Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:9]=O)[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[CH3:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1.C(OC(=O)C)(=O)C>C1(C)C(C)=CC=CC=1>[N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[CH:11]=[CH:9][C:1]1[CH:2]=[CH:3][C:4]([CH:7]=[O:8])=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(C=O)cc1
Reactant: Cc1ccc2ccccc2n1
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1C
Product: O=Cc1ccc(C=Cc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Yield: 35 %

Procedure:
1,4-Benzenedialdehyde (30 g, 0.22 mol), 2-methylquinoline (21 g, 0.15 mol) and acetic anhydride (41.5 ml, 0.40 mol) were dissolved in 160 ml of xylene, followed by heating under reflux for 7 hours. After the reaction mixture was allowed to cool down to room temperature, 200 ml of petroleum ether were added and the resulting precipitate was collected by filtration. Further, the mother liquor was concentrated under reduced pressure and the residue was recrystallized from diethyl ether, whereby 13.6 g of the title compound were obtained (yield: 35%).
Reaction SMILES: C([N+]1(C)CCCC1)C=C.[NH2:10][C:11]1[S:15][N:14]=[C:13](/[C:16](=[N:20]/[O:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)/[C:17]([O-:19])=O)[N:12]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[NH2:58][C@@H:59]1[C:66](=[O:67])[N:65]2[C@@H:60]1[S:61][CH2:62][C:63](/[CH:71]=[C:72]1/[C:73](=[O:96])[N:74]([CH2:77][C:78]3[CH:83]=[CH:82][N+:81]([CH2:84][C:85](=[O:95])[NH:86][C:87]4[CH:92]=[CH:91][C:90]([OH:93])=[C:89]([F:94])[CH:88]=4)=[CH:80][CH:79]=3)[CH2:75][CH2:76]/1)=[C:64]2[C:68]([O-:70])=[O:69]>CN(C=O)C>[NH2:10][C:11]1[S:15][N:14]=[C:13](/[C:16](=[N:20]/[O:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)/[C:17]([NH:58][C@@H:59]2[C:66](=[O:67])[N:65]3[C@@H:60]2[S:61][CH2:62][C:63](/[CH:71]=[C:72]2/[C:73](=[O:96])[N:74]([CH2:77][C:78]4[CH:79]=[CH:80][N+:81]([CH2:84][C:85](=[O:95])[NH:86][C:87]5[CH:92]=[CH:91][C:90]([OH:93])=[C:89]([F:94])[CH:88]=5)=[CH:82][CH:83]=4)[CH2:75][CH2:76]/2)=[C:64]3[C:68]([O-:70])=[O:69])=[O:19])[N:12]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)[O-])=C(/C=C3\CCN(Cc4cc[n+](CC(=O)Nc5ccc(O)c(F)c5)cc4)C3=O)CS[C@H]12
Reactant: Nc1nc(/C(=N/OC2CCCC2)C(=O)[O-])ns1
Agent: C=CC[N+]1(C)CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(/C(=N/OC2CCCC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(/C=C4\CCN(Cc5cc[n+](CC(=O)Nc6ccc(O)c(F)c6)cc5)C4=O)CS[C@H]23)ns1
Reaction time: 78 h

Procedure:
A solution of (Z)-(5-amino-[1,2,4]thiadiazol-3-yl)-cyclopentyloxyimino-acetate 1-allyl-1-methyl-pyrrolidinium salt in 10 ml DMF was treated with HBTU (170 mg, 0.45 mmol) for 1.5 h at room temperature. (E)-(6R,7R)-7-Amino-3-[1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-ium-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate trifluoroacetic acid salt (300 mg, 0.45 mmol) was added and the mixture was stirred for 78 h before it was concentrated in vacuo. The residue was dissolved in ethylacetate and extracted with water. The organic phase was evaporated and the residue triturated with diethylether. The product was purified by gel chromatography (MCI-gel, using a gradient of water with increasing concentrations of acetonitrile). Yield: 40 mg (11%).
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][C:14]([OH:25])([CH2:17][NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(CC)CC)C.ClCCl.[C:36](Cl)(Cl)=[O:37]>C1(C)C=CC=CC=1>[C:19]1([N:18]2[CH2:17][C:14]3([CH2:13][CH2:12][N:11]([C:1]([O:3][CH2:4][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=4)=[O:2])[CH2:16][CH2:15]3)[O:25][C:36]2=[O:37])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Cl)Cl
Reactant: O=C(OCc1ccccc1)N1CCC(O)(CNc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC2(CC1)CN(c1ccccc1)C(=O)O2
Yield: 50.7 %

Procedure:
To a mixture of 2.2 g 1-carbobenzyloxy-4-hydroxy-4-anilinomethylpiperidine, 3 ml triethylamine and 20 ml dichloromethane is added a solution of 3 g phosgene in 25 ml toluene. After 30 minutes the mixture is washed with 100 ml, 1 N hydrochloric acid. Removal of solvent by evaporation followed by recrystallization from diethyl ether-hexane affords 1.2 g of 3-phenyl-8-carbobenzyloxy-1-oxa-3,8-diazaspiro[4.5]decan-2-one, mp 100°-102°.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH:31]3[CH2:33][CH2:32]3)=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[OH-].[K+].[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][OH:45])[CH2:39][CH2:38]1>O.CS(C)=O.C1COCC1>[CH:31]1([C:16]2[C:15]3[C:19](=[CH:20][CH:21]=[CH:22][C:14]=3[NH:13][C:11]([C:8]3[N:5]4[CH:6]=[CH:7][C:2]([O:45][CH2:44][CH2:43][N:40]5[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]5)=[CH:3][C:4]4=[N:10][CH:9]=3)=[O:12])[N:18]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)[N:17]=2)[CH2:32][CH2:33]1
Reactant: Cc1cccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(Cl)ccn45)cccc32)n1
Reactant: CN1CCN(CCO)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(OCCN6CCN(C)CC6)ccn45)cccc32)n1
Temperature: 95 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
7-Chloro-N-(3-cyclopropyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (5.0 g, 10.9 mmol), potassium hydroxide (3.38 g, 60.2 mmol), DMSO (50 mL), and 2-(4-methylpiperazin-1-yl)ethanol (3.16 g, 21.9 mmol) were combined under nitrogen and heated to 95° C. for 16 hours. The mixture was cooled to ambient temperature and THF (300 mL) was added. The slurry was stirred at ambient temperature for 3 hours. The solids were filtered off and the THF removed from the filtrates under vacuum to give a DMSO solution of the product. The DMSO solution was heated to 60° C. and water (100 mL) was added to precipitate out the product. The slurry was cooled to ambient temperature and stirred for 18 hours. The solids were collected by filtration and washed with water (100 mL) and MTBE (50 mL). The material was dried under vacuum at 40° C. to give N-(3-cyclopropyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide (4.54 g). MS (ES+APCI) m/z=565.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:32]=[CH:31][C:23]([O:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([CH3:33])[CH:3]=1.Cl.[NH2:35][OH:36].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:32]=[CH:31][C:23]([O:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][CH:21]=2)[CH2:9]/[C:10](=[N:35]\[OH:36])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([CH3:33])[CH:3]=1
Reactant: NO
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(OCCCC(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(OCCCC(=O)O)cc1

Procedure:
In analogy to example 151, step 3, 4-{4-[1-(4-chloro-2-methyl-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-propyl]-phenoxy}-butyric acid was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound containing less than 10% of the corresponding Z isomer as a colourless solid, MS (ESI−): m/z=481.1 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[C:19]([Cl:20])=[CH:18][C:5]2[N:6]([C@H:9]3[CH2:14][C@H:13]([OH:15])[C@@H:12]([CH2:16][OH:17])[O:11][CH2:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1.CN(C=O)C.N1C=CN=C1.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>O>[Cl:1][C:2]1[C:19]([Cl:20])=[CH:18][C:5]2[N:6]([C@H:9]3[CH2:14][C@H:13]([OH:15])[C@@H:12]([CH2:16][O:17][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[O:11][CH2:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: OC[C@H]1OC[C@@H](n2cnc3cc(Cl)c(Cl)cc32)C[C@@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1OC[C@@H](n2cnc3cc(Cl)c(Cl)cc32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a stirred suspension of (3S,5S,6R)-5,6-dichloro-1-(tetrahydro-5-hydroxy-6-(hydroxymethyl)-2H-pyran-3-yl)-1H-benzimidazole (example 36, 1.50 g, 4.73 mmol) in 15 ML of dry DMF at 0° C. was added imidazole (0.40 g, 5.68 mmol) followed by tert-butyldimethylsilyl chloride (0.81 g, 5.20 mmol). The reaction was allowed to warm to room temperature, stirred overnight then diluted with water (100 ML) and extracted with chloroform (100 ML). The organic layer was dried over sodium sulfate, filtered and the solvents were removed under reduced pressure. Purification by flash chromatography on silica gel 60 eluting with 50% ethyl acetate-hexanes afforded the title compound as a white solid (1.00 g, 50%) along with 0.40 g recovered starting material; m.p. 143-155° C.; 1H-NMR (DMSO-d6, 200 MHz) δ: 8.51, 8.09, 8.00 (s, each 1H), 4.90 (d, J=5.6 Hz, 1H), 4.89 (m, 1H), 4.26 (m, 1H), 3.91 (m, 1H), 3.86 (m, 1H), 3.55-3.42 (m, 1H), 3.32-3.24 (m, 2H), 2.29-2.19 (m, 1H), 1.97-1.83 (m, 1H), 0.91 (s, 9H), 0.97, 0.78 (s, each 3H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:9][C:8]2[CH:10]=[C:11]3[O:16][CH2:15][O:14][C:12]3=[CH:13][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[N:5][NH:4]1.Cl.[CH3:27][C:28]([CH3:30])=O>>[CH3:27][C:28]1([CH3:30])[N:4]2[N:5]=[C:6]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)[C:7]3[CH:13]=[C:12]4[O:14][CH2:15][O:16][C:11]4=[CH:10][C:8]=3[CH2:9][CH:3]2[CH2:2][O:1]1
Reactant: O=[N+]([O-])c1ccc(C2=NNC(CO)Cc3cc4c(cc32)OCO4)cc1
Reactant: CC(C)=O
Agent: Cl
Product: CC1(C)OCC2Cc3cc4c(cc3C(c3ccc([N+](=O)[O-])cc3)=NN21)OCO4
Reaction time: 0.5 h

Procedure:
1.87 g (5.48 mmol) of 8-hydroxymethyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine is dissolved in 25 ml of acetone and mixed with 0.54 ml (6.67 mmol) of 37% HCl. After 30 minutes, the reaction mixture is cooled, and the hydrochloride is filtered off. The dichloromethane suspension of this salt is shaken with 20 ml of 8% NaHCO3 solution until the salt is dissolved. The organic phase is separated, washed with water, dried and concentrated by evaporation. After recrystallization, 1.7 g (81%) of the title compound, melting point 171-173° C., is obtained.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[C:12]([O:18]C)[CH:11]=2)[CH2:5]1)[CH:2]=[CH2:3].[BrH:20]>>[BrH:20].[CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:18])[CH:11]=2)[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCCC(c2ccc(OC)c(OC)c2)C1
Agent: Br
Product: C=CCN1CCCC(c2ccc(O)c(O)c2)C1

Procedure:
A solution of 5.55 g of N-allyl-3-(3',4'-dimethoxyphenyl)-piperidine in 55 ml of 66% hydrobromic acid was refluxed for an hour and was evaporated to dryness. The residue was crystallized from isopropanol and then acetonitrile to obtain 3.27 g of N-allyl-3-(3',4'-dihydroxyphenyl)-piperidine hydrobromide melting at 235° C.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:7][CH2:6][CH2:5][C:4]2=[O:8])[CH2:2]1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1>[OH-].[Na+]>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[C:5]2[CH2:6][CH2:7][C:3]3([CH2:2][CH2:1]3)[C:4]2=[O:8])=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O=C1CCCC12CC2
Agent: [Na+]
Agent: [OH-]
Product: O=C1C(=Cc2ccc(Cl)cc2)CCC12CC2

Procedure:
It is known that spiro-[2.4]-heptan-4-one can be reacted with 4-chlorobenzaldehyde in methanolic sodium hydoxide solution to give 5-(4-chlorobenzylidene)spiro[2.4]-heptan-4-one (see DE-A 43 20 498, Example 1). A disadvantage is the extremely long reaction time required, of 50 hours.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][N:6]2[CH:15]=1.[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[N:24]1[CH2:25][CH2:26][N:27]([CH2:2][C:3]2[N:4]=[C:5]3[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][N:6]3[CH:15]=2)[CH2:28][CH2:29]1
Reactant: FC(F)(F)c1ccc2nc(CCl)cn2c1
Reactant: Clc1ccc(N2CCNCC2)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccc2nc(CN3CCN(c4ccc(Cl)cc4Cl)CC3)cn2c1
Yield: 77.4 %

Procedure:
A mixture of 2-(chloromethyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine (0.452 g), 1-(2,4-dichlorophenyl)piperazine (Example 31, Step 1; 0.468 g), diisopropylethylamine (Aldrich; 0.299 g), and THF (4 mL) is stirred at reflux for 21 h. After cooling, the mixture is partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate, concentrated. and the residue chromatographed on silica gel using methanol/dichloromethane (2.5/97.5) to give 0.64 g of 2-[[4-(2,4-dichlorophenyl)-1-piperazinyl]methyl]-6-(trifluoromethyl)imidazo[1,2-a]pyridine. The methanesulfonate salt is prepared by dissolving 2-[[4-(2,4-dichlorophenyl)-1-piperazinyl]methyl]-6-(trifluoromethyl) imidazo[1,2-a]pyridine in ethyl acetate/hexane and adding methanesulfonic acid (0.143 g) dissolved in methanol. The mixture is concentrated under reduced pressure and the residue is crystallized from ethyl acetate to give 0.691 g of the title compound; mp 161-162° C.; MS m/z 428; IR (mineral oil) 1162, 1225, 1033, 1130, 1142, 1337 cm-1. 1H NMR (CDCl3) δ2.78, 3.09, 3.83, 6.96, 7.18, 7.31, 7.35, 7.66, 7.68, 8.47.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:18]([OH:20])=[O:19])=[N:6][C:7]=1[C:8]1[CH2:17][CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10][CH:9]=1.[CH3:21]CN=C=NCCCN(C)C.Cl.CO>C(Cl)Cl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:18]([O:20][CH3:21])=[O:19])=[N:6][C:7]=1[C:8]1[CH2:17][CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10][CH:9]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc(F)c(C2=CCC3(CC2)OCCO3)n1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(F)c(C2=CCC3(CC2)OCCO3)n1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of 5-fluoro-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)picolinic acid (1.0 equiv.) in DCM (0.3 M) was added EDC-HCl (1.0 equiv.), DMAP (1.0 equiv.), and MeOH (10 equiv.). The reaction mixture was allowed to stir at room temperature for 5 days, then diluted with ethyl acetate, washed with water, brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography eluting with 25-50% ethyl acetate in hexanes to yield methyl 5-fluoro-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)picolinate as the desired product in 35% yield. LC/MS=294.2 (M+H), Rt=0.79 min.
Reaction SMILES: [CH2:1]([NH:13][C:14](=[O:36])[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[C:18]([O:31][CH2:32][CH2:33]O)=[C:17]([Br:35])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(Br)(Br)(Br)[Br:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:1]([NH:13][C:14](=[O:36])[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=2)[C:18]([O:31][CH2:32][CH2:33][Br:38])=[C:17]([Br:35])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCBr)c(-c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of N-dodecyl-3-bromo-5-(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)-benzamide (0.996 g, 1.74 mmol, 1 eq) in CH2Cl2 (9 mL) was added carbon tetrabromide (0.760 g, 2.29 mmol 1.3 eq) and triphenylphosphine (0.603 g, 2.29 mmol, 1.3 eq). The reaction was stirred at overnight at rt and concentrated m vacuo. The residue was purified by flash chromatography (15% EtOAc:hexane) to afford N-dodecyl-3-bromo-4-(2-bromo-ethoxy)-5-(m-trifluoromethylphenyl)-benzamide (0.951 g, 89%) as a colorless oil. 1H NMR (CDCl3) δ7.98 (d, 1H); 7.78-7.40 (m, 5H); 6.20 (bt, 1H); 4.52 (dd, 2H); 3.95 (dd, 2H); 3.42 (dd, 2H); 1.50 (m, 2H); 1.30 (m, 18H); 0.92 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]([CH:29]=[CH:30][CH:31]=2)[CH:15]=[C:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)=[N:9][CH:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:19]1[CH2:20][CH2:21][C:16](=[CH:15][C:14]2[CH:13]=[C:12]([CH:31]=[CH:30][CH:29]=2)[O:11][C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:33])([F:1])[F:32])=[CH:10][N:9]=2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(OCC(F)(F)F)cn3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)COc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
To a solution of tert-butyl 4-(3-(5-(2,2,2-trifluoroethoxy)pyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (0.36 g, 0.77 mmol) in CH2Cl2 (3 mL) cooled to 0° C. under a N2 atmosphere was added TFA (0.46 mL, 5.97 mmol). The resulting mixture was stirred for 2 h at RT. The solution was concentrated and then quenched with saturated NaHCO3 solution. The mixture was extracted with CH2Cl2 and the organic extract was dried over Na2SO4, and concentrated under reduced pressure to give the title compound (0.282 g, 99%). m/z (365.1, M+ H+).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:37][C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=1)[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]2[N:23]([CH2:24][CH2:25][CH2:26][O:27][CH3:28])[C:22]3[C:29]([C:33]([O:35][CH3:36])=[O:34])=[CH:30][CH:31]=[CH:32][C:21]=3[N:20]=2)[CH2:14]1)=[O:12])=O)(C)(C)C>C(Cl)Cl>[NH2:8][C@H:9]([CH2:37][C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=1)[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]2[N:23]([CH2:24][CH2:25][CH2:26][O:27][CH3:28])[C:22]3[C:29]([C:33]([O:35][CH3:36])=[O:34])=[CH:30][CH:31]=[CH:32][C:21]=3[N:20]=2)[CH2:14]1)=[O:12]
Reactant: COCCCn1c(C2CCCN(C(=O)C[C@@H](Cc3ccc4ccccc4c3)NC(=O)OC(C)(C)C)C2)nc2cccc(C(=O)OC)c21
Solvent: ClCCl
Product: COCCCn1c(C2CCCN(C(=O)C[C@H](N)Cc3ccc4ccccc4c3)C2)nc2cccc(C(=O)OC)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
Methyl 2-(1-((R)-3-(tert-butoxycarbonylamino)-4-(naphthalen-2-yl)butanoyl)piperidin-3-yl)-1-(3-methoxypropyl)-1H-benzo[d]imidazole-7-carboxylate (440) (0.04 mmol, 25 mg) in DCM (5 mL) was added TEA (1 mL). The reaction solution was stirred at rt for 1 hr and then concentrated in vacuo. The residue was purified by preparative LC/MS (20-50% a CH3CN in H2O) to afford methyl 2-(1-((R)-3-amino-4-(naphthalen-2-yl)butanoyl)piperidin-3-yl)-1-(3-methoxypropyl)-1H-benzo[d]imidazole-7-carboxylate (112) (0.018 mmol, 10 mg, yield: 45.0%). ESI-MS: 543.5 m/z (M+H)+. 1H NMR (400 MHz, MeOD) δ ppm 1.52-1.74 (m, 2H) 1.85-2.11 (m, 4H) 2.15-2.32 (m, 2H) 2.65 (s, 2H) 2.69-2.89 (m, 4H) 2.90-3.09 (m, 4H) 3.23 (s, 1H) 3.35 (t, J=5.53 Hz, 1H) 3.40-3.50 (m, 1H) 3.89 (d, J=13.83 Hz, 1H) 4.34-4.44 (m, 2H) 4.57 (dd, 2H) 4.66 (d, 0.1=13.07 Hz, 2H) 7.43 (t, J=8.12 Hz, 1H) 7.47-7.53 (m, 2H) 7.56 (t, J=8.72 Hz, 1H) 7.76-7.93 (m, 4H) 7.93-7.98 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@H:4]([NH:7]C(=O)OC(C)(C)C)[C:3]1=[O:15].O1CCOCC1.[ClH:22]>>[ClH:22].[NH2:7][C@H:4]1[CH2:5][CH2:6][N:2]([CH3:1])[C:3]1=[O:15]
Reactant: CN1CC[C@H](NC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CN1CC[C@H](N)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
(S)-tert-Butyl 1-methyl-2-oxopyrrolidin-3-ylcarbamate (prepared according to Example 10; 300 mg, 1.40 mmol) was dissolved in 4M hydrogen chloride in dioxane (3.5 mL, 14 mmol), and the reaction was allowed to stir at ambient temperature for 16 hours. The reaction mixture was concentrated to yield (S)-3-amino-1-methylpyrrolidin-2-one hydrochloride (211 mg, 100%) which was taken onto the next step without purification.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][C:9](CN)=[C:8]([O:14][CH3:15])[CH:7]=1.Cl.CCN(CC)CC.C1C2C(COC(ON3C(=O)CCC3=O)=O)C3C(=CC=CC=3)C=2C=CC=1>CO.CC#N>[CH3:15][O:14][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:5]([OH:16])=[O:4]
Reactant: COC(=O)c1ccc(CN)c(OC)c1
Agent: Cl
Agent: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CC#N
Product: COc1cccc(C(=O)O)c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
A 1 N solution of NaOH (6.15 mL; 6.14 mmol) was added dropwise to a solution of 4-(aminomethyl)-3-methoxybenzoic acid methyl ester C (1.2 g; 6.14 mmol) in MeOH (25 mL) heated at 40° C. After stirring 8 h at 45° C. the solution was stirred over night at room temperature. A 1 N solution of NaOH (0.6 mL; 0.6 mmol) was added and the mixture heated at 40° C. for 4 h. The solution was concentrated, acidified with 1 N HCl (8 mL; 8 mmol), extracted with EtOAc (2×10 mL) then the aqueous layer was concentrated to 15 mL. This solution (pH 4.5) was cooled at 0° C. and Et3N (936 μL; 6.75 mmol) was added (pH 11). A solution of N-(9-fluorenylmethoxycarbonyloxy)succinimide (3.04 g; 9 mmol) in MeCN (30 mL) was added dropwise (final pH 9) and a white solid precipitated. After stirring 1 h at room temperature the solid was filtered, suspended in 1N HCl (15 mL) and the suspension was stirred for 30 min. The solid was filtered to provide 4-[[[9H-fluoren-9-ylmethoxy)carbonyl]amino]methyl]-3-methoxybenzoic acid E as a white solid (275 mg; 0.7 mmol).
Reaction SMILES: [CH:1]1([N:4]([CH2:34][CH2:35]O)[C:5]([C:7]2[C:12]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]3([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:27][CH2:26][CH2:25][CH2:24]3)[N:8]=2)=[O:6])[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]2[CH2:35][CH2:34][N:4]([CH:1]3[CH2:2][CH2:3]3)[C:5](=[O:6])[C:7]=12)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccccc4)CCCC3)n2CCN1C1CC1
Reaction time: 0.17 h
Yield: 61.8 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid cyclopropyl-(2-hydroxyethyl)-amide (285) (300 mg, 0.62 mmol) in dichloromethane (30 mL) were added triphenyl phosphine (242 mg, 0.92 mmol) and diisopropyl azodicarboxylate (0.2 mL, 1.23 mmol) at room temperature. Stirring was continued for 10 min at room temperature. The reaction mixture was concentrated under reduced pressure to get a crude product, which was purified by Combi-Flash column (triphenyl phosphine oxide was eluted in ethyl acetate and the product was eluted at 2% methanol in dichloromethane). It was again purified by preparative TLC plate to remove traces of triphenyl phosphine oxide (mobile phase: ethyl acetate) and 9-benzyloxy-2-cyclopropyl-6-(1-phenyl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (286) (180 mg, 62.3%) was obtained as a white sticky solid.