80 (d, 1H), 7.47 (td, 1H), 7.36 (td, 1H), 5.39 (q, 1H), 2.76 (d, 1H), 1.84 (d, 3H) ppm; IR (KBr) ν 3136, 1544, 1494, 1478, 1451, 1374, 1250, 1200, 1123, 1103, 1093, 752, 729, 711 cm-1 ; MS m/z 219 (M+), 148 (M+ -CH3CH(OH)CN)
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C@H:8]([CH2:19][N:20]1[CH:25]=[C:24]([CH3:26])[C:23](=[O:27])[N:22](C(=O)C2C=CC=CC=2)[C:21]1=[O:36])[C@H:9]([O:11][Si](C(C)(C)C)(C)C)[CH3:10])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[OH-].[Na+]>C1COCC1.CO.O>[CH3:26][C:24]1[C:23](=[O:27])[NH:22][C:21](=[O:36])[N:20]([CH2:19][C@H:8]([C@H:9]([OH:11])[CH3:10])[CH2:7][OH:6])[CH:25]=1
Reactant: Cc1cn(C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@@H](C)O[Si](C)(C)C(C)(C)C)c(=O)n(C(=O)c2ccccc2)c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cn(C[C@@H](CO)[C@@H](C)O)c(=O)[nH]c1=O
Reaction time: 2 h
Yield: 77.8 %

Procedure:
To a solution of 32 (1.9 g, 3.38 mmol) in 20 ml of THF was added 6 ml of 1 M TBAF in THF. After being kept at room temperature for 2 hrs the reaction was diluted with methanol (100 ml), water (100 ml) and treated with 10 ml of 1 M NaOH. The reaction was allowed to proceed overnight, then combined with 10 g of Dowex 66 and 20 g of Dowex 50 w×8×200 and stirred for 1 h. The resin was removed by filtration, washed with 50% methanol and the combined filtrates concentated to afford 0.6 g (77%) of 33 as a white solid. This material contained some impurities but was considered to be pure enough for further use without additional purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][O:20][NH2:21])=[CH:17][CH:16]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=O)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])=[CH:28][CH:27]=1.C(O)(=O)C.C([O-])(=O)C.[Na+]>C(OCC)(=O)C.CCCCCC.O.CO>[CH3:24][O:25][C:26]1[CH:27]=[CH:28][C:29](/[C:32](=[N:21]/[O:20][CH2:19][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]3[N:4]=[C:5]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[O:6][C:2]=3[CH3:1])=[CH:23][CH:22]=2)/[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])=[CH:30][CH:31]=1
Reactant: COC(=O)CCCCCCC(=O)c1ccc(OC)cc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CON)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCCCCC
Product: COC(=O)CCCCCC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccc(OC)cc1
Temperature: 25 °C
Yield: 58.9 %

Procedure:
After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine (600 mg), methyl 8-(4-methoxyphenyl)-8-oxooctanoate (538 mg), acetic acid (0.331 ml), sodium acetate (317 mg) and methanol (20 ml) was heated to reflux for 16 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain methyl E-8-(4-methoxyphenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoate (650 mg, yield 59%) as a colorless oil from an ethyl acetate-hexane (2:7, v/v)-eluted fraction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[N:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[CH:4][CH:3]=1.[CH2:19]=[C:20]([CH3:22])[CH3:21].B(F)(F)F.CCOCC.C(#N)C>[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:8][CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[CH2:19][C:20]2([CH3:22])[CH3:21]
Reactant: O=[N+]([O-])c1cccc(/C=N/c2ccc(Cl)cc2)c1
Reactant: C=C(C)C
Agent: FB(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOCC
Product: CC1(C)CC(c2cccc([N+](=O)[O-])c2)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.2 %

Procedure:
To a mixture of 4-chloro-phenylamine (12.8 g 100 mmol) and 3-nitro-benzaldehyde (15.1 g, 100 mmol) was added 100 mL of toluene. The resulting solution was heated to reflux with a dean-stark trap for 3 h. The toluene was removed and the residue was collect to afford (4-chloro-phenyl)-[1-(3-nitro-phenyl)-meth-(E)-ylidene]-amine as yellow solid (26.5 g, yield: 95%). (4-Chloro-phenyl)-[1-(3-nitro-phenyl)-meth-(E)-ylidene]-amine (10.0 g, 36.5 mmol), isobutene (31 ml, 365.4 mmol, 10 g), boron trifluoride etherate (1.98 ml, 7.31 mmol) and acetonitrile (40 ml) were added into a autoclave and was stirred at room temperature for 72 h. Brine was added and the organic layer was separated, dried and concentrated to afford 6-chloro-4,4-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline as yellow solid (8.7 g, yield: 73%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:12]([CH3:14])[N:13]=2)[CH:5]=[C:6]([C:8]([NH2:10])=[O:9])[CH:7]=1.[CH2:20]([C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:23]=1[CH2:24]Cl)[CH3:21].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(Cl)Cl.CC(C)=O>[NH2:10][C:8]([C:6]1[CH:7]=[C:2]([NH:1][CH2:24][C:23]2[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:22]=2[CH2:20][CH3:21])[C:3]2[N:4]([C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:12]([CH3:14])[N:13]=2)[CH:5]=1)=[O:9]
Reactant: CCOC(=O)c1c(C)nc2c(N)cc(C(N)=O)cn12
Reactant: CCc1cccc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1c(C)nc2c(NCc3c(C)cccc3CC)cc(C(N)=O)cn12
Yield: 56 %

Procedure:
Ethyl 8-amino-6-(aminocarbonyl)-2-methylimidazo[1,2-a]pyridine-3-carboxylate (0.41 g, 1.6 mmol), 2-ethyl-6-methylbenzylchloride, sodium carbonate (0.7 g, 6.6 mmol), sodium iodide (0.15 g, 1.0 mmol) and acetone (20 ml) were refluxed for 44 h. Methylene chloride was added and the solids were removed by filtration. The filtrate was evaporated under reduced pressure and purification of the residue by column chromatography on silica gel eluting with methylene chloride:methanol (100:4) gave 0.35 g (56%) of the title compound. 1H-NMR (300 MHz, CDCl3): δ1.25 (t, 3H), 1.45 (t, 3H), 2.35 (s, 3H), 3.65 (s, 3H), 2.7 (q, 2H), 4.4-4.45 (m, 4H), 5.0 (t, 1H), 6.95 (s, 1H), 7.0-7.2 (m, 3H), 9.2 (s, 1H)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:39])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:30]=[N:31][C:32]([CH:36]3[CH2:38][CH2:37]3)=[CH:33][C:34]=2[CH3:35])[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:36]1([C:32]2[N:31]=[CH:30][C:29]([C:25]3[CH:24]=[C:23]([C:21]4[CH2:20][C:19](=[O:39])[NH:18][C:9]5[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=5[N:7]=4)[CH:28]=[CH:27][CH:26]=3)=[C:34]([CH3:35])[CH:33]=2)[CH2:38][CH2:37]1
Reactant: Cc1cc(C2CC2)ncc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)ccc2NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C2CC2)ncc1-c1cccc(C2=Nc3ccc(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (2-{3-[3-(6-cyclopropyl-4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M264) (260 mg, 0.47 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (67 mg, 33%).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C@H:3]([OH:37])[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=2)[CH2:7][CH:6]1[C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30]([O:32]C)=[O:31].O.[OH-].[Li+]>CO.[Cl-].[NH4+]>[F:39][C:2]([F:1])([F:38])[C@H:3]([OH:37])[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=2)[CH2:7][CH:6]1[C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30]([OH:32])=[O:31]
Reactant: COC(=O)c1cccc(C2CN(Cc3cccc(OC(F)(F)F)c3)c3ccccc3N2C[C@@H](O)C(F)(F)F)c1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(C2CN(Cc3cccc(OC(F)(F)F)c3)c3ccccc3N2C[C@@H](O)C(F)(F)F)c1
Temperature: 60 °C

Procedure:
Methyl 3-{1-[(R)-3,3,3-trifluoro-2-hydroxypropyl]-4-[3-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydroquinoxalin-2-yl}benzoate (700 mg, 1.262 mmol) is made as described in Example 16 but with one stereochemical center unresolved. The compound was dissolved in MeOH (12.6 mL), lithium hydroxide monohydrate (530 mg, 12.62 mmol) was added, and the reaction mixture was heated to 60° C. for 4 hours. The crude mixture was dissolved in saturated ammonium chloride solution and extracted into EtOAc, the organic phase was dried with anhydrous magnesium sulfate, filtered, concentrated, and purified on a silica gel column with a 0-100% Hex/EtOAc gradient. The major peak was concentrated to afford 3-{1-[(R)-3,3,3-trifluoro-2-hydroxypropyl]-4-[3-(trifluoromethoxy)benzyl]-1,2,3,4-tetra-hydroquinoxalin-2-yl}benzoic acid. MS m/z=541.09.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33](O)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][C@@H:37]1[C@@H:42]([OH:43])[CH2:41][CH2:40][N:39]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33]([NH:36][C@@H:37]4[C@@H:42]([OH:43])[CH2:41][CH2:40][N:39]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:38]4)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@@H](N)C1
Reactant: COc1cc(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F
Product: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CN(C(=O)OC(C)(C)C)CC[C@@H]4O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c10) and tert-butyl (3S*,4S*)-3-amino-4-hydroxy-piperidine-1-carboxylate (Example C3) the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.[N:21]([CH2:24][C:25](OCC)=[O:26])=[C:22]=[O:23]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:25](=[O:26])[CH2:24][NH:21][C:22]2=[O:23])=[CH:16][CH:15]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(N)cc2)C1
Reactant: CCOC(=O)CN=C=O
Solvent: CC#N
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(N3C(=O)CNC3=O)cc2)C1
Reaction time: 4 h
Yield: 118 %

Procedure:
4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (95 mg; preparation as described in WO2004085404) was dissolved in acetonitrile (2 ml) and ethyl isocyanatoacetate (30 mg) was added dropwise with stirring. After 4 hours, the solution was concentrated and the residue purified by means of preparative HPLC. The fractions comprising product were combined, the acetonitrile was removed on a rotary evaporator, and the aqueous residue was neutralized with potassium carbonate and extracted three times with ethyl acetate. Drying over magnesium sulfate was followed by concentration to dryness. The residue was taken up with aqueous hydrochloric acid and freeze-dried. 107 mg of the desired compound were obtained.
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:22]=[CH:23][CH:24]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=3)=[O:31])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1csc(Cn2ncc(N)n2)n1
Reactant: COc1cccc(-c2ocnc2C(=O)O)c1
Product: COc1cccc(-c2ocnc2C(=O)Nc2cnn(Cc3nc(C(C)(F)F)cs3)n2)c1

Procedure:
Following general procedure Z2, starting from 2-[4-(1,1-difluoro-ethyl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-methoxy-phenyl)-oxazole-4-carboxylic acid.