Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1N=C([O:8][C@@H:9]([C@H:11]2[CH2:15][N:14]([C@@H:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH3:17])[C:13](=[O:26])[CH2:12]2)[CH3:10])C2N(C)C=NC=2C=1.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>>[OH:8][C@@H:9]([C@H:11]1[CH2:15][N:14]([C@@H:16]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[CH3:17])[C:13](=[O:26])[CH2:12]1)[CH3:10].[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(Br)cc4ncn(C)c34)CC2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)O)CC2=O)cc1
Temperature: 25 °C

Procedure:
A solution of (R)-4-((R)-1-(6-bromo-3-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 2.61 (256 mg, 0.54 mmol) in TFA (8 mL) was heated at 55° C. for 16 h, cooled to rt and then evaporated to give (R)-4-((R)-1-hydroxyethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 2.62 as TFA salt, which was used without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])/[CH:4]=[CH:5]\[C@H:6]([CH3:44])[C@H:7]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[C@@H:8]([CH3:35])[CH2:9][N:10]([C:12](=[O:34])[C@H:13]([CH3:33])[C@@H:14]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C@H:15]([CH3:24])[C@@H:16]([OH:23])[C@@H:17]([CH3:22])/[CH:18]=[CH:19]\[CH:20]=[CH2:21])[CH3:11].ClC(Cl)(Cl)[C:48]([N:50]=C=O)=[O:49]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:45])/[CH:4]=[CH:5]\[C@H:6]([CH3:44])[C@H:7]([O:36][Si:37]([C:40]([CH3:43])([CH3:41])[CH3:42])([CH3:38])[CH3:39])[C@@H:8]([CH3:35])[CH2:9][N:10]([C:12](=[O:34])[C@H:13]([CH3:33])[C@@H:14]([O:25][Si:26]([C:29]([CH3:30])([CH3:31])[CH3:32])([CH3:27])[CH3:28])[C@H:15]([CH3:24])[C@@H:16]([O:23][C:48]([NH2:50])=[O:49])[C@@H:17]([CH3:22])/[CH:18]=[CH:19]\[CH:20]=[CH2:21])[CH3:11]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: C=C/C=C\[C@H](C)[C@H](O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(=O)N(C)C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\C(=O)OC
Solvent: ClCCl
Product: C=C/C=C\[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(=O)N(C)C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a solution of (2Z,4S,5S,6S)-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-7-[[(2R,3S,4R,5S,6S,7Z)-3-[[(1, 1-dimethylethyl)dimethylsilyl]oxy]-5-hydroxy-2,4,6-trimethyl-1-oxo-7,9-decadienyl]methylamino]-4,6-dimethyl-2-heptenoic acid methyl ester (1.8 g, 2.7 mmol) in CH2Cl2 (10 mL) at room temperature, is added trichloroacetyl isocyanate (763 mg, 4.05 mmol) in one portion. The mixture is stirred at room temperature for 1 h, and concentrated in vacuo. The residue is dissolved in MeOH (10 mL), and then K2CO3 (0.4 g) is added. After stirring at room temperature for 2 h, the mixture is concentrated in vacuo, then purified by column chromatography with silica gel eluted with hexane/EtOAc (70/30) to give the desired compound (1.77 g, 92.4%) as a colorless glassy solid.
Reaction SMILES: [CH2:1]1[O:13][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:14]([NH2:17])[CH2:15][NH2:16]>CO>[CH2:14]([NH:17][CH2:1][CH:2]([OH:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:15][NH:16][CH2:1][CH:2]([OH:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: NCCN
Reactant: CCCCCCCCCCC1CO1
Solvent: CO
Product: CCCCCCCCCCC(O)CNCCNCC(O)CCCCCCCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-dodecene oxide (100 g.) and ethylenediamine (16.3 g.) and recrystallization of part (20 g.) of the resulting product (55.3 g.) from methanol gave N,N'-ethylenebis[2-hydroxydodecylamine] (I: R = CH3 (CH2)9, R' = H, X = (CH2)2, Z = H) (13.4 g., m.p. 137.0°-142.0° C.).
Reaction SMILES: [BrH:1].O[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)[CH3:4]>CC(O)=O>[Br:1][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)[CH3:4]
Reactant: Cc1ccc(C(C)O)cc1
Reactant: Br
Solvent: CC(=O)O
Product: Cc1ccc(C(C)Br)cc1

Procedure:
This compound is prepared by the procedure described in Preparation 3.4 from 30 ml of a 33% solution of HBr in AcOH and 7 ml of 1-(1-hydroxyethyl)-4-methylbenzene. 9 g of the expected product are obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[C@@H:3]([C:14]([OH:16])=[O:15])[NH:4][C:5](N(C)CCCC=C)=[O:6].[CH3:19][C:20]([NH2:27])([CH2:22][CH2:23][CH2:24][CH:25]=[CH2:26])[CH3:21]>>[CH3:19][C:20]([NH:27][C:5]([NH:4][C@H:3]([C:14]([OH:16])=[O:15])[C:2]([CH3:1])([CH3:17])[CH3:18])=[O:6])([CH3:21])[CH2:22][CH2:23][CH2:24][CH:25]=[CH2:26]
Reactant: C=CCCCC(C)(C)N
Reactant: C=CCCCN(C)C(=O)N[C@H](C(=O)O)C(C)(C)C
Product: C=CCCCC(C)(C)NC(=O)N[C@H](C(=O)O)C(C)(C)C

Procedure:
N-{[(1,1-Dimethylhex-5-enyl)amino]carbonyl}-3-methyl-L-valine was prepared according to the procedure for 3-methyl-N-{[methyl(pent-4-enyl)amino]carbonyl}-L-valine (Steps 4-5) by using 2-methylhept-6-en-2-amine instead of N-methylpent-4-en-1-amine in Step 4.
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[C:16]([C:29](O)=[O:30])=[CH:15]2.[NH2:32][C:33]1[CH:34]=[N:35][C:36]([N:39]([CH3:41])[CH3:40])=[CH:37][CH:38]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:40][N:39]([CH3:41])[C:36]1[N:35]=[CH:34][C:33]([NH:32][C:29]([C:16]2[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([F:11])=[CH:20][CH:19]=3)=[O:30])=[CH:38][CH:37]=1
Reactant: CN(C)c1ccc(N)cn1
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)c1ccc(NC(=O)c2cc3cc(F)ccc3n2Cc2cccc(F)c2)cn1
Reaction time: 0.17 h

Procedure:
0.27 ml (1.67 mmol) of diethyl cyanophosphonate is added dropwise at 20° C. under argon to a solution of 0.4 g (1.39 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (obtained in Example 1.1) and 0.229 g (1.67 mmol) of 3-amino-6-(dimethylamino)pyridine in 3.5 ml of dry dimethylformamide. The mixture is stirred for 10 minutes and then 0.43 ml (3.06 mmol) of triethylamine is added dropwise. The mixture is stirred at ambient temperature for 18 hours and concentrated under reduced pressure, and then the residue is taken up in 50 ml of ethyl acetate. This solution is then successively washed with three times 20 ml of a saturated sodium hydrogencarbonate solution, 50 ml of water and 20 ml of a saturated sodium chloride solution and then dried over sodium sulfate, filtered and concentrated under reduced pressure. The solid obtained is triturated from hot isopropyl ether. 0.423 g of a solid is collected by filtration, which solid is dried under reduced pressure and used as in the following stage.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:18][C@H:17]([C:19]2([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:20]2)[C@H:16]([C:30](OCC)=[O:31])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[CH2:7]([N:14]1[CH2:18][C@H:17]([C:19]2([NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:20][CH2:21]2)[C@H:16]([CH2:30][OH:31])[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1C1(NC(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1([C@H]2CN(Cc3ccccc3)C[C@H]2CO)CC1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
Under a nitrogen gas stream, lithium aluminum hydride (195.6 mg, 5.135 mmol) was suspended in dry tetrahydrofuran (40 ml). Under stirring at −15° C., a solution of ethyl cis-1-benzyl-4-(1-tert-butoxycarbonylaminocyclopropyl)-pyrrolidine-3-carboxylate (1.001 g, 2.577 mmol) in dry tetrahydrofuran (10 ml) was added dropwise thereinto over a period of 15 minutes. After stirring the reaction suspension under ice cooling for 3.5 hours, cooling water (5 ml) was slowly added thereto and the mixture was stirred at room temperature for an additional 15 minutes. The reaction suspension was filtered through celite (washed with diethyl ether). The filtrate was concentrated under reduced pressure and dried to obtain 833.9 mg (93.4%) of the title compound as a colorless oily substance.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][CH:5]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[Cl:22])[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[C:34]([OH:36])=[O:35]>>[Cl:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[CH:5]1[N:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[NH:8][C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[C:34]([OH:36])=[O:35])=[C:4]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: O=C(O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2ccccn2)=NC1c1ccc(F)cc1Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2ccccn2)=NC1c1ccc(F)cc1Cl
Yield: 54.6 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.69 g, 1.53 mmol) (The compound was synthesized according to the procedure as described in WO2010069147) was reacted with morpholine-3-carboxylic acid (0.2 g, 1.53 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.42 g, 55%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=O)C.[C:11]([C:15]1[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].[OH-].[K+]>[Cu].O>[C:5]1([NH:4][C:18]2[CH:19]=[CH:20][C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:16][CH:17]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: CC(C)(C)c1ccc(Br)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)c1ccc(Nc2ccccc2)cc1
Yield: 58.9 %

Procedure:
8.2 g (0.061 mol) of acetanilide, 19.2 g (0.090 mol) of p-tertiarybutylbromobenzene, 9.95 g (0.072 mol) of anhydrous potassium carbonate, and 0.50 g (0.008 mol) of copper powder were mixed. The reaction mixture was then allowed to undergo reaction at a temperature of 190° C. to 203° C. for 23 hours. The reaction product was then extracted with 75 ml of toluene. The insoluble contents were removed by filtration. The filtrate was then concentrated to dryness. The concentrate was then dissolved in 30 ml of isoamyl alcohol. The material was then hydrolyzed with 1.1 g of water and 7.9 g (0.12 mol) of 85% potassium hydroxide at a temperature of 125° C. The material was then subjected to steam distillation to distill off isoamyl alcohol and excess p-tertiarybutylbromobenzene. The residue was extracted with 80 ml of toluene, washed with water, and then concentrated to dryness. The concentrate was then recrystallized from 100 ml of n-hexane to obtain 8.1 g (yield: 58.9%) of N-phenyl-p-tertiarybutylaniline.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([OH:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:14]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([O:13][CH3:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(O)c(C)cc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1cc(OC)c(C)cc1Br

Procedure:
A mixture of 800 mg of material from step b. 10 ml of dry reagent grade acetone, 456 mg of K2CO3, and excess methyl iodide was stirred a refluxed for 3 days. Ether extraction provided the ester in a form suitable for further transformation.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:9]1)=O)(C)(C)C.[ClH:32]>O1CCOCC1>[ClH:32].[C:26]1([CH2:25][CH2:24][CH2:23][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][CH:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(COc2ccccc2CCCCc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(CCCCc2ccccc2OCC2CNCCO2)cc1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
671 mg of 4-t-butoxycarbonyl-2-[2-(4-phenylbutyl)phenoxymethyl]morpholine [prepared as described in step (a) above] was dissolved in 10 ml of a 4N solution of hydrogen chloride in dioxane, whilst ice-cooling, and the resulting solution was allowed to stand at room temperature for 30 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting oily residue was dissolved in 20 ml of ethyl acetate. The solution thus obtained was then allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo, to give 494 mg (yield 86%) of the title compound as colorless crystals, melting at 131°-132° C.
Reaction SMILES: Br[C:2]1[CH:12]=[N:11][C:5]2[O:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:13]1([C:2]2[CH:12]=[N:11][C:5]3[O:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=3[CH:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1COc2ncc(Br)cc2N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: O=C1COc2ncc(-c3ccccc3)cc2N1
Yield: 44.2 %

Procedure:
To a 10 ml flask equipped with refluxing apparatus, 7-bromo-1H-pyrido[2,3-b][1,4]oxazin-2-one (48 mg, 0.21 mmol), phenyl boronic acid (PhB(OH)2, 28 mg, 0.23 mmol), triphenylphosphine (PPh3, 11 mg, 0.04 mmol), palladium acetate (Pd(OAc)2, 5 mg, 0.02 mmol), potassium carbonate (44 mg, 0.31 mmol) were dissolved in acetonitrile (1.6 ml) and water (0.4 ml). The mixture was heated to 90□ and then refluxed for 15 hours. The mixture was evaporated and water was added, and then the mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica eluting with a solvent of dichloromethane:methanol=30:1. The fractions containing the product were collected and evaporated to obtain pale-brown solid (21 mg, 44%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[C:15]([O:19][C:20]([NH:22][C:23]1[O:27][N:26]=[C:25]([C:28](O)=[O:29])[CH:24]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.ClCCl.C(OCC)(=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:28]([C:25]1[CH:24]=[C:23]([NH:22][C:20](=[O:21])[O:19][C:15]([CH3:17])([CH3:16])[CH3:18])[O:27][N:26]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)Nc1cc(C(=O)O)no1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
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: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)no1
Yield: 94.5 %

Procedure:
This compound was prepared following Method A starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.505 g; 2.14 mmol), the INTERMEDIATE 14: 5-(tert-butoxycarbonylamino)isoxazole-3-carboxylic acid (0.513 g; 2.25 mmol), HATU (0.896 g; 2.36 mmol) and N,N-diisopropylethylamine (0.935 mL; 5.35 mmol) in DMF (5 mL). Flash chromatography on silica gel eluting with 2 to 20% of ethyl acetate in dichloromethane afforded 0.819 g (94%) of tert-butyl 3-(2-(5-chloro-1H-indol-3-yl)ethylcarbamoyl)isoxazol-5-ylcarbamate as a white solid.
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]([CH3:17])[C:12](OCC)=O)[NH:7][C:6]=2[C:5]([F:18])=[C:4]([F:19])[CH:3]=1.[NH2:20][C:21]1[CH:43]=[CH:42][C:24]([C:25]([NH:27][CH2:28][CH2:29][O:30][C:31]2[CH:41]=[CH:40][CH:39]=[CH:38][C:32]=2[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:26])=[CH:23][C:22]=1[NH:44][CH3:45]>CN1C(=O)N(C)CCC1>[F:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]([C:12]3[N:44]([CH3:45])[C:22]4[CH:23]=[C:24]([C:25]([NH:27][CH2:28][CH2:29][O:30][C:31]5[CH:41]=[CH:40][CH:39]=[CH:38][C:32]=5[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:26])[CH:42]=[CH:43][C:21]=4[N:20]=3)[CH3:17])[NH:7][C:6]=2[C:5]([F:18])=[C:4]([F:19])[CH:3]=1
Reactant: CCOC(=O)c1ccccc1OCCNC(=O)c1ccc(N)c(NC)c1
Reactant: CCOC(=O)C(C)c1nc2c(F)cc(F)c(F)c2[nH]1
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)c1ccccc1OCCNC(=O)c1ccc2nc(C(C)c3nc4c(F)cc(F)c(F)c4[nH]3)n(C)c2c1
Temperature: 195 °C
Reaction time: 4 h
Yield: 48.7 %

Procedure:
Ethyl 2-(4,6,7-trifluoro-1H-benzoimidazol-2-yl)propionate (988 mg, 3.63 mmol) and ethyl 2-[2-(4-amino-3-methylaminobenzoylamino)ethoxy]benzoate (1.3 g, 3.63 mmol) were combined and placed under vacuum for 4 hours and then further combined with DMPU (4 ml). The mixture was stirred until in solution, evacuated overnight under high vacuum to remove residual gases, heated to 195° C. under a nitrogen stream for 4 hours, cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica (stepwise gradient of 100% hexane to 100% ethyl acetate) and further purified by crystallization from MeOH/THF/water to provide ethyl 2-(2-{2-[1-(4,6,7-trifluoro-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-carbonylamino}ethoxy}benzoate (1.0 g, 49%) as a white crystalline solid:
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=O)[CH:11]([CH2:17][OH:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:1]([O:8][N:9]1[CH2:10][CH:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:17]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCC(CO)C(=O)NOCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCC1CN(OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To a mixture of 2-hydroxymethyl-heptanoic acid benzyloxyamide (5.36 g, 20.23 mmol) and triphenylphosphine (5.31 g, 20.23 mmol) in THF (200 mL) at 0° C. was added dropwise diethyl azodicarboxylate (3.3 mL, 20.23 mmol). The reaction was stirred at room temperature overnight. The reaction was then quenched by adding water (200 mL). The aqueous layer was extracted with EtOAc (200 mL×2). The combined organic layer was washed with brine, and dried over MgSO4. After removing the solvent under vacuum, the residue was purified by flash column chromatography (hexane:EtOAc 5/1) to provide the title compound (4.68 g, 94%). 1H NMR (400 MHz, CHCl3) δ 7.35–7.25 (m, 5H), 4.87 (s, 2H), 3.28 (t, J=4.85 Hz, 1H), 2.84 (q, J=2.35 Hz, 1H), 2.77 (m, 1H), 1.62 (m, 1H), 1.36 (m, 1H), 1.25 –1.16 (m, 6H), 0.88 (t, J=6.9 Hz, 3H). MH+ 248.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([S:28]([OH:31])(=O)=[O:29])=[CH:24][CH:23]=5)[CH:19]=[CH:18][CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.O=S(Cl)[Cl:34].CN(C=O)C>O=P(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([S:28]([Cl:34])(=[O:31])=[O:29])=[CH:24][CH:23]=5)[CH:19]=[CH:18][CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(Nc1cccc(-c2ccc(S(=O)(=O)O)cc2)n1)C1(c2ccc3c(c2)OCO3)CC1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Nc1cccc(-c2ccc(S(=O)(=O)Cl)cc2)n1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 75 °C

Procedure:
4-(6-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)pyridin-2-yl)benzenesulfonic acid (1.9 g, 4.3 mmol) was dissolved in POCl3 (30 mL) followed by the addition of SOCl2 (3 mL) and DMF (100 μl). The reaction mixture was heated at 70-80° C. for 15 min. The volatiles were evaporated and then re-evaporated with chloroform-toluene. The residual brown oil was diluted with chloroform (22 mL) and used for sulfonylation immediately. ESI-MS m/z calc. 456.0, found 457.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35]OS(C)(=O)=O>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: CS(=O)(=O)OCc1ccccn1
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4ccccn4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Yield: 29 %

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with methanesulfonic acid pyridin-2-ylmethyl ester (described in WO 9955318) gave the desired product in 29% yield;
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[C:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[N:4][N:3]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)[CH2:24][CH2:23]1>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=3)[C:2]([NH:21][CH:22]3[CH2:23][CH2:24][N:25]([CH2:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH:30]=4)[CH2:26][CH2:27]3)=[N:3][N:4]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2nnc(Cl)c3ccc(C)cc23)cc1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Product: COc1ccc(-c2nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c3ccc(C)cc23)cc1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-4-(4-methoxyphenyl)-6-methylphthalazine with 4-amino-1-(naphthalen-2-ylmethyl)piperidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5]([NH:28]C=O)[CH:6]=[C:7]([CH:19]1[CH2:24][CH2:23][N:22]([C:25](=[O:27])[CH3:26])[CH2:21][CH2:20]1)[CH2:8][P:9]([O:15]C(C)C)([O:11]C(C)C)=[O:10])[CH3:2].C[Si](C)(C)Br.C(O)C>ClCCl>[CH2:1]([O:3][C:4](=[O:31])[CH:5]([NH2:28])[CH:6]=[C:7]([CH:19]1[CH2:20][CH2:21][N:22]([C:25](=[O:27])[CH3:26])[CH2:23][CH2:24]1)[CH2:8][P:9]([OH:15])([OH:11])=[O:10])[CH3:2]
Reactant: CCOC(=O)C(C=C(CP(=O)(OC(C)C)OC(C)C)C1CCN(C(C)=O)CC1)NC=O
Agent: C[Si](C)(C)Br
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(N)C=C(CP(=O)(O)O)C1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3.15 g (6.84 mmol) of 4-(1-acetylpiperidin-4-yl)-5-diisopropylphosphono-2-formylamino-pent-3-enoic acid ethyl ester are dissolved in 17 ml of dichloromethane, and 3.54 ml (27.3 mmol) of trimethylbromosilane are added dropwise at room temperature. The mixture is left to stand at room temperature for 16 hours, 17 ml of ethanol are added dropwise, the mixture is left to stand for a further 18 hours and is concentrated by evaporation in a rotary evaporator, the residue is dissolved in 12 ml of ethanol, and a mixture of 3 ml of propylene oxide and 3 ml of ethanol is added. A suspension forms, which is stirred for a further 2 hours at room temperature and for 2 hours with ice cooling and is then filtered with suction. 2-amino-4-(1-acetylpiperidin-4-yl)-5-phosphono-pent-3-enoic acid ethyl ester having a melting point of 225° (decomp.) is obtained.