Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:14][N:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16](Cl)=[O:17]>>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:3][C:2]([O:1][C:16](=[O:17])[N:15]([CH3:14])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:7][CH:6]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(-c2ccccc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-hydroxybiphenyl and N-methyl-N-phenylcarbamoyl chloride applying. The crude product was recrystallized (ethanol) (75%, white crystals).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][C@H:9]1[C@H:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:12][N:11]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:10]1)=[O:7].[H-].[Na+]>C1COCC1>[O:7]=[C:6]1[CH2:5][CH2:4][CH2:3][CH2:2][N:8]1[C@H:9]1[C@H:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:12][N:11]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:10]1
Reactant: CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1NC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1N1CCCCC1=O
Yield: 85.9 %

Procedure:
To a solution of trans-1-tert-butyl 4-ethyl 3-(5-bromopentanamido)piperidine-1,4-dicarboxylate 8 (3.0 g, 6.9 mmol, 1.0 equiv) in THF (20 mL), NaH (276 mg, 6.9 mmol, 1.0 equiv) was carefully added in small portions at 0° C. The reaction solution was stirred at reflux condition for 4 h. The mixture was quenched with H2O (20 mL), and extracted with EtOAc (30 mL×3). The organic layer was collected, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica, petroleum ether/EtOAc=1:2) to give (trans)-1′-tert-butyl 4′-ethyl 2-oxo-[1,3′-bipiperidine]-1′,4′-dicarboxylate 9 as a slight yellow oil (2.1 g, yield: 88%). ESI-MS (M+H-56)+: 299.1. 1H NMR (400 MHz, CDCl3) δ: 4.10 (q, 4H), 3.38-3.19 (m, 4H), 2.70-2.61 (m, 1H), 2.36-2.31 (m, 2H), 1.95-1.92 (m, 1H), 1.75-1.71 (m, 6H), 1.46 (s, 9H), 1.23 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2]>CO.[Rh]>[C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCc1ccccc1)C(=O)O
Agent: [Rh]
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Yield: 89.4 %

Procedure:
A solution of (R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-phenylpentanoic acid (2.2 g, 7.5 mmol) and 5%Rh/C (0.22 g) in methanol (220 ml) was stirred at room temperature, under hydrogen (150 p.s.i.) for 24 hours and then filtered through celite. The filtrate was concentrated in vacuo to leave the title compound as an oil (2.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19])[CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11](=O)[NH:12][N:13]=1.P(Cl)(Cl)([Cl:24])=O.[OH-].[Na+]>O>[Cl:24][C:11]1[N:12]=[N:13][C:8]([CH2:7][CH2:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:17]([O:18][CH3:19])=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:9][CH:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(CCc2ccc(=O)[nH]n2)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(CCc2ccc(Cl)nn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-(3,4,5-Trimethoxyphenethyl)pyridazin-3(2H)-one (2.80 g; 9.65 mmol) and phosphorus oxychloride (70 ml) was heated at 100° for 1 h, cooled to room temperature and hydrolysed by careful, gradual addition to water over 3 h, so that the temperature did not exceed 30°. The mixture was then basified to pH12 by the addition of sodium hydroxide solution (10N, 700 ml) and then left at 4° overnight. The precipitate was filtered at the pump, washed well with water to remove inorganic salts and the residue on the sinter taken up in dichloromethane. After drying (sodium sulphate), removal of the solvent gave a light-brown solid (2.84 g) which was purified by `flash` chromatography on silica, with 10% of ethyl acetate/dichloromethane as the eluent. Appropriate fractions were combined to give a white solid (2.16 g), m.p. 105°-106°.
Reaction SMILES: [CH:1]([NH:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:7]=[C:6]1[CH3:18])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:27])C=1.C([O-])([O-])=O.[Na+].[Na+]>ClCCCl>[CH:1]([NH:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-:27])=[CH:9][C:8]=2[N:7]=[C:6]1[CH3:18])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nc2cnc3ccccc3c2n1NC(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2c[n+]([O-])c3ccccc3c2n1NC(C)C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
A solution of N-isopropyl(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)amine (1.84 g, 7.66 mmol) dissolved in 50 mL of 1,2-dichloroethane was treated with MCPBA (77% max., 2.36 g, 9.58 mmol). After stirring for 3 h, the reaction mixture was treated with 2% Na2CO3 solution and extracted into CH2Cl2. The organic portion was washed with saturated 2% Na2CO3 solution, H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated to give N-isopropyl(2-methyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)amine (1.95 g) as a light orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[CH3:20])=[C:4]([Cl:23])[CH:3]=1.ON1C2C=CC=CC=2N=N1.[Br:34][CH2:35][CH2:36][CH2:37][C:38](O)=[O:39].O>CN(C)C=O.Cl.CN(C)CCCN=C=NCC>[Br:34][CH2:35][CH2:36][CH2:37][C:38]([NH:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[CH3:20])=[C:4]([Cl:23])[CH:3]=1)=[O:39]
Reactant: O=C(O)CCCBr
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(N)cc3Cl)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(NC(=O)CCCBr)cc3Cl)c2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.8 %

Procedure:
Methyl 3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (450 mg) was suspended in N,N-dimethylformamide (5 ml) and 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (391 mg), 1-hydroxybenzotriazole (276 mg) and 4-bromobutanoic acid (318 mg) were added, which was followed by stirring at room temperature for 24 hr. Water (50 ml) was added to the reaction mixture under ice-cooling and the precipitated crystals were collected by filtration and dried under reduced pressure with heating to give methyl 3-(4-((4-bromobutyryl)amino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (436 mg) as pale-yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:29](OC)(OC)(OC)[CH2:30][CH2:31][CH3:32]>>[CH2:30]([C:29]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:31][CH3:32]
Reactant: CCOC(=O)CCCCCCCCCCCNc1c(N)cnc2ccccc12
Reactant: CCCC(OC)(OC)OC
Product: CCCc1nc2cnc3ccccc3c2n1CCCCCCCCCCCC(=O)OCC
Yield: 93.1 %

Procedure:
The general method described in Step 3 of Example 15 was used to cyclize ethyl 12-(3-aminoquinolin-4-ylamino)dodecanoate (30.4 g, 78.8 mmol) by reaction with trimethyl orthobutyrate (13.4 g, 90.6 mmol) to provide ethyl 12-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)dodecanoate (32.1 g) as a solid that was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].[CH2:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)[CH2:21][CH3:22]>>[C:9]1([C:7]2[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[NH:4][C:3](=[O:19])[CH:2]([NH:1][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:23]([CH2:20][CH2:21][CH3:22])=[CH:24][CH:25]=3)[N:8]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Reactant: CCCc1ccc(C(=O)Cl)cc1
Product: CCCc1ccc(C(=O)NC2N=C(c3ccccc3)c3ccccc3NC2=O)cc1

Procedure:
The procedure of Example 134 was carried out using 3(RS)-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (39.2 mg, 0.156 mmole) in place of 1,3-dihydro-3(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin- 2-one and 4-n-propylbenzoyl chloride (28.5 mg, 0.156 mmole) in place of p-trifluoromethylbenzoyl chloride. The product was chromatographed on silica gel (15% (v/v) Et2O in CH2Cl2 elution). The combined product fractions were evaporated to dryness in vacuo and crystallized from Et2O to give the title compound which was dried in vacuo at 82° C.: (m.p.. 158°-162° C.).
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10].CC([O-])(C)C.[K+].O>O1CCCC1>[CH3:13][C:8]1([C:9]([O:11][CH3:12])=[O:10])[C:1]2([CH2:5][CH2:4][CH2:3][CH2:2]2)[O:6]1
Reactant: COC(=O)C(C)Cl
Reactant: O=C1CCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(C)OC12CCCC2
Reaction time: 1.5 h
Yield: 56.6 %

Procedure:
9.3 g (0.11 mol) of cyclopentanone and 13.5 g (0.11 mol) of methyl 2-chloropropionate are cooled to 0 to 2° C.; at this temperature, 13.6 g (0.12 mol) of potassium tert-butylate suspended in 200 ml of tetrahydrofuran are added slowly dropwise with stirring over a period of about 90 minutes, after which the mixture is stirred for a further 60 minutes without cooling. A little water is added to the reaction mixture, which is subjected to extraction with diethyl ether; the organic phase is dried over sodium sulfate, the drying agent is filtered off, and evaporation of the solvent gives 10.6 g of methyl 2-methyl-1-oxaspiro[2.4]heptane-2-carboxylate, which can be employed without further purification in the subsequent stage (see b).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][C:4]([CH3:10])=[N:3]1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][CH:44]=1)[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[N:35]=2)[N:32]=1>CN(C)C(=O)C.O1CCCC1>[C:37]([NH:36][C:34]1[N:35]=[C:30]2[CH:29]=[CH:28][C:27]([O:26][C:25]3[CH:24]=[C:23]([NH:22][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[CH:5]=4)=[O:9])[CH:44]=[CH:43][CH:42]=3)=[N:32][N:31]2[CH:33]=1)(=[O:41])[CH:38]([CH3:40])[CH3:39]
Reactant: CC(C)C(=O)Nc1cn2nc(Oc3cccc(N)c3)ccc2n1
Reactant: Cc1cc(C(=O)O)n(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C(C)C)cn4n3)c2)n(C)n1
Yield: 72.5 %

Procedure:
Using 1,3-dimethyl-1H-pyrazole-5-carboxylic acid (108 mg, 0.77 mmol), tetrahydrofuran (3.2 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (134 μL, 1.54 mmol), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-methylpropanamide (200 mg, 0.64 mmol) and N,N-dimethylacetamide (4.0 mL) as starting materials and in the same manner as in Example 119, the title compound (201 mg, 72%) was obtained as a white powder.
Reaction SMILES: BrC1C([C@H](NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)CC2C=C(F)C=C(F)C=2)=NC(SC)=NC=1.[F:37][CH:38]([F:56])[C:39]1[C:47]2[C:46]([F:49])([F:48])[CH2:45][CH2:44][C:43]([F:51])([F:50])[C:42]=2[N:41]([CH2:52][C:53]([OH:55])=O)[N:40]=1.Cl.[N:58]1([CH2:63][CH2:64][NH:65][C:66]2[N:71]=[C:70]([C@@H:72]([NH2:82])[CH2:73][C:74]3[CH:79]=[C:78]([F:80])[CH:77]=[C:76]([F:81])[CH:75]=3)[C:69]([C:83]3[CH:84]=[CH:85][C:86]([F:92])=[C:87]([CH:91]=3)[C:88]([NH2:90])=[O:89])=[CH:68][N:67]=2)[CH:62]=[CH:61][N:60]=[N:59]1>>[N:58]1([CH2:63][CH2:64][NH:65][C:66]2[N:71]=[C:70]([C@@H:72]([NH:82][C:53](=[O:55])[CH2:52][N:41]3[C:42]4[C:43]([F:50])([F:51])[CH2:44][CH2:45][C:46]([F:49])([F:48])[C:47]=4[C:39]([CH:38]([F:37])[F:56])=[N:40]3)[CH2:73][C:74]3[CH:79]=[C:78]([F:80])[CH:77]=[C:76]([F:81])[CH:75]=3)[C:69]([C:83]3[CH:84]=[CH:85][C:86]([F:92])=[C:87]([CH:91]=3)[C:88]([NH2:90])=[O:89])=[CH:68][N:67]=2)[CH:62]=[CH:61][N:60]=[N:59]1
Reactant: O=C(O)Cn1nc(C(F)F)c2c1C(F)(F)CCC2(F)F
Reactant: NC(=O)c1cc(-c2cnc(NCCn3ccnn3)nc2[C@@H](N)Cc2cc(F)cc(F)c2)ccc1F
Agent: CSc1ncc(Br)c([C@@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1
Agent: Cl
Product: NC(=O)c1cc(-c2cnc(NCCn3ccnn3)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)ccc1F

Procedure:
The title compound (23F) was prepared according to the method presented for the synthesis of compound 11G of Example 11 utilizing 2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid and 23E. 1H NMR (400 MHz, CD3OD) δ 8.71 (d, J=7.6 Hz, 1H), 8.06 (s, 1H), 7.99 (s, 1H), 7.74 (s, 1H), 7.43-7.25 (m, 2H), 7.20 (dd, J=10.8, 8.5 Hz, 1H), 6.97-6.58 (m, 2H), 6.42 (d, J=6.2 Hz, 2H), 5.32-5.18 (m, 2H), 5.09 (s, 2H), 4.73 (m, 2H), 4.01 (m, 2H), 3.01 (m, 2H), 2.66-2.34 (m, 4H). MS (m/z) 767.06 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15]1[CH2:24][CH2:23][C:18]2([O:22][CH2:21][CH2:20][O:19]2)[CH2:17][CH:16]=1>[Pd]>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:24][CH2:23][C:18]2([O:19][CH2:20][CH2:21][O:22]2)[CH2:17][CH2:16]1
Reactant: COCOc1ccc(C2=CCC3(CC2)OCCO3)c(OCOC)c1
Agent: [Pd]
Product: COCOc1ccc(C2CCC3(CC2)OCCO3)c(OCOC)c1
Yield: 99.9 %

Procedure:
8-[2,4-Bis(methoxymethoxy)phenyl]-1,4-dioxaspiro[4.5]dec-7-ene (0.950 g) and palladium (200 mg, 10% on carbon) were stirred under an atmosphere of hydrogen for 15 hr. The mixture was then filtered through a plug of Celite, washing with ethyl acetate. The filtrate was then evaporated to dryness, affording the desired product (0.955 g, 100%) as a colourless oil. δH (CDCl3) 1.67-1.87 (8H, m), 2.90-2.99 (1H, m), 3.46 (3H, s), 3.48 (3H, s), 3.97 (4H, s), 5.12 (2H, s), 5.18 (2H, s), 6.65 (1H, dd), 6.78 (1H, d), 7.12 (1H, d).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14]2[N:18]=[CH:19][C:20](I)=[CH:21][C:13]1=2)=[O:11].[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][N:31]=2)[CH2:26][CH2:25]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14]2[N:18]=[CH:19][C:20]([C:34]3[CH:33]=[CH:32][N:31]=[C:30]([N:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)[CH:35]=3)=[CH:21][C:13]1=2)=[O:11]
Reactant: O=C(Cc1cc(F)ccc1F)N1CCNc2ncc(I)cc21
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: CN1CCN(c2cc(-c3cnc4c(c3)N(C(=O)Cc3cc(F)ccc3F)CCN4)ccn2)CC1
Yield: 15 %

Procedure:
2-(2,5-Difluorophenyl)-1-(7-iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)-ethanone (30 mg) was reacted with 1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine as in General Procedure 4A to give the title compound as a light yellow solid (15% yield). M.p.>300° C., LCMS: m/z=465.02 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.36 (s, 3H), 2.52-2.57 (m, 2H), 3.52-3.62 (m, 6H), 3.90-3.96 (m, 4H), 5.11 (bs, 1H), 6.70 (d, J=8.8 Hz, 1H), 6.90-7.04 (m, 3H), 7.41-7.58 (m, 2H), 8.07 (s, 1H), 8.32 (s, 1H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)[CH:5]=[CH:4][CH:3]=1.[NH:35]([CH3:37])[CH3:36]>O1CCCC1.[Pd]>[CH3:36][N:35]([CH3:37])[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3ccccc3n2COCCc2cccc(Br)n2)CC1
Reactant: CNC
Agent: [Pd]
Solvent: C1CCOC1
Product: CN(C)c1cccc(CCOCn2c(NC3CCN(C(=O)OC(C)(C)C)CC3)nc3ccccc32)n1
Temperature: 100 °C
Reaction time: 16 h
Yield: 85.6 %

Procedure:
A mixture of (±)-1,1-dimethylethyl 4-[[1-[(6-bromo-2-pyridinyl]ethoxymethyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate (0.00189 mol) (interm. 33), Pd (0.026 g), (R)-(+)-2,2′-bis(diphenyl-phosphino)-1,1′-binaphtyl (0.046 g) and NH(CH3)2 gas (10 g) in tetrahydrofuran (200 ml) was stirred in an autoclave at 100° C. for 16 hours under pressure of CO (30 atm). The mixture was filtered and the filtrate was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/(CH3OH/NH3) 99/1). The pure fractions were collected and the solvents was evaporated, yielding 0.8 g of (±)-1,1-dimethylethyl 4-[[1-[[6-(dimethylamino)-2-pyridinyl]ethoxymethyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate (86%) (interm. 14).
Reaction SMILES: OC(C1C=CC=CC=1)(C1C=CC=CC=1)C1CCN(CCCC([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22])=[CH:16][CH:15]=2)=O)CC1.[BH4-].[Na+]>CO>[CH3:25][C:20]([C:17]1[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1)([CH3:24])[C:21]([OH:23])=[O:22]
Reactant: CC(C)(C(=O)O)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[4-[4-(hydroxydiphenylmethyl)- 1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylacetic acid, prepared in accordance with Example 12, and 300 mg of NaBH4 in 25 mL of CH3OH was stirred overnight at room temperature. The mixture was then concentrated in vacuo. The residue was partitioned between EtOAc and H2O. The aqueous portion was treated with concentrated HCl until pH 6, then extracted with EtOAc. The organics were concentrated in vacuo. The residue was dissoIved in EtOAc, filtered, and concentrated in vacuo to an oil. The oil was dissolved in CH3OH and concentrated to a solid. The solid was slurried with EtOAc, filtered, and rinsed with EtOAc to afford 4-[4-[4-hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetic acid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[C:11]([CH2:14]Cl)([CH3:13])[CH3:12])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+]>CN(C)C=O>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:12][C:11]([CH3:14])([CH3:13])[C:10]2=[O:16])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(CCl)C(=O)Nc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CN(c2cccc(C(F)(F)F)c2)C1=O
Temperature: 5 °C
Yield: 82.1 %

Procedure:
Dissolved in dimethylformamide were 1.4 g of N-[3-(trifluoromethyl) phenyl]-2-chloromethyl-2-methylpropionamide, and 0.24 g of sodium hydride were added with stirring at 5° C. After stirring the mixture at room temperature for 15 hours, it was added with ice water and extracted with diethyl ether. The extract was dried over magnesium sulfate. Diethyl ether was distilled off, and the residue was purified by column chromatography on silica gel to obtain 1.00 g (yield: 82%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][PH:18](=[O:22])[O:19][CH2:20][CH3:21])=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pt]=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][PH:18](=[O:22])[O:19][CH2:20][CH3:21])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCO[PH](=O)CCCCC1=CC(NC(=O)OC(C)(C)C)CC1
Agent: O=[Pt]
Solvent: CO
Product: CCO[PH](=O)CCCC[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)C1

Procedure:
A solution of (±)-ethyl [3-(t-butyloxycarbonyl)aminocyclopentenyl]butylphosphinate (13) (2.95 g, 8.90 mmol) in methanol (30 cm3) was hydrogenated over platinum oxide (50 mg) at 40 psi for 3 hours. The catalyst was removed by filtration through celite and then washed with methanol (3×30 cm3). The solvent was removed in vacuo to yield the desired title compound (14) in quantitative yield (>90% cis isomer by NMR spectroscopy) as a colourless oil, which was used in the next step without further purification (2.14 g, 72%) (data for cis isomer only is reported): 1H-NMR (300 MHz, CDCl3) δH 0.93 (3H, 2×d, J=6.9 and 7.2 Hz, PCH2CH2CH2CH3),1.21-2.32 (25H, m, C(1)—H, C(2)—H, C(2)—H′, C(4)—H, C(4)—H′, C(5)—H and C(5)—H′, POCH2CH3, PCH2CH2CH2CH3, PCH2CH2CH2CH3, PCH2CH2CH2CH3, C(CH3)3), 4.13 (4H, m, OCH2CH3, C(3)—NH, C(3)—H); 13C-NMR (75 MHz, CDCl3) δC13.49 (s, PCH2CH2CH2CH3), 16.65 (d, 3JPOCC=3.98 Hz, POCH2CH3), 23.61 (s, C(5)), 23.85 (s, PCH2CH2CH2CH3), 23.88 and 24.04 (d, 3JPC=12.53 Hz, PCH2CH2CH2CH3),26.34 and 27.50 (2×d, JPC=87.08 and 87.38 Hz, PCH2CH2CH2CH3),28.38 (s, C(CH3)3), 33.02 (s, C(2)), 33.50 and 33.63 (2×d, 3JPC=9.08 and 9.98 Hz, C(4)), 34.24 and 35.50 (2×d, JPC=94.43 and 94.73 Hz, C(1)), 52.25 (m, C(CH3)3), 60.45 and 60.54 (d, 2JPOC=6.83 Hz, POCH2CH3), 78.79 and 79.11 (d, 3JPC=24.15 Hz, C(3)), 155.42 (s, C═O); 31P-NMR (121 MHz, CDCl3) δP 59.85 and 60.99; MS (CI, CH4) m/z 334.0 (12%) (MH+), 234.2 (100), 278.2 (23), 362.2 (16). Synthesis of (±)-cis-(3-aminocyclopentanyl)butylphosphinic acid (15)
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1B1OC(C)(C)C(C)(C)O1.Br[C:35]1[CH:36]=[CH:37][C:38]([O:45][CH3:46])=[C:39]([CH2:41][C:42]([OH:44])=[O:43])[CH:40]=1>>[CH3:46][O:45][C:38]1[CH:37]=[CH:36][C:35]([C:16]2[CH:17]=[CH:18][C:19]([C:21]([F:22])([F:24])[F:23])=[CH:20][C:15]=2[CH2:14][N:3]2[C@@H:2]([CH3:1])[C@@H:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:5][C:4]2=[O:13])=[CH:40][C:39]=1[CH2:41][C:42]([OH:44])=[O:43]
Reactant: COc1ccc(Br)cc1CC(=O)O
Reactant: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Product: COc1ccc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)cc1CC(=O)O

Procedure:
Prepared according to the procedure described in Example 7, Step 2, using the following starting materials: (4S,5R)-4-methyl-5-phenyl-3-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-oxazolidin-2-one and 5-bromo-2-methoxyphenylacetic acid. M+H is 500.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][N:6]([CH3:11])[C:7]=1[C:8](O)=[O:9])#[N:2].[CH2:12]([SH:14])[CH3:13].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([C:3]1[N:4]=[CH:5][N:6]([CH3:11])[C:7]=1[C:8](=[O:9])[S:14][CH2:12][CH3:13])#[N:2]
Reactant: Cn1cnc(C#N)c1C(=O)O
Reactant: CCS
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCSC(=O)c1c(C#N)ncn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
In a 1 l, three-necked flask fitted with a magnetic stirrer and a reflux condenser under inert atmosphere, 4-cyano-1-methyl-1H-imidazole-5-carboxylic acid x84 (24.5 g, 0.162 mol) and CH2Cl2 (500 ml) are stirred at room temperature. To this suspension, ethanethiol (13.2 ml, 0.178 mol) and DMAP (1.98 g, 0.016 mol) are added, followed by DCC (36.77 g, 0.178 mol) in two portions. The temperature rises to 35° C. and the mixture is stirred at room temperature for 16 h. Ethanethiol (0.0324 mol) is further added and stirring is continued overnight. The mixture is filtered and the solvent is evaporated. The residue is purified by chromatography on silicagel (Hexane/AcOEt: 6/4 (v/v)) to give 29.5 g of S-ethyl 4-cyano-1-methyl-1H-imidazole-5-carbothioate x85.