Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:4][NH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:22]([N:3]1[CH2:2][CH2:1][C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:4]1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: c1ccc2c(c1)CC[C@@H]1CNCC[C@@H]21
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(CCN2CC[C@H]3c4ccccc4CC[C@@H]3C2)cc1
Yield: 25.1 %

Procedure:
Following the procedure of Example 3, step 4, 0.307 g (1.64 mmol) of crude trans-1,2,3,4,4a,5,6,10b-octahydrobenz[f]isoquinoline in 8 ml of anhydrous DMF was reacted with 0.249 g (1.80 mmol) of anhydrous potassium carbonate and 0.222 ml (1.64 mmol) of (2-bromoethyl)benzene. Chromatography on flash silica, eluting with 20-50% ethyl acetate/petroleum ether, gave 0.12 g (25%) of the title product as a colourless oil. The hydrochloride salt was made using ethereal hydrogen chloride. Upon evaporation of the solvent the title product hydrochloride was obtained as a white solid, m.p. 277°-283° C. (dec). NMR δ(D2O) 1.54-1.92 (4H, m), 2.72 (2H, m), 2.93-3.00 (3H, m), 3.13-3.26 (3H, m), 3.46 (2H, t), 3.71 (1H, m), 3.84 (1H, m), 7.24-7.28 (3H, m), 7.37-7.44 (6H, m). m/z (CI+, NH3) 292 (M+H)+, 200 (M-CH2Ph)+. Analysis calcd. for C21H26ClN: C, 76.92; H, 7.99; N, 4.27%. Found: C, 76.94; H, 7.98; N, 4.44%.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[NH:14]1[CH2:19][CH2:18][S:17][CH2:16][CH2:15]1>C(O)(C)C>[Br:1][C:2]1[C:3]([N:14]2[CH2:19][CH2:18][S:17][CH2:16][CH2:15]2)=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(C)c([N+](=O)[O-])c(Cl)c1Br
Reactant: C1CSCCN1
Solvent: CC(C)O
Product: Cc1nc(C)c([N+](=O)[O-])c(N2CCSCC2)c1Br

Procedure:
11.68 Grams (0.044 mol) of 5-bromo-4-chloro-2,6-dimethyl-3-nitro-pyridine and 9.11 g (0.088 mol) of thiomorpholine are heated at boiling point for 18 hours in 50 ml of isopropanol. Upon completion of the reaction the solvent is removed, the residue is digested with water, and the yellow precipitate is filtered off with suction and recrystallized from isopropanol.
Reaction SMILES: [NH2:1][C:2]([C:27]1[CH:28]=[N:29][C:30]([Cl:33])=[CH:31][CH:32]=1)([C:21]1[N:22]([CH3:26])[CH:23]=[N:24][CH:25]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH:7]=[C:6]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1.[CH:34](=O)[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1.[OH-].N.C(OCC)(=O)C>C(O)(=O)C>[Cl:20][C:16]1[CH:15]=[C:14]([C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([C:2]([C:27]4[CH:28]=[N:29][C:30]([Cl:33])=[CH:31][CH:32]=4)([N:1]=[CH:34][C:35]4[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=4)[C:21]4[N:22]([CH3:26])[CH:23]=[N:24][CH:25]=4)[CH:4]=3)[NH:9][C:8](=[O:13])[CH:7]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Cn1cncc1C(N)(c1ccc(Cl)nc1)c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1
Agent: N
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(C=NC(c2ccc(Cl)nc2)(c2ccc3[nH]c(=O)cc(-c4cccc(Cl)c4)c3c2)c2cncn2C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.8 %

Procedure:
To a solution of the title compound of example 42 (11.89 g, 25.03 mmol) in acetic acid (75 ml) was added p-anisaldehyde (6.09 ml, 50.06 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 4 hours after which time it was cooled to 0° C. 10 ml of ammonia hydroxide was added followed by addition of ethyl acetate. After separation, the organic layer was washed with brine, dried over MgSO4 and concentrated under vacuum to yield the crude product. It was chromatographed on silica gel with MeOH—CHCl3—NH4OH (1:99:0.1 to 5:95:0.1) as eluents to afford the title compound of Example 43A as a white solid (11.58 g, 78% yield).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:7][C:8]2[O:12][C:11]([CH3:24])([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[CH2:10][C:9]=2[C:25]=1[C:26]([CH3:29])([CH3:28])[CH3:27])(=[O:3])[CH3:2]>C(OCC)(=O)C.[C].[Pd]>[C:1]([O:4][C:5]1[C:6]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:7][C:8]2[O:12][C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=3)([CH3:24])[CH2:10][C:9]=2[C:25]=1[C:26]([CH3:29])([CH3:28])[CH3:27])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(COc1ccc([N+](=O)[O-])cc1)O2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(COc1ccc(N)cc1)O2
Yield: 100 %

Procedure:
A solution of 5.5 g of 5-acetoxy-4,6-di-t-butyl-2-methyl-2-(4-nitrophenoxymethyl)-2,3-dihydrobenzofuran in 50 ml of ethyl acetate was catalytically reduced with 1.1 g of 10% palladium-carbon under a hydrogen atmosphere for 14 hours. After reaction, 10% palladium-carbon was filtered off and the solvent was distilled off to give 5.14 g of 5-acetoxy-2-(4-aminophenoxymethyl)-4,6-di-t-butyl-2-methyl-2,3-dihydrobenzofuran (rotamer mixture) as a colorless oil (yield 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[N:16][O:17][CH2:18][CH2:19][OH:20])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O[C:22]1[CH:54]=[CH:53][C:25]([CH2:26][CH:27]2[S:31][C:30](=[O:32])[N:29]([C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]2=[O:52])=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[N:16][O:17][CH2:18][CH2:19][O:20][C:22]3[CH:54]=[CH:53][C:25]([CH2:26][CH:27]4[S:31][C:30](=[O:32])[N:29]([C:33]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)[C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:28]4=[O:52])=[CH:24][CH:23]=3)[CH3:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=NOCCO)c1ccc(-c2ccc(C)cc2)cc1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(-c2ccc(C)cc2)cc1
Yield: 86.5 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 539 mg of 2-[1-(4'-methylbiphenyl-4-yl)ethylideneaminooxy]ethanol (prepared as described in Preparation 26), 931 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 577 mg of triphenylphosphine and 366 mg of diethyl azodicarboxylate, 1.24 g of the title compound were obtained as a foam-like solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:44])[C@H:15]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:26])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1.O=[CH:46][CH2:47][NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:51]([O:50][C:49]([NH:48][CH2:47][CH2:46][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:44])[C@H:15]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2[C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])=[O:26])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[CH2:10][CH2:9]1)=[O:55])([CH3:54])([CH3:53])[CH3:52]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2N)CC1
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Yield: 67.7 %

Procedure:
The title compound was prepared according to the procedure described in Example 25 (Step a) using tert-butyl 3-(N-{(1R)-2-[4-(2-aminophenyl)piperidyl]-1-[(4-chlorophenyl)methyl]-2-oxoethyl}carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Example 20) (462 mg, 0.75 mmol), tert-butyl N-(2-oxoethyl)carbamate (Aldrich) (131 mg, 0.83 mmol) and NaBH(OAc)3 (Aldrich) (176 mg, 0.83 mmol) in CH2Cl2 (20 mL). Purification by silica gel chromatography (1:10 McOH:EtOAc) provided the title compound as a white foam (386 mg). MS (ESI, pos. ion) m/z: 760 (M+1); (ESI, neg. ion) m/z: 758 (M−1). Calc'd for C42H54ClN5O6: 759.38.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Mg].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18].[Cl-].[NH4+]>O.O1CCCC1>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1)[OH:18]
Reactant: O=C(c1ccccc1)c1ccccc1F
Reactant: CN1CCC(Cl)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(C(O)(c2ccccc2)c2ccccc2F)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
To a stirred and refluxing Grignard complex previously prepared starting from 80.2 parts of 4-chloro-1-methylpiperidine, 14.6 parts of magnesium and 270 parts of tetrahydrofuran, was added dropwise a solution of 101 parts of (2-fluorophenyl)phenylmethanone in 450 parts of tetrahydrofuran. Upon completion, stirring was continued for 18 hours at reflux temperature. The reaction mixture was cooled in an ice-bath and decomposed with a solution of 32 parts of ammonium chloride in 160 parts of water. After stirring for 30 minutes, the product was filtered off and washed with tetrahydrofuran. The filtrate was evaporated, the residue was taken up in methylbenzene and the latter was evaporated again in a boiling water-bath. The residue was dissolved in 700 parts of 2,2'-oxybispropane. The turbid solution was filtered and gaseous hydrogen chloride was bubbled through the filtrate. The solid product was filtered off and suspended in 1000 parts of water. The suspension was treated with ammonium hydroxide and extracted twice with 280 parts of 1,1'-oxybisethane. The combined extracts were dried, filtered and evaporated. The oily residue was crystallized from 240 parts of acetonitrile. After cooling to 0° C., the product was filtered off and dried, yielding 66 parts (44%) of α-(2-fluorophenyl)-1-methyl-α-phenyl-4-piperidinemethanol (intermediate 33).
Reaction SMILES: [C:1]1(Cl)[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[CH3:8].O.O.B(F)(F)F.S(=O)(=O)(O)O>C1C=CC=CC=1>[CH2:7]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:1][C:2]=1[CH3:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cccc(Cl)c1C
Agent: FB(F)F
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccccc1Cc1ccccc1
Reaction time: 6 h
Yield: 91.1 %

Procedure:
A solution of 70 parts of xylyl chloride in 240 parts of benzene is added to a mixture of 60 parts of boron fluoride dihydrate and 250 parts of 75 per cent strength by weight sulfuric acid at from 75° to 78° C, whilst stirring vigorously. After 6 hours, the organic phase is separated off and 82 parts (91.1% of theory) of o-benzyl-toluene boiling at 98° C at 0.2 mm Hg are isolated by distillation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14]O)=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[C:10]([S:19][CH3:20])[N:9]=2)=[CH:4][CH:3]=1.ClCCl.P(Br)(Br)[Br:25]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14][Br:25])=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[C:10]([S:19][CH3:20])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CSc1nc(-c2ccc(F)cc2)c(CO)c(C(C)C)n1
Reactant: BrP(Br)Br
Solvent: O
Solvent: ClCCl
Product: CSc1nc(-c2ccc(F)cc2)c(CBr)c(C(C)C)n1
Yield: 90.1 %

Procedure:
14.6 g (50 mmol) of compound (9) and 200 ml of dichloromethane were added into a 500 mL three-neck round bottomed flask, equipped with a mechanical stirrer and a dropping funnel, followed by addition of 67 g (0.1 mol) of phosphorus tribromide dropwise at room temperature. After TLC assay showed that the starting compound (9) was depleted, 100 mL of water was added, and the organic layer was collected. The organic phase was then washed with 5% aqueous NaHCO3 solution, dried over anhydrous calcium chloride, and evaporated under reduced pressure to remove the solvent, obtaining 16 g raw product of compound (7), which was used directly in the next step without purification.
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].Cl.Cl.[CH2:26]([NH:33][NH2:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O>[CH2:26]([N:33]1[C:2]2[C:3](=[CH:14][CH:15]=[C:16]([OH:18])[CH:17]=2)[C:4]([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=2[OH:13])=[N:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Reactant: NNCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Oc1ccc(-c2nn(Cc3ccccc3)c3cc(O)ccc23)c(O)c1
Temperature: 90 °C
Yield: 37.3 %

Procedure:
A mixture of 2,2′,4,4′-tetrahydroxybenzophenone (0.123 g, 0.5 mmol), sodium acetate (0.164 g, 2.0 mmol) and benzylhydrazine dihydrochloride (0.39 g, 2.0 mmol) in 2 mL H2O was heated at 90° C. overnight. The cooled reaction mixture was partitioned with EtOAc and 1 N HCl. The organic layer was dried (Na2SO4) and concentrated in vacuo to give the crude product. The residue was purified by HPLC chromatography using a silica gel column 150×12 mm (Biotage) at 10 mL/min with methyl-t-butyl ether/hexane (1:3, v/v) to give 0.062 g of product as an amber solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].O.ON1C2C=CC=CC=2N=N1.[CH:38]1([C:41]2[N:46]=[C:45]([O:47][CH3:48])[C:44]([CH2:49][CH2:50][NH2:51])=[CH:43][CH:42]=2)[CH2:40][CH2:39]1.Cl.C(N=C=NCCCN(C)C)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:18])[NH:51][CH2:50][CH2:49][C:44]3[C:45]([O:47][CH3:48])=[N:46][C:41]([CH:38]4[CH2:39][CH2:40]4)=[CH:42][CH:43]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: COc1nc(C2CC2)ccc1CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(C5CC5)nc4OC)cc3)c(Cl)cc21
Reaction time: 5 h
Yield: 46.5 %

Procedure:
To a stirred solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (200 mg, 0.531 mmol) and 1-hydroxybenzotriazole monohydrate (89.4 mg, 0.584 mmol) was added 2-(6-cyclopropyl-2-methoxypyridin-3-yl)ethanamine (117 mg, 0.610 mmol) (in dimethylformamide, 3 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (112 mg, 0.584 mmol) was added and the reaction was stirred for 5 hours. The reaction was loaded onto silica gel and eluted with 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes to yield ethyl 6-chloro-7-(4-(2-(6-cyclopropyl-2-methoxypyridin-3-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylate (136 mg, 0.247 mmol, 46.5% yield). MS (apci+es, positive) m/z=552.2.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15](C=O)=[C:14]([CH:18]([CH3:20])[CH3:19])[N:13]=[C:12]([O:21][CH3:22])[C:11]=2[CH2:23][O:24][CH3:25])=[CH:6][CH:5]=1.O.O.C(O)(=O)C(O)=O.[O:34]1C[CH2:37][CH2:36][CH2:35]1>O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15](/[CH:37]=[CH:36]/[CH:35]=[O:34])=[C:14]([CH:18]([CH3:20])[CH3:19])[N:13]=[C:12]([O:21][CH3:22])[C:11]=2[CH2:23][O:24][CH3:25])=[CH:6][CH:5]=1
Reactant: COCc1c(OC)nc(C(C)C)c(C=O)c1-c1ccc(F)cc1
Reactant: C1CCOC1
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COCc1c(OC)nc(C(C)C)c(/C=C/C=O)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
804 (3.1 mmol) of diethyl 2-(cyclohexylamino)-vinyl-phosphate dissolved in 6 ml of dry tetrahydrofuran are added dropwise under nitrogen to a suspension of 59 mg (2.5 mmol) of sodium hydride in 6 ml of dry tetrahydrofuran at -5° C. After 30 min, 0.65 g (2.05 mmol) of the compound from Example 9 in 15 ml of dry tetrahydrofuran is added dropwise at the same temperature and the mixture is heated to reflux for 30 min. After cooling to room temperature, the mixture is added to 200 ml of ice-cold water and extracted three times using 100 ml of ethyl acetate each time. The combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulphate. After concentration in vacuo, the residue is taken up in 5 ml of toluene, treated with a solution of 0.9 g (7 mmol) of oxalic acid dihydrate in 12 ml of water and heated to reflux for 90 min. After cooling to room temperature, the phases are separated, and the organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. The residue is dissolved in methylene chloride and filtered through silica gel.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:15]2[N:16]=[N:17][NH:18][N:19]=2)[OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1>CN(C=O)C.CCOC(C)=O>[Si:24]([O:14][CH:13]([C:15]1[N:16]=[N:17][NH:18][N:19]=1)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:21]([CH3:23])([CH3:22])[CH3:20])([CH3:26])[CH3:25]
Reactant: OC(CCCCCCc1ccccc1)c1nn[nH]n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1nn[nH]n1
Yield: 74.4 %

Procedure:
A solution of 7-phenyl-1-(2H-tetrazol-5-yl)-heptan-1-ol (36 mg, 0.14 mmol), TBSCl (63 mg, 0.42 mmol) and imidazole (28 mg, 0.42 mmol) in DMF (0.7 mL) was stirred at room temperature for 72 h before it was diluted with EtOAc, and washed with H2O and saturated aqueous NaCl. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure to afford the crude material that was purified by flash chromatography (SiO2, 1.5×15 cm, 10% acetone-hexanes) to afford 5-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-2H-tetrazole (39 mg, 75%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 7.26 (dd, 2H, J=6.3, 8.4 Hz), 7.16 (m, 3H), 5.25 (t, 1H, J=5.8 Hz), 2.57 (t, 2H, J=7.7 Hz), 1.85 (m, 2H), 1.58 (m, 2H), 1.31 (m, 6H), 0.90 (s, 9H), 0.13 (s, 3H), 0.01 (s, 3H).
Reaction SMILES: Cl.[C:2]1([CH2:8][C:9](=[NH:13])[O:10][CH2:11][CH3:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(Cl)Cl.CCOC(C)=O>[CH2:18]([O:17][C:15]([N:13]=[C:9]([O:10][CH2:11][CH3:12])[CH2:8][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:16])[CH3:19]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=N)Cc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)N=C(Cc1ccccc1)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Ethyl 2-phenylacetimidate hydrochloride (1.7 g, 8.5 mmol) was dissolved in DCM (10.6 mL) and cooled to 0° C. TEA (7.1 mL, 51.1 mmol) was added dropwise the mixture was stirred for 1 h. Ethyl chloroformate (1.6 g, 14.8 mmol) was added and the reaction mixture was allowed to warm to RT and stirred for 12 h. The mixture was diluted with EtOAc (100 mL) and the solids were removed by filtration through diatomaceous earth. The filter cake was washed with EtOAc (3×10 mL) and the combined filtrates were concentrated in vacuo to afford ethyl N-ethoxycarbonyl-2-phenylacetimidate (1.9 g, 93%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 7.27-7.26 (m, 5H), 4.01-4.00 (m, 4H), 3.70 (s, 2H), 1.18-1.08 (m, 6H).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]([N:13]([CH2:32][C:33]([NH:35][CH2:36][C:37]1[CH:48]=[CH:47][C:40]([C:41]([O:43][CH2:44][C:45]#[N:46])=[O:42])=[C:39]([OH:49])[CH:38]=1)=[O:34])[CH2:14][C:15](=[O:31])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH2:27][C:28]#[N:29])=[O:25])=[C:20]([OH:30])[CH:19]=1)=[O:12])=O)(C)(C)C.FC(F)(F)C(O)=O>ClC(Cl)C>[NH2:8][CH2:9][CH2:10][C:11]([N:13]([CH2:14][C:15]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH2:27][C:28]#[N:29])=[O:25])=[C:20]([OH:30])[CH:19]=1)=[O:31])[CH2:32][C:33](=[O:34])[NH:35][CH2:36][C:37]1[CH:48]=[CH:47][C:40]([C:41]([O:43][CH2:44][C:45]#[N:46])=[O:42])=[C:39]([OH:49])[CH:38]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)NCCC(=O)N(CC(=O)NCc1ccc(C(=O)OCC#N)c(O)c1)CC(=O)NCc1ccc(C(=O)OCC#N)c(O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: N#CCOC(=O)c1ccc(CNC(=O)CN(CC(=O)NCc2ccc(C(=O)OCC#N)c(O)c2)C(=O)CCN)cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The crude Cyanomethyl 4-{[2-(3-[(tert-Butoxy)carbonylamino]-N-{[N-({4-[(cyanomethyl)oxycarbonyl]-3-hydroxyphenyl}methyl)carbamoyl]methyl}propanoyl-amino)acetylamino]methyl}-2-hydroxybenzoate from above was dissolved in 20 mL of dichloroethane and 10 mL of trifluoroacetic acid (26.0 mmole) was added. The deprotection reaction was stirred for 2 hours at room temperature. Dichloroethane and trifluoroacetic acid were removed in vacuo. The resulting oil was dissolved in 10 mL of ethyl acetate, and the resulting solution was added dropwise to 150 mL of rapidly stirred methyl tert-butyl ether. The product precipitated over the course of one hour and was collected by filtration, washed with methyl tert-butyl ether and dried in vacuo under a high vacuum. Obtained 2.78 grams (65% for two steps) of product as a white solid.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([O:18]C)=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)[CH:2]=1.[OH-].[Li+].CO>C1COCC1>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)[CH:2]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(-c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1cccc(-c2ccccc2)c1

Procedure:
The title compound was synthesized from methyl 4-(biphenyl-3-ylmethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.041 g, 0.124 mmol) and lithium hydroxide (0.055 g, 1.31 mmol in 1 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (2 mL) was used. The resulting product was purified by reverse phase HPLC, eluting with a gradient of 40-100% MeOH: water (with 0.1% formic acid) to afford the title compound: 24.0 mg, 61% yield. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.08-2.20 (m, 1H), 2.50-2.62 (m, 3H), 2.77-2.90 (m, 2H), 3.27-3.30 (m, 1H), 6.39 (s, 1H), 7.17 (d, J=7.57 Hz, 1H), 7.26-7.44 (m, 6H), 7.53-7.58 (m, 2H); LCMS-MS (ESI−) 316.2 (M−H); HPLC (UV=97.3%), (ELSD=100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH2:31]([N:33]=[C:34]=[O:35])[CH3:32]>CO.CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH:30][C:34]([NH:33][CH2:31][CH3:32])=[O:35])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CCN=C=O
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Solvent: CC#N
Solvent: CO
Product: CCNC(=O)Nc1nc2nc(NCCCN3CCN(C)CC3)ncc2cc1-c1c(Cl)cccc1Cl
Yield: 74.3 %

Procedure:
6-(2, 6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 36 was reacted with 0.159 g of ethyl isocyanate according to the general procedure of Example 37 to give 0.86 g of 1-{6-(2,6-dichlorophenyl)-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrido-[2,3-d]pyrimidin-7-yl}-3-ethyl-urea, MS (ES+20/80 MeOH/CH3CN+0.1% ACOH): M+ +H=517; mp 82-90° C.