Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:32])([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[C:23]3[C:18](=[C:19]([CH3:24])[N:20]=[CH:21][CH:22]=3)[C:17](=[O:25])[N:16]([CH3:26])[C:15]=2[CH:27]=1)(C)(C)C.C1C(=O)N([Cl:41])C(=O)C1>C(#N)C>[NH2:7][C:8]([CH3:32])([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:9][O:10][C:11]1[C:12]([Cl:41])=[CH:13][C:14]2[C:23]3[C:18](=[C:19]([CH3:24])[N:20]=[CH:21][CH:22]=3)[C:17](=[O:25])[N:16]([CH3:26])[C:15]=2[CH:27]=1
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OCC(C)(CC(C)C)NC(=O)OC(C)(C)C)ccc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Cc1nccc2c1c(=O)n(C)c1cc(OCC(C)(N)CC(C)C)c(Cl)cc21
Reaction time: 2 h
Yield: 13.3 %

Procedure:
To the stirred solution of 8-((2-amino-2,4-dimethylpentyl)oxy)-4,6 dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (Prepared in Example 32, Part B) (0.08 g, 0.226 mmol) in acetonitrile (5 mL) was added NCS (0.030 g, 0.226 mmol)) at RT and the reaction mixture was stirred for 2 h. The mixture was then evaporated to dryness. The residue was purified by reverse phase HPLC (0.1% TFA in water/AcCN) to afford 8-((2-amino-2,4-dimethylpentyl)oxy)-9-chloro-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (12 mg, 0.030 mmol, 13% yield). LC/MS (ESI) m/e 388.0 [(M+H)+, calcd for C21H27ClN3O2, 388.2] as an off-white solid. LC/MS retention time (method C): tR=2.13 min. HPLC retention time (method A): tR=8.97 min; HPLC retention time (method B): tR=10.16 min. 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.99-1.02 (m, 6H), 1.30 (s, 3H), 1.54-1.66 (m, 2H), 1.84-1.90 (m, 1H), 3.05 (s, 1H), 3.73 (s, 1H), 4.04 (q, J=23.20 Hz, 2H), 7.03 (s, 1H), 8.06 (d, J=6.00 Hz, 1H), 8.39 (s, 1H), 8.54 (d, J=6.00 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:3]([N:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)=[C:4]([C@H:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[O:29]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:17]([O:16][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:39]2[CH:40]=[CH:41][C:36]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:37][CH:38]=2)[C:3]=1[N:21]1[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(Br)c1N1CCC(C)(C)CC1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(Oc3ccccc3)cc2)c1N1CCC(C)(C)CC1
Reaction time: 2 h
Yield: 29.7 %

Procedure:
A mixture of (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (0.0462 g, 0.101 mmol), (4-phenoxyphenyl)boronic acid (0.033 g, 0.152 mmol) and 2M Na2CO3 (0.127 ml, 0.254 mmol) degassed for 10 min. Then, Pd(Ph3P)4 (0.012 g, 10.14 μmol) added, degassed for 5 min and placed in a pre-heated oil bath 110° C. After 2 h, cooled and purified by pre-HPLC to afford (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(4-phenoxyphenyl)pyridin-3-yl)acetate (0.0162 g, 0.030 mmol, 29.3% yield) as white solid. 1H NMR (500 MHz, CDCl3 δ7.34-7.39 (m, 2H), 7.24-7.28 (m, 1H), 7.09-7.17 (m, 4H), 7.04-7.08 (m, 2H), 6.09 (s, 1H), 4.14-4.30 (m, 2H), 3.20 (d, J=12.3 Hz, 1H), 2.88 (t, J=11.7 Hz, 1H), 2.62 (s, 3H), 2.33 (d, J=11.5 Hz, 1H), 2.25 (s, 3H), 2.12 (t, J=11.4 Hz, 1H), 1.57 (dt, J=4.3, 12.5 Hz, 1H), 1.37-1.44 (m, 1H), 1.26 (t, J=7.1 Hz, 4H), 1.19-124 (m, 1H), 1.22 (s, 9H), 1.12 (d, J=12.1 Hz, 1H), 0.93 (s, 3H), 0.72 (s, 3H). LCMS (M+H)=545.4.
Reaction SMILES: [C:1]([C:3]([CH3:9])([CH3:8])[C:4]([NH:6][NH2:7])=O)#[N:2].Cl.[F:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](=[NH:19])OC)=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]2[N:19]=[C:4]([C:3]([CH3:9])([CH3:8])[C:1]#[N:2])[NH:6][N:7]=2)=[CH:14][CH:13]=1
Reactant: CC(C)(C#N)C(=O)NN
Reactant: COC(=N)c1ccc(F)cc1
Agent: Cl
Product: CC(C)(C#N)c1nc(-c2ccc(F)cc2)n[nH]1
Yield: 70 %

Procedure:
This compound was synthesized from 2-cyano-2-methylpropanehydrazide and methyl 4-fluorobenzimidate hydrochloride as described in example 64 step 3 (300 mg, yield 70%). 1H NMR (300 MHz, MeOD) δ 8.03-7.98 (m, 2H), 7.29-7.23 (m, 2H), 1.81 (s, 6H). MS (ESI) m/z: Calculated for C12H11FN4: 230.10. found: 231.2 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:16][C:15](=[O:17])[C:14]([CH2:21][CH:22]=[CH2:23])([CH2:18][CH:19]=[CH2:20])[C@H:9]1[C:10]([O:12]C)=[O:11])(OC(C)(C)C)=O.[Li+].[OH-].Cl>O.CO>[CH2:21]([C:14]1([CH2:18][CH:19]=[CH2:20])[C:15](=[O:17])[CH2:16][NH:8][C@@H:9]1[C:10]([OH:12])=[O:11])[CH:22]=[CH2:23]
Reactant: C=CCC1(CC=C)C(=O)CN(C(=O)OC(C)(C)C)[C@@H]1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCC1(CC=C)C(=O)CN[C@@H]1C(=O)O
Yield: 187.3 %

Procedure:
To a solution of 0.099 g of N-(BOC)-3,3-diallyl-4-oxo-(L)-proline, methyl ester in 0.4 mL of water and 1.6 mL of MeOH was added 25.7 mg of LiOH.monohydrate. The reaction mixture was sonicated for 2 h. The mixture was acidified with 1.2N HCl to pH=2 and concentrated in vacuo. The residue was treated with 1.5 mL of HCl/dioxane solution for 1.5 h. After concentration in vacuo, 0.12 g of 3,3-diallyl-4-oxo-(L)-proline was obtained which was used in the next step without purification.
Reaction SMILES: CN(CCN(C)C)C.[Li]CCCC.[C:14]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN([CH:31]=[O:32])C>C1COCC1>[CH3:27][O:26][C:21]1[C:22]([CH:31]=[O:32])=[CH:23][CH:24]=[CH:25][C:20]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN(C)C=O
Reactant: COc1ccccc1-c1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1c(C=O)cccc1-c1ccccc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of 17.4 g (0.15 mol) of dry TMEDA in 600 mL of hexanes, 60.0 mL (0.15 mol) of 2.5 M nBuLi in hexanes was added at room temperature. This mixture was stirred for 30 min, and then 27.6 g (0.15 mol) of 2-phenylanisol was added. This mixture was stirred for 4 hr at 55° C., then heated to 100° C., and a solution of 28.0 g (0.38 mol) of DMF in 200 mL of THF was added dropwise with vigorous stirring. The resulting mixture was evaporated to dryness, and the product was isolated by flash chromatography on silica gel 60 (40-63 um, eluent: hexanes-diethyl ether from 100:1 to 20:1, vol.) to yield 26.1 g (82%) of the title product.
Reaction SMILES: C1(N[C:8]2([C:22]([O:24]CC3C=CC=CC=3)=[O:23])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)C=CC=CC=1.[OH-].[NH4+:33]>[Pd].CO>[C:16]1([NH:33][CH:10]2[CH2:9][CH:8]([C:22]([OH:24])=[O:23])[CH2:13][CH2:12][N:11]2[CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(OCc1ccccc1)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Reactant: [NH4+]
Agent: [Pd]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCN(CCc2ccccc2)C(Nc2ccccc2)C1
Temperature: 25 °C

Procedure:
A mixture of 60 parts of phenylmethyl 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylate and 320 parts of methanol is hydrogenated at normal pressure and at room temperature with 10 parts of palladium-on-charcoal catalyst 10%. Upon the addition of a concentrated ammonium hydroxide solution, the precipitate, which is formed during the hydrogenation, is dissolved. The catalyst is filtered off and the filtrate is concentrated. Methanol is added and the whole is concentrated again. After cooling to room temperature the product is filtered off and dried in vacuo at 120° C, yielding 43.7 parts of 4-(phenylamino-1-(2-phenylethyl)-4-piperidinecarboxylic acid; mp. 268° C.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH2:37][CH2:38][NH:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][N:41]=1>C(Cl)(Cl)Cl>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:36][CH2:37][CH2:38][NH:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][N:41]=2)=[O:18])=[CH:19][CH:20]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: COc1ccc(NCCN)nc1
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(NCCNC(=O)c2ccc(OC/C=C(\C)CCC=C(C)C)cc2)nc1
Reaction time: 1 h
Yield: 74.9 %

Procedure:
4-geranyloxybenzoic acid(1.92 g) was dissolved in chloroform(50 ml) and triethylamnine(1.95 ml), and then diphenylphosphinic chloride(1.34ml) was added thereto while being cooled with ice. After being stirred for 1 hour, the mixture, with 2-(2-aminoethylamino)-5-methoxypyridine(1.17 g) added thereto, was stirred for 8 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 2.22 g of the aimed compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.C(=O)([O-])[O-].[K+].[K+].O1CCCC1.[F:32][C:33]([F:44])([F:43])[CH2:34]OS(C(F)(F)F)(=O)=O>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:34][C:33]([F:44])([F:43])[F:32])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1N(CC(F)(F)F)c2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Reaction time: 4 h
Yield: 38.2 %

Procedure:
To a suspension of 0.50 g (0.0017 mole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-20), 0.50 g (0.0034 mole) of potassium carbonate and 10 mL of tetrahydrofuran was added 0.46 g (0.0020 mole) of trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester. After stirring at 75 degrees for four hours, the mixture was cooled and water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with ethyl acetate-hexane (gradient, 100:0-30:70) gave 0.25 g of 2-chloro-9-cyclopentyl-7,7-difluoro-5-(2,2,2-trifluoro-ethyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-150)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]([CH3:15])[CH2:13][CH3:14])[C:5](Cl)=[O:6].[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:30]([O:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]2[CH:19]=[CH:18][C:17]([O:16][C:5](=[O:6])[C:4]3[CH:8]=[CH:9][C:10]([CH2:11][CH:12]([CH3:15])[CH2:13][CH3:14])=[C:2]([Br:1])[CH:3]=3)=[CH:22][CH:21]=2)=[CH:24][CH:25]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCC(C)Cc1ccc(C(=O)Cl)cc1Br
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(-c2ccc(OC(=O)c3ccc(CC(C)CC)c(Br)c3)cc2)cc1
Reaction time: 2 h

Procedure:
This 3-bromo-4-(2'-methylbutyl)benzoic acid chloride (11.5 g, 0.04 mol) was dropwise added to a mixture of 4-hydroxy-4'-octyloxybiphenyl with anhydrous pyridine under ice cooling, followed by agitating the resulting mixture at 50°-60° C. for 2 hours, adding toluene (100 ml), sufficiently agitating the mixture, washing it with 6N-HCl, then with 2N-NaOH aqueous solution and further with water, further drying over anhydrous MgSO4, distilling off toluene and recrystallizing the residue from a mixture of ethanol (100 ml) with ethyl acetate (60 ml) to obtain 3-bromo-4-(2'-methylbutyl)benzoic acid 4'-octyloxy-4-biphenylyl ester (12.2 g), which exhibited liquid crystalline properties and had the following phase transistion points: ##STR45##
Reaction SMILES: CON(C)[C:4](=[O:14])[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH3:6].[CH3:16][Mg]Br>O1CCCC1.CCCCCCC>[CH3:6][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[C:4](=[O:14])[CH3:16]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)C(C)(C)c1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CC(=O)C(C)(C)c1ccccc1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To 2.1 g (10.1 mmol) of N-Methoxy-N-methyl-2-phenyl-isobutyramide in 80 ml of dry tetrahydrofuran at ambient temperature was added 6.7 ml (20.2 mmol) of 3M methymagnesium bromide in heptane, and the solution was warmed to 60° C. After 6 hours, the mixture was allowed to cool to ambient temperature and was quenched with 1M HCl. The resulting mixture was partitioned between water and ether, and the phases were separated. The ether phase was washed once each with 1M HCl and brine, dried over Na2SO4, filtered, and concentrated in vacuo to an oil. The oil was chromatographed to give the title compound as a clear oil: 1H NMR CDCl3 δ (ppm): 1.49 (s, 6H), 1.93 (s, 3H), 7.24-7.34 (m, 5H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][C@@:11]2([CH2:17][OH:18])[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[C:21]([F:28])=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:16])[NH:24][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[C:20]([Cl:19])[C:21]=2[F:28])[CH2:12][C@@:11]2([CH2:17][OH:18])[C@@H:9]1[CH2:10]2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1[C@H]2C[C@@]2(CO)C[C@H]1C(=O)O
Reactant: NCc1cccc(Cl)c1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@H]2C[C@@]2(CO)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a diastreoisomeric mixture of (1R,3S,5S) and (1S,3S,5R)-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (312 mg, 1.21 mmol), 3-chloro-2-fluorobenzylamine (232 mg, 1.46 mmol), HBTU (690 mg, 1.82 mmol) in CH2Cl2 (6 mL) was added DIPEA (0.623 mL, 3.64 mmol). The resulting solution was stirred at RT under nitrogen overnight. DIPEA (0.21 mL, 1.21 mmol), HBTU (230 mg, 0.6 mmol) and 3-chloro-2-fluorobenzylamine (97 mg, 0.606 mmol) were added and the mixture was further stirred overnight at RT under N2. The mixture was poured into an aqueous solution of HCl 1N (pH-1) and extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 40:60) to give (1S,3S,5R)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester: TLC, Rf (EtOAc)=0.55 (stained with ninhydrine); MS (UPLC-MS): 399.2/401.2 [M+H]+, 299.2/301.2 [MH−Boc]+, 343.2/345.2 [MH−tBu]+, 443.2/445.3 [M+HCOO]−; tR (HPLC conditions f): 1.95 min, and (1R,3S,5S)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester: TLC, Rf (EtOAc)=0.45 (stained with ninhydrine); MS (UPLC-MS): 399.2/401.2 [M+H]+, 299.2/301.2 [MH−Boc]+, 343.2/345.2 [MH−tBu]+, 443.2/445.3 [M+HCOO]−; tR (HPLC conditions f): 1.89 min.
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].Br[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][CH:7]=1>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:17][O:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH:1]=[CH2:2]
Reactant: C=C[Mg]Cl
Reactant: COc1ccc2nccc(Br)c2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: C=Cc1ccnc2ccc(OC)cc12
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 21.6 %

Procedure:
InCl3 (1.1 g, 5 mmol) was dried under HV by heating with a heat gun. After cooling under N2 atmosphere, THF (25 mL) was added and the mixture sonicated until a solution had formed. This solution was cooled to −78° C., and a 1.7M solution of vinyl magnesium chloride (15 mmol) was added dropwise. The mixture was stirred at −78° C. for 15 min, warmed to rt and the resulting solution was added to a refluxing mixture of 4-bromo-6-methoxy-quinoline (1.85 g, 10 mmol) and Pd(dppf)Cl2.CH2Cl2 complex (0.408 g) in THF (25 mL). The mixture was refluxed for 2 h until tlc indicated complete conversion. The mixture was cooled to rt, quenched by addition of a few drops of MeOH and SiO2 (20 g) was added. The volatiles were removed under reduced pressure and the residue was chromatographed over SiO2 (Hex/EA 1:1) to give the desired compound (0.4 g, 21% yield) as a yellowish oil.
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][Cl:14].C(N(CC)CC)C>C1COCC1>[Cl:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][S:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: ClCCCCCBr
Reactant: Sc1ncccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: ClCCCCCSc1ncccn1
Yield: 51.7 %

Procedure:
2.8 g (25 mmol) of 2-mercaptopyrimidine, 4.64 g (25 mmol) of 1-bromo-5-chloropentane and 2.58 g (25.5 mmol) of triethylamine in 100 ml of THF were refluxed for 4 hours. After cooling, filtration with suction and concentration, the residue was purified by chromatography (mobile phase: cyclohexane/ethyl acetate=92/8). 2.8 g of product were obtained (=52% yield).
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:41])[C@@H:15]([NH:26][C:27]([C:29]2[CH:38]=[C:37]([OH:39])[C:36]3[C:31](=[CH:32][C:33]([CH3:40])=[CH:34][CH:35]=3)[N:30]=2)=[O:28])[CH2:16][CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[C:48]([O:52][C:53](=[O:56])[CH2:54]Br)([CH3:51])([CH3:50])[CH3:49]>CN(C=O)C.O>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:41])[C@@H:15]([NH:26][C:27]([C:29]2[CH:38]=[C:37]([O:39][CH2:54][C:53]([O:52][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:56])[C:36]3[C:31](=[CH:32][C:33]([CH3:40])=[CH:34][CH:35]=3)[N:30]=2)=[O:28])[CH2:16][CH2:17][O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCOCc2ccccc2)NC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCOCc2ccccc2)NC(=O)c2cc(OCC(=O)OC(C)(C)C)c3ccc(C)cc3n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 650 mg of 4-{(S)-4-Benzyloxy-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid butyl ester in 7.7 ml of DMF, 414 mg of cesium carbonate and 248 mg of Bromo-acetic acid tert-butyl ester was added and the reaction mixture was stirred for 2 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 590 mg.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].N1C=CC=CC=1.[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[C:21](Cl)=[O:22]>C(Cl)Cl>[OH:3][CH2:2][CH2:1][O:4][C:21]([C:12]1[CH:13]=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=1)=[O:22]
Reactant: OCCO
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OCCO)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
15.6 g (252 mmol) of ethylene glycol (manufactured by TOKYO CHEMICAL INDUSTRY CO., LTD.) was dissolved in 100 mL of dehydrated methylene chloride (manufactured by Kanto Chemical Co., Inc.) and 3.49 g (44.0 mmol) of pyridine was added to the solution followed by cooling down with ice water. To this solution, a solution in which 8.00 g (42.0 mmol) of 2-naphthalene carbonyl chloride (manufactured by TOKYO CHEMICAL INDUSTRY CO., LTD.) was dissolved in 80 mL of methylene chloride was dripped in one hour while being stirred. Subsequent to two hour stirring, the resultant was stirred for six hours at room temperature. The reaction solution was rinsed with water and thereafter the organic phase was isolated followed by drying with magnesium sulfate (manufactured by Kanto Chemical Co., Inc.) and the solvent was distilled away. The remainder was refined by silica gel column chromatography with a solvent mixture of a methylene chloride (manufactured by JUNSEI CHEMICAL CO., LTD.) and methanol (manufactured by Kanto Chemical Co., Inc.) with a volume ratio of 97:3 serving as an eluent to obtain 6.88 g of 2-naphthoic acid 2-hydroxyethyl ester.
Reaction SMILES: [CH3:1][CH:2]1[C:14](=[O:15])[C:6]2[S:7][CH:8]=[C:9]([S:10](Cl)(=[O:12])=[O:11])[C:5]=2[CH2:4][CH2:3]1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([OH:27])[CH2:24][NH:25][CH3:26])=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]([OH:27])[CH2:24][N:25]([CH3:26])[S:10]([C:9]2[C:5]3[CH2:4][CH2:3][CH:2]([CH3:1])[C:14](=[O:15])[C:6]=3[S:7][CH:8]=2)(=[O:12])=[O:11])=[CH:21][CH:22]=1
Reactant: CC1CCc2c(S(=O)(=O)Cl)csc2C1=O
Reactant: CNCC(O)c1ccc(F)cc1
Product: CC1CCc2c(S(=O)(=O)N(C)CC(O)c3ccc(F)cc3)csc2C1=O

Procedure:
From 6-methyl-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-sulfonyl chloride (the compound of Preparation Example 13) (140 mg) and 1-(4-fluorophenyl)-2-methylamino ethanol (the compound of Preparation Example 17) (108 mg), the title compound (orange oily substance) (155 mg) was obtained as a mixture of diastereomers, in the same way as Preparation Example 41.
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[C:40]([C:42]1[CH:50]=[CH:49][C:45]([C:46](Cl)=[O:47])=[CH:44][CH:43]=1)#[N:41]>>[C:40]([C:42]1[CH:50]=[CH:49][C:45]([C:46]([O:1][CH:2]2[CH2:20][CH:19]3[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]4[C:16]([C:22]([NH:24][S:25]([CH:28]5[CH2:30][CH2:29]5)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]3=[O:21])[CH2:15]4)[CH2:3]2)=[O:47])=[CH:44][CH:43]=1)#[N:41]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3ccc(C#N)cc3)CN2C1=O
Yield: 36.9 %

Procedure:
Prepared by way of method II using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 4-cyanobenzoyl chloride (87 mg, 0.53 mmol). The final trituration (diethyl ether/hexane) and filtration gave 45 mg (37%) of 18-(4-cyanobenzoyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 99.0% pure (HPLC), MS m/z 696 (M−H)−, HRMS: calcd. 715.3125 and found 715.3147 (M+NH4)+, mp 164-166° C.