Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[F:2][C:3]([F:13])([F:12])[CH2:4][N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1.C(O)CCC>CO.[Pd]>[F:2][C:3]([F:13])([F:12])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([NH2:1])[CH2:7][CH2:6]1
Reactant: N
Reactant: O=C1CCN(CC(F)(F)F)CC1
Agent: [Pd]
Solvent: CCCCO
Solvent: CO
Product: NC1CCN(CC(F)(F)F)CC1
Reaction time: 18 h

Procedure:
A 25% aqueous solution of ammonia (170 mL), 10% Pd/C (7.4 g), and a solution of the above 1-(2,2,2-trifluoroethyl)piperidin-4-one/butanol mixture (72.5 g, 0.344 mol, 86:14 weight ratio) in methanol (420 mL) were placed into a 2 L glass autoclave purged with argon. The reaction mixture was hydrogenated in a Parr apparatus at a hydrogen pressure of 40 psi for 18 h. The catalyst was removed by filtration. The filtrate was concentrated in vacuo to 150 mL. Potash (46 g) and ether (200 mL) were added, and the mixture was vigorously stirred for 20 min. The organic layer was separated, and the aqueous one was extracted with ether (100 mL). The combined organic layers were dried over anhydrous Na2SO4 and evaporated to afford a mixture (74.4 g) of 1-(2,2,2-trifluoroethyl)piperidin-4-amine and 1-(2,2,2-trifluoroethyl)-N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]piperidin-4-amine in 72:28 weight ratio (containing butanol). This mixture was fractionated at 7-8 mmHg on a 15 cm Vigreaux column (a fraction with bp 75-95° C. was collected) to afford 1-(2,2,2-trifluoroethyl)piperidin-4-amine (38.5 g) as a colorless liquid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]=1.[NH2:15][C:16]1[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]=[C:2]([NH:15][C:16]2[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[CH:18][CH:17]=2)[N:7]=1
Reactant: FC(F)(F)COc1nc(Cl)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)cc1
Reaction time: 16 h
Yield: 65 %

Procedure:
To a solution of 2,4-dichloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazine (10 g, 40.3 mmol) in THF (100 mL) was added tert-butyl 4-aminobenzoate (7.79 g, 40.3 mmol) and Hunig's Base (7.04 mL, 40.3 mmol). The resulting mixture was stirred for 16 h. The precipitate was filtered and washed with Et2O, dried, then washed with water and dried to give the tert-butyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (10.6 g).
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[CH2:3][C:4]1[C:5]([O:16]C(=O)C)=[CH:6][CH:7]=[C:8]([O:12]C(=O)C)[C:9]=1[CH2:10]2.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C1(C)C(C)=CC=CC=1>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([C@@H:2]2[CH2:3][C:4]3[C:5]([OH:16])=[CH:6][CH:7]=[C:8]([OH:12])[C:9]=3[CH2:10][C@H:11]2[OH:1])[CH2:30][CH2:29]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CC(=O)Oc1ccc(OC(C)=O)c2c1CC1OC1C2
Solvent: Cc1ccccc1C
Product: COc1ccccc1N1CCN([C@@H]2Cc3c(O)ccc(O)c3C[C@H]2O)CC1
Yield: 21.6 %

Procedure:
A solution of 13.1 g of 6,7-epoxy-5,6,7,8-tetrahydro-1,4-diacetoxynaphthalene and 29.8 g of 1-(o-methoxyphenyl)piperazine in 200 ml of xylene is refluxed under nitrogen for 48 hours. The reaction mixture is then cooled, the crystalline precipitate filtered, washed with ether, and dried in vacuo to afford 10.55 g of crude crystalline product. Recrystallization of 7.50 g of this material from ethyl acetate/ethanol gives 4.0 g of the title compound, melting point 222°-224° C.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[C:10]1[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][CH:11]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[C:10]1[CH:19]=[CH:18][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(-c2nc3ccccc3[nH]2)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCc1ccc(-c2nc3ccccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a solution of methyl 4-(benzimidazol-2-yl)-benzoate (0.23 g, 0.9 mmol) in THF (10 mL) at 0° C. was added a solution of DIBAL-H (5.0 mL, 1.0 M in THF, 5.0 mmol). The reaction was allowed to warm to room temperature, stirred for 1 h and quenched with a saturated potassium sodium tartrate solution (20 mL). The biphasic mixture was stirred vigorously for 1 h, the phases separated and the organic layer dried (MgSO4), filtered, concentrated and purified by column chromatography on silica gel (7% MeOH/CH2Cl2) to give 4-(benzimidazol-2-yl)-benzyl alcohol (0.175 g, 87%). 1H NMR (CD4OD) δ3.30 (s, 1H (OH)), 4.69 (s, 2H), 7.26 (m, 2H), 7.53 (d, 2H, J=8.4 Hz), 7.60 (m, 2H), 8.07 (d, 2H, J=8.1 Hz).
Reaction SMILES: FC1C=CC([C:8]2[C:9](=[O:23])[N:10]([CH3:22])[C:11](SC)=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=CC=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1C(N)CCN>>[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:11]2[N:10]([CH3:22])[C:9](=[O:23])[CH:8]=[C:13]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)[N:12]=2)=[CH:27][CH:26]=1
Reactant: CSc1nc(-c2ccncc2)c(-c2ccc(F)cc2)c(=O)n1C
Reactant: NCCC(N)c1ccccc1F
Product: Cn1c(-c2ccc(F)cc2)nc(-c2ccncc2)cc1=O
Reaction time: 3 h

Procedure:
2-34 2-((3-Amino-3-(2-fluorophenyl)propyl-amino)-5-(4-fluorophenyl-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone was prepared from 5-(4-fluorophenyl)-3-methyl-2-methylthio-6-(4-pyridyl)-4(3H)-pyrimidinone and 1-(2-fluorophenyl)-1,3-propanediamine according to the General Procedure. The reaction was done at 190μ C. for 3 h. MS (m/z): 448.1 (M+H)+; C25H23F2N5O requir. 447.5 (free base).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([O:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][OH:15])=[CH:10][CH:9]=1)[CH2:5][CH3:6].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](F)[N:20]=1>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[F:18][C:19]1[N:20]=[C:21]([O:15][CH2:14][CH2:13][O:12][C:11]2[CH:16]=[CH:17][C:8]([O:7][CH:4]([CH3:3])[CH2:5][CH3:6])=[CH:9][CH:10]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: CCC(C)Oc1ccc(OCCO)cc1
Reactant: Fc1cccc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCC(C)Oc1ccc(OCCOc2cccc(F)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of sodium hydride (0.12 g) in 5 ml of THF and 4 ml of HMPA, cooled in an ice bath, is added, dropwise, a solution of 2-[4-(1-methylpropoxy)phenoxy]ethanol (1.00 g) in 5 ml of THF. The mixture is stirred at RT for 2 hours, after which 2,6-difluoropyridine (0.65 g) is added and the mixture is stirred at RT overnight. The THF is removed by rotoevaporation and the product is isolated by column chromatography on silica gel to give 6-fluoro-2-{2-[4-(1-methylpropoxy)phenoxy]ethoxy}pyridine, MS m/e 306 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[N+:9]([O-])([OH:11])=[O:10].[OH-].[Na+]>S(=O)(=O)(O)O>[NH2:1][C:2]1[C:7]([N+:9]([O-:11])=[O:10])=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
100 ml of concentrated sulfuric acid were added to 25.0 g of 2-amino-5-bromopyridine, and 8.9 ml of concentrated nitric acid were then added dropwise to the mixture at a temperature of 50° to 60° C. over a period of 1 hour. The mixture was then stirred at 60° C. for 30 minutes. At the end of this time, the reaction mixture was poured into ice-water and neutralized by the addition of an aqueous solution of sodium hydroxide. The crystals which precipitated were collected by filtration and washed with ethanol, to give 19.1 g of the title compound, melting at 180°-182° C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](=[O:22])[NH:19][C:18]4=[O:23])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[C:30]([O:34][C:35]([N:37]1[CH2:41][C@@H:40](O)[C@H:39]([F:43])[CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35]([N:37]1[CH2:38][C@H:39]([F:43])[C@H:40]([N:19]2[C:18](=[O:23])[C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=3[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]4)[S:21][C:20]2=[O:22])[CH2:41]1)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](F)C1
Reactant: O=C1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CC(C)(C)OC(=O)N1C[C@@H](N2C(=O)SC(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)[C@@H](F)C1

Procedure:
3-{5-[1-(4-Chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-2,4-dioxothiazolidin-3-yl}-(cis)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]thiazolidine-2,4-dione (from Example 1) and (trans)-3-fluoro-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester following General Procedure J.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC>C1COCC1>[CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[N:14]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:26](=[O:28])[NH:24][C:8]=12)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(CC)Oc1cc(C)nc2c1[nH]c(=O)n2-c1c(C)cc(C)cc1C

Procedure:
The title compound was prepared by reacting 4-(1-ethyl-propoxy)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3-diamine with triphosgene, NEt3 in THF at room temperature. A white solid was isolated, mp. 184–186° C. Anal. For C21H27N3O2 calc. C, 71.36; H, 7.70; N, 11.89; found: C, 71.09; H, 7.75; N, 11.63.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[N:11][N:10]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1.[ClH:36]>C(Cl)Cl>[ClH:36].[F:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([N:6]2[CH2:7][C@@H:2]([CH3:1])[N:3]([C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)=[N:11][N:10]=3)[CH2:4][C@@H:5]2[CH3:8])=[O:35])=[CH:29][CH:28]=1
Reactant: C[C@@H]1CN(c2nnc(-c3ccc(F)cc3)c3ccccc23)[C@@H](C)CN1
Reactant: O=C=Nc1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)Nc2ccc(F)cc2)[C@@H](C)CN1c1nnc(-c2ccc(F)cc2)c2ccccc12
Yield: 43 %

Procedure:
Treat a solution of 1-(trans-2,5-dimethylpiperazin-1-yl)-4-(4-fluorophenyl)phthalazine (0.3 g, 0.89 mmol) in CH2Cl2 (5 mL) with 1-fluoro-4-isocyanatobenzene (0.17 g, 1.25 mmol). Stir the reaction at ambient temperature for 1 h. Purify the reaction mixture by flash silica gel chromatography (0-50% EtOAc in hexanes). Pool and concentrate the appropriate fractions. Dissolve the mixture of N-(4-fluorophenyl)-4-(4-(4-fluorophenyl) phthalazin-1-yl)-trans-2,5-dimethylpiperazine-1-carboxamide isomers (0.3 g, 0.59 mmol) in MeOH (2 mL). Separate the mixture of trans-isomers by chiral chromatography (Chiralcel OJ-H, flow rate 30 mL/min, detection 225 nm, 6:4 MeOH: acetonitrile). Collect first eluting peak as Isomer 1 and the second eluting peak as Isomer 2. Pool and concentrate appropriate fractions. Dissolve the separated isomers in MeOH (1 mL) and treat each solution with 1 equivalent of 1 N aqueous HCl. Concentrate to give the hydrochloride salts of Isomer 1 (0.131 g, 44%) and Isomer 2 (0.129 g, 43%). Isomer 1: ES/MS m/z 474.2 (M+1), 99% ee. Isomer 2: ES/MS m/z 474.2 (M+1), 99% ee.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:34]([NH:37][CH2:38][CH2:39][CH3:40])[CH2:35][CH3:36]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([N:37]([CH2:38][CH2:39][CH3:40])[CH2:34][CH2:35][CH3:36])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: C[C@@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CCCNCCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)[C@H](C)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 50 °C
Yield: 52.1 %

Procedure:
A solution of (S)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0166 mole), 1,1'-carbonyldiimidazole (3.21 g, 0.0198 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 3 hours with nitrogen bubbling through it. A solution of dipropylamine (5.04 g, 0.050 mole) in tetrahydrofuran (7 ml) was added and the solution was heated at 50° C. overnight under nitrogen. The solvents were evaporated under reduced pressure and the resulting oil was partitioned between ethyl acetate (50 ml) and water (50 ml). The layers were separated and the aqueous layer was re-extracted with ethyl acetate (50 ml). The combined organic layers were washed once with water (50 ml) followed by two (50 ml) portions of 5% potassium hydroxide solution and then by water again (50 ml). The organic layer was dried over magnesium sulfate, charcoaled, filtered and evaporated to an oil which was crystallized from hot isopropyl ether. The solid was collected by filtration, and dried under high vacuum at room temperature to give 3.33 g (52%) of title compound, mp 96°-99° C.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C@@H:20]([CH2:26][CH:27]1[CH2:29][CH2:28]1)[C:21]([N:23]([CH3:25])[CH3:24])=[O:22]>>[CH:27]1([CH2:26][C@H:20]([NH:19][C:15]([C:7]2[CH:6]=[N:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[C:21](=[O:22])[N:23]([CH3:24])[CH3:25])[CH2:29][CH2:28]1
Reactant: CN(C)C(=O)[C@@H](N)CC1CC1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: CN(C)C(=O)[C@H](CC1CC1)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 6, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g) and (S)-2-amino-3-cyclopropyl-N,N-dimethyl-propionamide hydrochloride (1:1) (Example 25b) as starting materials, and isolated (80 mg, 86%) as light yellow oil; LC-MS (UV peak area, ESI) 100%, 373.2231 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][N:18]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:23][C:22]1[C:17]([CH3:16])=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1ncccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cccnc3C)c2cc1OC
Temperature: 135 °C
Reaction time: 48 h
Yield: 99.8 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (245 mg), 2-methyl-3-pyridinol (227 mg), and 4-dimethylaminopyridine (420 mg) were suspended in o-dichlorobenzene (13 ml), and the suspension was stirred at 135° C. for 2 days. The reaction solution was cooled to room temperature. The solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography using acetone-chloroform to give the title compound (324 mg, yield 100%).
Reaction SMILES: [P:1]([O:8]CC)([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[CH3:11][O:12][C:13](=[O:37])[CH:14]([NH:34][CH:35]=[O:36])[CH:15]=[C:16]([CH2:32]Br)[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>>[CH3:11][O:12][C:13](=[O:37])[CH:14]([NH:34][CH:35]=[O:36])[CH:15]=[C:16]([CH2:32][P:1]([O:2][CH2:3][CH3:4])([O:5][CH2:6][CH3:7])=[O:8])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]
Reactant: CCOP(OCC)OCC
Reactant: COC(=O)C(C=C(CBr)CCCCNC(=O)OCc1ccccc1)NC=O
Product: CCOP(=O)(CC(=CC(NC=O)C(=O)OC)CCCCNC(=O)OCc1ccccc1)OCC

Procedure:
5 ml of triethyl phosphite are added to 1.45 g (3.3 mmol) of 8-(N-benzyloxycarbonylamino)-4-bromomethyl-2-formylamino-oct-3-enoic acid methyl ester, and the mixture is heated at 75° for 8 hours with stirring. The excess triethyl phosphite is distilled off under reduced pressure to give an oily residue which is purified by chromatography on a silica gel column with first ethyl acetate and then ethyl acetate/methanol (9:1). 8-(N-benzyloxycarbonylamino)-4-diethylphosphonomethyl-2-formylamino-oct-3-enoic acid methyl ester is obtained.
Reaction SMILES: C1(=O)[O:6][C:4](=O)[CH:3]2[CH2:7][CH2:8][CH:9]=[CH:10][CH:2]12.C1(=O)O[C:15](=[O:16])C2CCCCC12>>[CH:3]1([CH2:4][OH:6])[CH2:2][CH2:10][CH:9]([CH2:15][OH:16])[CH2:8][CH2:7]1
Reactant: O=C1OC(=O)C2CCC=CC12
Reactant: O=C1OC(=O)C2CCCCC12
Product: OCC1CCC(CO)CC1

Procedure:
Tetrahydrophthalic anhydride was obtained from Janssen Chemical. Hexahydrophthalic anhydride and hydrogenated bisphenol A were obtained from Milliken Chemical. 1,4-Cyclohexanedimethanol was obtained from either Aldrich Chemical Co. or from Eastman Chemical Co. 1,4-Cyclohexane dicarboxylic acid was provided by Eastman Chemical Co. Trimethylolpropane mentioned in the examples below was obtained from Aldrich Chemical Co. Tin catalyst (Fascat 4100) was obtained from Elf Atochem. Equilibrium peracetic acid (35%) was purchased from Aldrich Chemical Co.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].[C:10]1([CH2:16][CH2:17][C:18](=O)[CH3:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O>[C:2]([NH:6][N:7]=[C:18]([CH2:17][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:19])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)NN
Reactant: CC(=O)CCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(CCc1ccccc1)=NNC(C)(C)C
Yield: 49 %

Procedure:
A solution of 50.46 g t-butyl hydrazine hydrochloride and 32 g of 50 percent aqueous sodium hydroxide in 70 ml of water is stirred in an ice water bath. About 55 g of 4-phenyl-2-butanone is added with stirring. The reaction and isolation are continued as in Example (a). The title compound is isolated as a fraction distilled under 0.9 mm pressure at 110° C.-119° C. The yield is about 49 percent based upon the initial amount of 4-phenyl-2-butanone added.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([CH3:6])[CH2:4][OH:5].[Cl:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3F)[N:18]=[CH:17][N:16]=2)[CH:11]=[CH:10][C:9]=1[OH:26]>>[Cl:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[O:5][CH2:4][C@H:3]([NH:2][CH3:1])[CH3:6])[N:18]=[CH:17][N:16]=2)[CH:11]=[CH:10][C:9]=1[OH:26]
Reactant: Oc1ccc(Nc2ncnc3cccc(F)c23)cc1Cl
Reactant: CN[C@H](C)CO
Product: CN[C@H](C)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Yield: 100 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using (2R)-2-(methylamino)propan-1-ol (obtained as described in Becker et al., J. Chem. Soc. 1957, 858) and 2-chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol (obtained as described in Example 4.5, preparation of starting materials) to give 2-chloro-4-[(5-{[(2R)-2-(methylamino)propyl]oxy}quinazolin-4-yl)amino]phenol in >100% yield; NMR spectrum (DMSO-d6) 1.20 (d, 3H), 2.40 (s, 3H), 3.30 (m, 1H), 4.25 (dd, 1H), 4.35 (dd, 1H), 7.00 (d, 1H), 7.10 (d, 1H), 7.30 (d, 1H), 7.60 (dd, 1H), 7.70 (t, 1H), 7.90 (d, 1H), 8.50 (s, 1H); Mass spectrum MH+ 359.1
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH3:21])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:20])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:19])[C:16]([OH:18])=O)=[O:5])[CH3:2].[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH3:21])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:20])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:19])[C:16]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:18])=[O:5])[CH3:2]
Reactant: C1CCNCC1
Reactant: CCOC(=O)C=C(C)CCC=C(C)CCC=C(C)C(=O)O
Product: CCOC(=O)C=C(C)CCC=C(C)CCC=C(C)C(=O)N1CCCCC1

Procedure:
Starting materials: 11-ethoxycarbonyl-2,6,10-trimethyl-2,6,10-undecatrienoic acid and piperidine.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[CH2:28][C:29]([OH:31])=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[CH3:33][NH:34][O:35][CH3:36].ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[CH2:28][C:29]([N:34]([O:35][CH3:36])[CH3:33])=[O:31])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CNOC
Reactant: O=C(O)Cc1cc(Cl)ccc1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)Cc1cc(Cl)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(3-Dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (8.6 g) was added to a solution of (2-benzyloxy-5-chlorophenyl)-acetic acid (10.6 g), N,O-dimethylhydroxylamine hydrochloride (4.4 g), 1-hydroxybenzotriazole (6.9 g) and N,N-diisopropylethylamine (20 ml) in DMF (150 ml) and the mixture stirred at RT for 16 h, then partitioned between ethylacetate and water. The organics were washed with 2M hydrochloric acid, water, dried, and evaporated under reduced pressure. Yield 12.2 g
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:40])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([NH:29][C@@H:30]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[C:31](O)=[O:32])=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.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.[CH2:74]([O:76][C:77]([N:79]1[CH2:84][CH2:83][NH:82][CH2:81][CH2:80]1)=[O:78])[CH3:75]>CN(C=O)C>[CH2:74]([O:76][C:77]([N:79]1[CH2:80][CH2:81][N:82]([C:31](=[O:32])[C@@H:30]([NH:29][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)=[O:40])[N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:19]=2)=[O:28])[CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:83][CH2:84]1)=[O:78])[CH3:75]
Reactant: O=C(N[C@H](C(=O)O)C1CCCCC1)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reactant: CCOC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)[C@@H](NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)C2CCCCC2)CC1
Reaction time: 12 h

Procedure:
To a mixture of 122 mg (S)-({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-cyclohexyl-acetic acid in 2.5 ml DMF were added 84 mg HATU, 116 l DIPEA and 32 l 1-ethoxycarbonylpiperazine. After stirring for 12 h it was concentrated and the crude product thus obtained was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound. Yield: 60 mg MS (ES+): m/e=692.